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Evaluating All Potential Oral Complications of Diabetes Mellitus

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DOI: 10.3389/fendo.2019.00056

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 REVIEW
published: 18 February 2019
doi: 10.3389/fendo.2019.00056

Evaluating All Potential Oral

Complications of Diabetes Mellitus
Martijn J. L. Verhulst 1*, Bruno G. Loos 1 , Victor E. A. Gerdes 2,3 and Wijnand J. Teeuw 1
1
Department of Periodontology, Academic Centre for Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit,
Amsterdam, Netherlands, 2 Department of Vascular Medicine, Amsterdam UMC, Amsterdam, Netherlands, 3 Department of
Internal Medicine, Spaarne Gasthuis, Hoofddorp, Netherlands

Diabetes mellitus (DM) is associated with several microvascular and macrovascular

complications, such as retinopathy, nephropathy, neuropathy, and cardiovascular
diseases. The pathogenesis of these complications is complex, and involves
metabolic and hemodynamic disturbances, including hyperglycemia, insulin resistance,
dyslipidemia, hypertension, and immune dysfunction. These disturbances initiate several
damaging processes, such as increased reactive oxygen species (ROS) production,
inflammation, and ischemia. These processes mainly exert their damaging effect on
endothelial and nerve cells, hence the susceptibility of densely vascularized and
innervated sites, such as the eyes, kidneys, and nerves. Since the oral cavity is also
highly vascularized and innervated, oral complications can be expected as well. The
Edited by: relationship between DM and oral diseases has received considerable attention in
Ioan Andrei Veresiu,
Iuliu Haţieganu University of Medicine
the past few decades. However, most studies only focus on periodontitis, and still
and Pharmacy, Romania approach DM from the limited perspective of elevated blood glucose levels only. In this
Reviewed by: review, we will assess other potential oral complications as well, including: dental caries,
Federico Biscetti,
dry mouth, oral mucosal lesions, oral cancer, taste disturbances, temporomandibular
Catholic University of Sacred Heart,
Italy disorders, burning mouth syndrome, apical periodontitis, and peri-implant diseases.
Mohd Ashraf Ganie, Each oral complication will be briefly introduced, followed by an assessment of
Sher-I-Kashmir Institute of Medical
Sciences, India
the literature studying epidemiological associations with DM. We will also elaborate
*Correspondence:
on pathogenic mechanisms that might explain associations between DM and oral
Martijn J. L. Verhulst complications. To do so, we aim to expand our perspective of DM by not only considering
[email protected]
elevated blood glucose levels, but also including literature about the other important
Specialty section:
pathogenic mechanisms, such as insulin resistance, dyslipidemia, hypertension, and
This article was submitted to immune dysfunction.
Diabetes,
a section of the journal Keywords: diabetes mellitus, oral complications, hyperglycemia, insulin resistance, dyslipidemia, hypertension,
Frontiers in Endocrinology immune dysfunction

Received: 21 August 2018

Accepted: 22 January 2019
Published: 18 February 2019
INTRODUCTION
Citation: Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia
Verhulst MJL, Loos BG, Gerdes VEA
resulting from defects in insulin secretion, insulin action, or both (1). In 2014, the global prevalence
and Teeuw WJ (2019) Evaluating All
Potential Oral Complications of
of DM was estimated to be 9% (2), and almost 1.6 million deaths worldwide were caused directly by
Diabetes Mellitus. DM in 2015 (3). DM is also associated with high morbidity due to a broad range of complications,
Front. Endocrinol. 10:56. such as retinopathy, nephropathy, neuropathy, and cardiovascular disease (4, 5). Prevention and
doi: 10.3389/fendo.2019.00056 management of these complications have become major aspects of modern diabetes care. Besides

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Verhulst et al. Oral Complications of Diabetes Mellitus

these well-known complications, oral complications of DM Despite the fact that each cell in the body is exposed to
can be expected as well (6–8). As a result, the International hyperglycemia, the damaging consequences mainly concern the
Diabetes Federation (IDF) published the “guideline on oral endothelial cells and peripheral nerve cells (21). These target
health for people with diabetes” in 2009, which encourages cells are not capable of maintaining a constant intracellular
implementation of oral care in diabetes care (9). Knowing which glucose level when blood glucose levels rise (22). The increased
oral complications can be expected, how often these occur intracellular glucose levels trigger reactive oxygen species (ROS)
in patients with DM, and understanding of the underlying production in the mitochondria. This is the upstream mechanism
pathogenesis is essential for a successful implementation of the that causes inhibition of the enzyme glyceraldehyde 3-phosphate
guideline. The large majority of studies into oral complications dehydrogenase (GAPDH). Consequently, four downstream
still approach patients with DM from the limited perspective mechanisms that are involved in tissue damage are activated:
of elevated blood glucose levels. However, we know that there (1) increased polyol pathway flux; (2) increased non-enzymatic
are many other pathogenic mechanisms that contribute to formation of advanced glycation end-products (AGEs) and
the development of other diabetic complications, including increased expression of receptors for AGEs (RAGEs); (3)
hyperglycemia, insulin resistance, dyslipidemia, hypertension, activation of protein kinase C (PKC); and (4) increased
and immune dysfunction. In this report, we will review the hexosamine pathway activity (21).
literature about oral complications of DM from this broader
perspective. To understand the biological mechanisms that might 1) Normally, the polyol pathway ensures that toxic components
be involved, the pathogenic mechanisms of the classic diabetic (aldehydes) are converted into harmless inactive alcohol
complications are discussed first. by an enzyme called aldose reductase. However, in case of
hyperglycemia, aldose reductase also converts the excess
intracellular glucose into sorbitol. To do so, it consumes
PATHOGENIC MECHANISMS OF DIABETIC NADPH, which is crucial for the maintenance of the
intracellular antioxidant reduced glutathione (GSH).
COMPLICATIONS Decreased amounts of GSH cause or worsen oxidative stress,
Complications of DM can be divided into acute and chronic leading to cell damage or death (21, 23).
complications (1). Associations between acute effects of DM 2) The non-enzymatic formation of advanced glycation
and oral complications have not yet been reported in the endproducts (AGEs) results from a complex interaction
literature. Since oral complications are most likely the result between glucose and lipids, proteins or nucleic acids (24). If
of long-term effects of diabetes, the focus of this review will hyperglycemia is persistent, AGEs can accumulate in both
be on chronic complications. These complications are typically tissue and serum, causing tissue damage through several
characterized by damage to the vasculature, usually grouped into mechanisms. They can alter intracellular proteins and thereby
microvascular and macrovascular diseases (5). Microvascular change cellular function (25). Also, AGEs can diffuse out of
diseases include retinopathy, nephropathy and neuropathy. the cell and cause disruption of the signaling between the
Macrovascular complications concern cardiovascular disease cell and its membrane, causing cell dysfunction (25). Finally,
(CVD), such as coronary artery disease, cerebrovascular disease, after diffusing out of the cell, they can modify circulating
and peripheral artery disease (10). plasma proteins, which in turn bind to AGE receptors (e.g.,
Hyperglycemia is the clinical characteristic that is used RAGE) on different types of cells, such as macrophages and
to define a patient with DM. However, several other—often endothelial cells. This then induces a pro-inflammatory state,
intertwined—pathogenic mechanisms that characterize DM are reflected by elevated levels of inflammatory cytokines in
also recognized: insulin resistance, dyslipidemia, hypertension, plasma, such as interleukin 6 and 1 alpha (IL-6, IL-1α) and
and immune dysfunction. In this section, we will describe how tumor necrosis factor alpha (TNF-α) (21, 26). These processes
these pathogenic mechanisms are involved in the development further elicit ROS production and cause the vascular damage
and progression of chronic diabetic complications (Figure 1) typical for diabetic complications (21, 23, 24, 26). AGES
(11). In the following sections, we will discuss possible can also form cross-links within collagen fibers, which
associations between DM and oral complications by using the changes their structure and functionality. In combination
very same perspective each time. with the abovementioned effects, this can result in damage
to connective tissue in the joints, and eventually cause a
condition called limited joint mobility (27).
Hyperglycemia 3) Intracellular hyperglycemia also causes activation of protein
Hyperglycemia is a key determinant for the development of kinase C (PKC), which has several effects on gene expression
complications in patients with T1DM or T2DM (12). This was within the cells (21). PKC can activate nuclear factor kappa
demonstrated through several large trials, where intensive blood B (NF-κB), which plays a pivotal role in the upregulation of
glucose control in patients with T2DM significantly reduced the inflammatory responses. For example, NF-κB regulates gene
risk for microvascular complications (13–18). In persons with expression of IL-6, IL-1α, and TNF-α (28). Also, endothelin-1
T1DM, intensive blood glucose control also reduced the long- (ET-1) is upregulated while endothelial nitric oxide synthase
term risk for macrovascular complications (19), even years after (eNOS) is downregulated, causing vasoconstriction and
the study was finished (20). thereby abnormal blood flow (29, 30). Transforming growth

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Verhulst et al. Oral Complications of Diabetes Mellitus

FIGURE 1 | Pathogenesis of diabetic complications. The figure presents the pathogenic mechanisms of diabetes mellitus (DM; red block, section Pathogenic
Mechanisms of Diabetic Complications of main text) that cause microvascular complications (blue block) and macrovascular complications (yellow block). Destruction
of pancreatic B cells in T1DM and insulin resistance in T2DM result in hyperglycemia. The resulting increase of intracellular glucose in microvascular target cells, such
as capillary endothelial cells, causes ROS production in the mitochondria, activating four pathogenic downstream pathways: polyol pathway, AGEs & RAGE pathway,
PKC pathway, hexosamine pathway (section Hyperglycemia of main text). Especially in T2DM, insulin resistance and the abundance of (visceral) adipose tissue result
in an excess flux of free fatty acids (FFAs), which are oxidized in the mitochondria of macrovascular endothelial cells. This causes activation of the same pathogenic
pathways, and downregulation of protective enzymes such as eNOS and prostacyclin synthase. Pathway-selective insulin resistance also contributes to microvascular
complications (section Insulin Resistance of main text). Moreover, insulin resistance and circulating FFAs result in dyslipidemia, contributing to both micro- and
macrovascular complications (section Dyslipidemia of main text). Hypertension contributes to the harmful processes by activating endothelial cells, inducing a cellular
inflammatory response and reducing the availability of nitric oxide, causing vasoconstriction (section Hypertension of main text). All these processes mainly exert their
harmful effects by upregulation of a pro-inflammatory state at vulnerable sites. Together with an impaired immune response and consequently higher susceptibility for
infections, this immune dysfunction plays a pivotal role in the development of diabetic complications (section Immune Dysfunction of main text). Possible oral
complications that are discussed in this review are listed in the green block at the bottom of the figure (section Potential Oral Complications of Diabetes Mellitus of
main text). eNOS, endothelial Nitric Oxide Synthase; FFAs, Free Fatty Acids; GAPDH, Glyceraldehyde 3-phosphate Dehydrogenase; GBM, Glomerular Basement
Membrane; PKC, Protein Kinase C; (R)AGEs, (Receptor for) Advanced Glycation End products; ROS, Reactive Oxygen Species.

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Verhulst et al. Oral Complications of Diabetes Mellitus

factor beta (TGF-β) and plasminogen activator inhibitor-1 In contrast to the macrovascular endothelial cells, FFA
(PAI-1) are also upregulated, causing capillary and vascular oxidation is not increased in microvascular endothelial cells in
occlusion (31, 32). An increased expression of vascular case of insulin resistance (21). However, insulin resistance might
endothelial growth factor (VEGF) causes increased vascular be involved in microvascular damage through other mechanisms.
permeability and angiogenesis (33). All these processes are DM and obesity are both associated with selective impairment
harmful for the vasculature (21). of some insulin signaling pathways (e.g., the PI3K pathway)
4) In the healthy situation, intracellular glucose is mainly that reduce nitric oxide availability and cause a compensatory
metabolized through glycolysis. However, in a state of hyperinsulinemia (48). The abundant insulin would then act
hyperglycemia, part of that glucose is diverted into another through other signaling pathways that are less affected by DM or
pathway known as the hexosamine pathway. This pathway obesity (e.g., the Ras/MAPK pathway). The upregulation of these
comprises a complex cascade of reactions, leading to increased specific pathways, and the reduced availability of nitric oxide have
productions of cytokines (such as PAI-1, TGF-α, and TGF-β1) unfavorable effects on the microvasculature, such as impaired
which in fact are harmful for the blood vessels (25). angiogenesis and vasoreactivity (48).
Throughout this report, we will refer to these processes as
Dyslipidemia
upstream (ROS production) and downstream (polyol, AGEs and
Already announced in the insulin resistance section, dyslipidemia
RAGE, PKC and hexosamine) pathways of hyperglycemia. Since
is the third pathogenic mechanism that plays a role in the
endothelial cells are the major target cells of hyperglycemia, it
development of diabetic complications. Dyslipidemia is more
is not surprising that highly vascularized organs are particularly
common in T2DM than in T1DM, and is typically characterized
susceptible to tissue damage. For example, damage to endothelial
by high levels of triglycerides and small dense low density
cells in the retina and kidney cause retinopathy (34, 35)
lipoprotein (sdLDL) cholesterol particles, in combination with
and nephropathy (36, 37), respectively. Also, injury to the
low levels of high density lipoprotein (HDL) cholesterol (i.e.,
vulnerable vascular supply of the peripheral nervous system
the “lipid triad”) (49). Typical characteristics of patients with
is likely to cause hypoxia in the endoneurium (38). On top
T2DM, such as visceral adiposity, insulin resistance, and excess
of that, neuronal cells themselves are also susceptible for
FFAs in the bloodstream play a major role in the development
damage caused by hyperglycemia. This results in damage to the
of this specific lipid profile. Because of its atherogenic
nerve, particularly in the most-distal fibers, eventually causing
properties, diabetic dyslipidemia is particularly important in the
peripheral neuropathy (38, 39).
development of macrovascular complications (50). Several trials
showed that lipid lowering therapy—especially with statins—
Insulin Resistance indeed decreased the risk of CVD in patients with T2DM (51, 52).
The second mechanism that is involved in chronic diabetic Dyslipidemia is also involved in microvascular complications, as
complications is insulin resistance. As its name already implies, shown in several intervention studies. Treatment with fibrates—
insulin resistance is characterized by a reduced sensitivity of body hypolipidemic agents that lower triglyceride levels and increase
cells to the actions of insulin. Since insulin resistance is closely HDL levels—prevented the progression of retinopathy (53),
related to obesity, it is more common in patients with T2DM, reduced albuminuria and prevented loss of glomerular filtration
where it is an important cause for hyperglycemia. Besides its rate (GFR) (54). High levels of plasma triglycerides are also
effect on blood glucose levels, insulin resistance also causes an associated with progression of diabetic neuropathy (55). How
excess flux of free fatty acids (FFAs) from adipose tissue into the dyslipidemia biologically contributes to the development of
bloodstream. This in turn increases the production and release microvascular complications remains mostly unknown (56).
of very low-density lipoprotein (VLDL) in the liver, resulting However, it is suggested that oxidation of LDL cholesterol
in a dyslipidemia (40). The role of dyslipidemia is discussed (oxLDL) causes increased ROS production in for example
in the next section. However, the circulating FFAs caused by neuronal cells (57).
insulin resistance also play a direct role in the development of
macrovascular complications (i.e., CVD). Increased flux of FFAs Hypertension
into arterial endothelial cells causes increased FFA oxidation in Hypertension, the fourth mechanism contributing to diabetic
their mitochondria, eliciting ROS production and subsequently complications, is more common in patients with DM compared
activating the same four pathways that we discussed in the to the general population (58). In fact, hypertension and T2DM
previous section (polyol, AGEs, PKC, and hexosamine) (21, 41). in particular share many etiologic factors, such as obesity,
Furthermore, protective enzymes such as eNOS and prostacyclin insulin resistance, and inflammation (59). As we discussed
synthase are downregulated due to insulin resistance (42), and before, patients with T2DM have a higher risk for CVD, mainly
adhesion of leukocytes to endothelial cells is increased (43). due to hyperglycemia, insulin resistance, and dyslipidemia.
Together, these processes result in enhanced vasoconstriction, Having high blood pressure increases that risk even more (58).
inflammation, and procoagulant alterations. In the arterial A large randomized controlled trial showed that tight blood
endothelial cells, this favors the development of atherosclerotic pressure control in patients with T2DM significantly reduced
lesions, which are the main cause of CVD (23, 44–46). A large the risk for CVD (60). Besides macrovascular complications,
prospective trial indeed showed that having insulin resistance hypertension is also considered as an important risk factor
almost doubled the risk for CVD (47). for microvascular complications such as retinopathy (61) and

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Verhulst et al. Oral Complications of Diabetes Mellitus

nephropathy (36). In the previously mentioned study, tight contributes to the development and progression of neuropathy
blood pressure control also resulted in a significant reduction (38), nephropathy (74), and retinopathy (75).
in the risk and progression of microvascular complications Finally, immune dysfunction itself can be one of the causes
(60). The biologic contribution of hypertension to diabetic of DM as well, since we know that T1DM is a form of
complications remains to be further elucidated. However, it diabetes that is caused by autoimmune destruction of pancreatic
was demonstrated that hypertension in patients with T2DM β cell. These patients are also susceptible to develop other
resulted in endothelial activation, reflected by increased levels of autoimmune diseases: Graves’ disease, Hashimoto’s thyroiditis,
soluble adhesion molecules such as E-selectin and vascular cell Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis,
adhesion molecule 1 (VCAM-1) (62). These adhesion molecules myasthenia gravis, and pernicious anemia (1).
play in important role in the initiation of inflammation. Also,
availability of nitric oxide might be decreased in the case of
hypertension, resulting in vasoconstriction (63). Both processes POTENTIAL ORAL COMPLICATIONS OF
are harmful for the vasculature and might eventually contribute DIABETES MELLITUS
to microvascular damage.
The previous section explained that chronic complications of
DM are the result of persistent metabolic and hemodynamic
Immune Dysfunction: Impaired Immune disturbances that mainly target endothelial cells, typically
Response and Proinflammatory State affecting specific regions in the body. It has been proposed in
As we have shown in Figure 1, immune dysfunction plays literature that the oral cavity of patients with DM might be
a pivotal role in the pathogenesis of diabetic complications. one of those regions, with an increased susceptibility for oral
DM can have a negative effect on several aspects of the complications as a result (6, 76). This section aims to provide an
immune system. For example, the innate (polymorphonuclear up-to-date overview of the oral complications that are possibly
neutrophils [PMNs], macrophages, and monocytes) and adaptive associated with DM. Figure 2 presents clinical pictures and
(T-lymphocytes) immune responses are often impaired (64). radiographs of the oral complications discussed in this review.
More specifically, PMNs show impaired chemotactic, phagocytic, Each oral complication is briefly introduced, after which we
and microbicidal properties in patients with DM (65, 66). Also, discuss the association with DM from an epidemiologic point of
adherence of microorganisms to several cell types, such as view. Next, we will use the five mechanisms we discussed before
epithelial and endothelial cells, is increased (64). The impaired (hyperglycemia, insulin resistance, dyslipidemia, hypertension, and
immune response is the major reason why patients with DM immune dysfunction) to assess possible pathogenic associations.
are more prone to opportunistic infections. Lower respiratory
tract infections, urinary tract infections, bacterial and mycotic Periodontal Diseases
skin and mucous membrane infections are all found to be Background
increased in patients with DM (67). However, the most impeding Periodontal disease can be subdivided into gingivitis, which is a
infection is probably the diabetic foot (68). Trauma, deformity, reversible inflammation of the gum (gingiva) around the teeth
and peripheral neuropathy are the most common underlying without loss of support, and periodontitis, which has the clinical
causes of foot ulcerations in individuals with DM (69). In appearance of gingivitis but also shows irreversible destruction
these patients, healing of ulcerations is impaired, with a crucial of the supporting structures around the teeth (root cementum,
role for the so-called pathogenic triad: neuropathy, ischemia periodontal ligament, and alveolar bone). Approximately 30–
(due to vascular damage and endothelial dysfunction), and 50% suffer from any form of periodontitis, including the mild and
trauma (70). This healing abnormality, in combination with the moderate variant, while the prevalence of severe periodontitis in
impaired immune response, causes ulcers to become a porte adults is estimated to be approximately 9–11% (77, 78). Severe
d’entrée for opportunistic micro-organisms. As a result, the periodontitis was ranked as the sixth most prevalent disease
tissue can get infected, which has major implications for further worldwide in 2010 (79–81). Several types of periodontitis have
development of the diabetic foot (71). Eventually, if the infection been described: aggressive or chronic periodontitis, necrotizing
does not resolve, amputation is the only remaining solution to gingivitis and periodontitis and finally periodontal abscesses
prevent sepsis (72, 73). (82, 83). Recently, a new classification and case definition
The immune dysfunction characterizing DM also manifests has been introduced. The proposed case definition extends
itself as a chronic pro-inflammatory state (11). As a response to beyond description based on severity to include characterization
the metabolic and hemodynamic disturbances discussed before, of biological features of the disease and represents a first
endothelial cells in the target tissues are activated. This is step towards adoption of precision medicine concepts to the
characterized by increased expression of adhesion molecules management of periodontitis (84). Periapical periodontitis—
(e.g., intracellular adhesion molecule 1 [ICAM-1] and VCAM-1) a specific type of periodontitis affecting the periodontium
and release of chemotactic factors (e.g., CCL5 and CCL5), which around the apex of the tooth—and peri-implantitis—a chronic
initiates immune cell recruitment and infiltration into the tissue. inflammation affecting the tissues around dental implants—will
These immune cells, and other cells at sites of complications (e.g., be discussed in separate sections.
adipocytes), release a wide variety of cytokines (e.g., IL-1β, IL-6, Periodontal disease is the result of an aberrant inflammatory
and TGF-α) that amplify the inflammatory response even further. host response to the biofilm that resides around the teeth.
If the inflammation remains unresolved and becomes chronic, it In some susceptible subjects, an initial gingivitis can progress

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Verhulst et al. Oral Complications of Diabetes Mellitus

FIGURE 2 | Oral complications of diabetes mellitus. 1A & 1B: Periodontitis. A clinical view of periodontitis is shown in figure 1A, with the corresponding radiograph
displayed in image 1B. The green dots in image 1B indicate where the bone level originally was, while the red dots show the actual bone level as a result of
inflammation. 2A & 2B: Dental caries. Image 2A displays a clinical view of dental caries, observed from the occlusal view. Picture 2B is a radiograph of an example of a
deep carious lesion, marked by the red circle. 3. Hyposalivation. The photo in image 3 shows a clinical view of fissured tongue, caused by severe hyposalivation. 4.
Oral candidiasis. Image 4 displays a clinical view of oral candidiasis, located at the palate. 5A & 5B: Oral cancer. At image 5, a clinical representation of leukoplakia
and oral cancer is shown at the buccal (5A) and palatal (5B) site. 6A & 6B: Apical periodontitis. Figure 6A shows a fistula, caused by apical periodontitis, with image
6B as the corresponding radiograph, where the lesion at the apex of the tooth is marked by the red circle. 7A & 7B: Temporomandibular disorders. Image 7A indicates
the location of pain often seen in patients with temporomandibular disorders, while 7B shows a measurement of limited jaw opening, another symptom of
temporomandibular disorders. 8A & 8B: Peri-implantitis. At figure 8A, a clinical view of peri-implantitis is presented, with 8B as the corresponding radiograph. Again,
the red dots indicate where ideally, the bone level should be, while the red dots show the actual reduced bone level as a result of the inflammatory process. The
authors thank the following colleagues for providing clinical pictures and/or radiographs: Dr. AJP van Strijp (dental caries), Prof. Dr. M Laine (hyposalivation), Dr. P
Wetselaar (temporomandibular disorders and apical periodontitis), all from ACTA, the Netherlands; Dr. RJJ van Es (oral cancer), UMC Utrecht, The Netherlands; Prof.
Em. Dr. I van der Waal (oral candidiasis).

into chronic periodontitis (82). Several risk factors that (the subgingival microbiome), genetics, systemic diseases (e.g.,
might influence the susceptibility for periodontitis have been DM and HIV/AIDS), lifestyle (e.g., oral hygiene, smoking, diet),
established in literature, clustered in five categories: environment and tooth related factors (e.g., iatrogenic causes or occlusal

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Verhulst et al. Oral Complications of Diabetes Mellitus

problems) (85, 86). In chronic periodontitis, irreversible loss of studies even indicate a possible causal relationship. However,
supporting tissue surrounding the teeth (due to destruction of the biologic mechanisms behind this relationship are still not
gingival connective tissue fibers, root cementum, periodontal completely understood. Several studies do show pathologic
ligament, and alveolar bone) results in deep periodontal pockets changes in the gingival vasculature of patients and animals with
and attachment loss, which are commonly used to define a diabetes, compared to control subjects without DM. Examples are
patient with periodontitis (87). This impairing process eventually basement membrane thickening, angiogenesis, and an increase
causes loosening of the teeth and ultimately, when no periodontal in osmotic tissue pressure (108–112). This strengthens the
treatment has been initiated, in tooth loss (88). hypothesis that DM might affect periodontal tissue in a way
similar to how it affects retinal, neural, and renal tissue,
Relationship With Diabetes Mellitus: Epidemiology namely through vascular damage. We hope to elucidate this
Periodontal disease has been linked with DM for a long time. by separately discussing the same five pathological mechanisms
Since Loë suggested to consider periodontal disease as the sixth (hyperglycemia, insulin resistance, dyslipidemia, hypertension,
complication of DM in 1993 (89), periodontitis became the most and immune dysfunction) that cause the well-known systemic
researched oral complication of DM. As summarized in several complications of DM (Figure 1):
narrative reviews (7, 8, 90–95), meta-analysis (96, 97), and a
major consensus report (98), DM is considered as a risk factor Hyperglycemia
for the development, progression, and severity of periodontitis. As we discussed earlier, poor glycemic control increases the
Many cross-sectional studies show an increased prevalence risk for periodontitis in patients with DM, and improvement
of periodontitis in patients with DM. However, longitudinal in HbA1c levels reduces periodontal inflammation (107).
studies are relatively scarce, even though these studies are Apparently, just as in the well-known diabetic complications,
necessary for establishing causal relationships. An important hyperglycemia is a key pathological determinant for
source of evidence is the research conducted with the Pima periodontitis. While the damaging processes through which
Indians in the 1990s, a population with one of the highest hyperglycemia contributes to the development and progression
T2DM prevalence in the world. Indeed, diabetic subjects within of the well-known complications are well-established (21), this
this population displayed an increased prevalence of periodontal is not the case for DM-associated periodontal disease. However,
disease (99, 100). More importantly however, analysis of there is evidence that the underlying upstream mechanism—
longitudinal data from this population also showed that the oxidative stress—affects periodontal health as well (113). Low
incidence of periodontitis in patients with (poorly controlled) antioxidant levels are often interpreted as indicator for oxidative
diabetes was more than twice as high, compared to subjects with stress, and several studies indeed found decreased levels of
well-controlled or no DM (101). The risk for alveolar bone loss antioxidants in serum, periodontal tissue, and saliva of patients
was higher in the poorly controlled diabetes group, as well as the with DM and periodontitis, compared to subjects without DM
severity of disease progression (102). Other prospective cohort (114–117). One study found that the presence of T2DM in a
studies confirmed the increased incidence of periodontitis in rodent periodontitis model accelerated the decrease in gingival
patients with (pre)diabetes (103, 104). Glycemic control appeared endothelial function (measured by Laser Doppler Flowmetry or
to be of particular importance, as patients with well-controlled LDF), mediated by oxidative stress (118).
diabetes showed a similar risk for periodontitis as matching Of the downstream effects of hyperglycemia (polyol pathway,
individuals without DM (102, 105). This was confirmed in a large AGE/RAGE, PKC, and hexosamine pathway) that might play
trial, where glycemic control rather than the etiology of DM was a role in the pathogenesis of periodontal diseases, AGEs, and
associated with deterioration of pocket depth and periodontal RAGE have been studied the most. We already mentioned that
attachment loss (106). Improving glycemic control in patients patients with DM are susceptible for joint related diseases, due
with DM and periodontitis reduced inflammation, expressed to damage to the connective tissues in these joints, caused
as gingival bleeding (107). Solid evidence on the association by AGEs accumulation. Periodontitis is also characterized by
between periodontal abscesses and DM is lacking. However, destruction of connective tissue, both in the gingiva and
based on clinical experiences, it is speculated that—while a single periodontal ligament, suggesting similar pathogenic pathways
periodontal abscess usually is the result of local factors—multiple via AGE accumulation. AGEs and RAGE are both increased
recurring abscesses might indicate an underlying systemic cause, in gingival tissue (119) and saliva (120) of patients with
such as uncontrolled DM (83). T1DM and T2DM. The mechanisms by which AGEs are
The majority of studies used the former classification of involved in periodontal tissue destruction are probably the
chronic periodontitis or at least did not specify the presentation same as in the well-known complications of DM: enhanced
of the disease. Since a new classification and case definition inflammation, impaired wound repair, and increased oxidative
for periodontitis has recently been proposed, we decided not to stress. In the specific case of periodontitis, this results in
distinguish different types of periodontitis in relation to DM in increased gingival connective tissue and periodontal ligament
this review (84). destruction and alveolar bone resorption (119–123). Increased
levels of AGEs in serum of patients with DM were also
Relationship With Diabetes Mellitus: Pathogenesis significantly associated with deterioration of periodontitis
From an epidemiologic point of view, DM has an adverse (124). We know that AGEs are particularly important in the
effect on periodontal health. A limited number of longitudinal progression of periodontitis in persons with DM, because

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Verhulst et al. Oral Complications of Diabetes Mellitus

research showed that blocking RAGE reduced periodontal tissue Dyslipidemia

breakdown (125). The independent effect of lipid dysregulation on periodontal
There is limited evidence that the polyol pathway plays a health has been studied in several populations without DM
role in periodontitis. Reduced glutathione (GSH) was one of (136). Strikingly, the lipid profile typical for patients with DM
the antioxidants that was found to be decreased in saliva (115, (low levels of HDL; high levels of triglycerides and slightly
117) and periodontal tissue (116) of patients with DM and increased LDL) was associated with worsened periodontal health,
periodontitis, compared to patients without DM. Another study characterized by increased periodontal attachment loss, pocket
also showed increased levels of oxidized glutathione (GSSH) depth, and bleeding gums (137). Comparable results were found
in saliva (114). As mentioned before in this review, decreased in other cross-sectional studies, although it should be noted that
levels of GSH and increased levels of GSSH are typical for different definitions of periodontitis and varying markers for
increased polyol pathway flux caused by hyperglycemia. In dyslipidemia were used (138–140). The mechanism by which
another study, therapy with aldose reductase inhibitors—possibly dyslipidemia contributes to periodontitis is not fully understood,
obstructing flux of excess glucose into the polyol pathway— and longitudinal studies to establish a causal relationship
prevented alveolar bone loss in rats with DM. This could are missing. However, it is hypothesized that—similar to
indicate that the polyol pathway is involved in the progression hyperglycemia—dyslipidemia stimulates a pro-inflammatory
of periodontitis in patients with DM (126). However, a similar state, and thereby increases the susceptibility for periodontitis
study showed similar results for non-diabetic rats, indicating (141). Furthermore, it is thought that, besides glucose, lipids can
that aldose reductase inhibitors might prevent alveolar bone also act as a source for ROS production in the gingiva through
loss through mechanisms other than obstructing the polyol lipid peroxidation (LPO). Patients with DM and dyslipidemia
pathway flux (127). have shown increased levels of markers for LPO (116, 142). These
Protein kinase C (PKC) activity is also increased in patients increased values were significantly correlated with parameters for
with DM and periodontal disease (128), but whether it periodontitis (% sites with bleeding, periodontal pockets ≥6 mm
actually contributes to alveolar bone loss in these patients and pocket suppuration) and several inflammatory markers (IL-
remains unclear. The possible role of the hexosamine pathway 6, IL-10, TNF-α) (142). A relatively new insight is the beneficial
in hyperglycemia-associated periodontitis has not been effect of statin therapy on periodontal treatment outcome in
studied yet. patients without DM, as described in several recent systematic
reviews (143–145). However, it should be noted that this is not
necessarily caused by statins’ lipid lowering effect; it could be the
Insulin resistance result of pleiotropic features of statins, such as antioxidant and
Analysis of periodontal pocket depth in a large population anti-inflammatory effects (143).
without DM showed an independent association with our
second pathogenic mechanism; insulin resistance. However,
the association was interpreted as periodontal inflammation Hypertension
being a risk factor for insulin resistance, rather than the other It is hypothesized that hypertension is associated with
way around (129). A comparable Korean cross-sectional study periodontal disease, although the majority of studies interpret
did not show such a relationship, but they did find impaired this relationship as periodontitis being a risk factor for
pancreatic β cell functioning in patients with periodontitis hypertension through inflammation (146). This hypothesis is
(130). In another large adult Korean population, insulin mainly based on findings that periodontal therapy is beneficial
resistance was associated with periodontitis, but only in post- for systolic and diastolic blood pressure (147). However,
menopausal women (131). Furthermore, a large cohort from the longitudinal research in the opposite direction is lacking;
United States suggested that the link between obesity and severe hypertension might very well be a risk factor for developing
periodontitis was mediated through insulin resistance (132). periodontitis as it is for other diabetic complications (148, 149).
However, the direction of the discovered relationships between A recent systematic review and meta-analysis found an OR
insulin resistance and periodontitis could not be established of 1.50 (95% CI: 1.27–1.78) for the association between the
in these cross-sectional studies. A study in Finland did not presence of hypertension and periodontitis, but again, the
find an independent association between insulin resistance and direction could not be established (150). It should also be stated
periodontitis at baseline (133). However, in the same cohort, after that there is a major overlap in risk factors for both conditions.
4 years of follow up, high levels of insulin resistance at baseline However, a few animal studies show that hypertension might
weakly but independently predicted the deepening of periodontal negatively affect alveolar bone quality (151) and gingival
pockets (134). Also, in a non-diabetic rat model, obesity-induced vasculature (152), and that it can exacerbate experimental
insulin resistance resulted in endothelial dysfunction and periodontitis (153). Treatment with an anti-hypertensive drug
inflammation of the gingiva, characterized by decreased eNOS in an animal model with periodontitis resulted in decreased
expression and increased activity of PKC, NF-κB, and oxidative levels of inflammatory cytokines (IL-1β and TNF-α), reduced
stress markers (135). Although this might indicate that insulin expression of markers for alveolar bone breakdown (MMP-2,
resistance negatively influences periodontal health, longitudinal MMP-9, RANKL/RANK), increased expression of a bone growth
studies with human subjects are necessary to confirm promoting marker (osteoprotegerin or OPG) and finally reduced
this hypothesis. alveolar bone loss (154).

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Verhulst et al. Oral Complications of Diabetes Mellitus

Immune dysfunction: impaired immune response and Dental Caries

proinflammatory state Background
As we stated in the background section, periodontitis is a A definition often used to describe dental caries (i.e., tooth decay
chronic disease characterized by an aberrant inflammatory host or cavities) is: “the localized destruction of susceptible dental
response to the biofilm. However, in patients with DM, this hard tissues (enamel, dentine, root cementum) by acidic by-
pro-inflammatory state seems to be even more exaggerated. products from bacterial fermentation of dietary carbohydrates”
PMNs, but also monocytes and macrophages, produce more (178). It can be subdivided into coronal caries (affecting the
inflammatory mediators and ROS, which could contribute crown portion of the tooth) and root caries (affecting the root
to tissue destruction in periodontal disease (128, 155–158). of the tooth). People are susceptible to caries throughout their
Prolonged retention of the PMN infiltrate ensures that the entire life. The increasingly older western population shows an
potentially damaging inflammatory response is maintained increase in retention of their natural dentition and therefore,
longer in patients with DM (159–161). Also, patients with DM these individuals remain susceptible for caries development, also
show increased levels of inflammatory cytokines in gingival at old age. Hence, an increase in prevalence of dental caries is
crevicular fluid and gingival tissue, such as IL-1β and IL- observed in this age category (179). Despite this, a clear drop
6, compared to healthy subjects (157, 162–166). TNF-α also in the total prevalence of caries has been observed in developed
contributes to periodontal tissue destruction by enhancing the countries over the last few decades (178, 180, 181). Nevertheless,
inflammatory response and activating osteoclasts responsible the earlier mentioned “Global burden of disease 2010 study”
for bone resorption (167). Another interesting cytokine is estimates a global prevalence of 35% for dental caries, ranking
receptor activator of NF-κB ligand (RANKL), since it is also this oral disease first on the list of the most common diseases of
involved in the inflammatory processes seen in other diabetic mankind (79, 80).
vascular complications (44). In the case of periodontal disease, As can be deduced from the earlier mentioned definition, on
RANKL and the ratio with OPG determine whether bone the one hand, dental caries is the result of a complex interaction
is generated (low ratio) or resorbed (high ratio). Especially between acid producing bacteria and fermentable carbohydrates
in patients with poorly controlled diabetes, this ratio is (such as: sucrose, fructose, and glucose). On the other hand, the
increased in the periodontal tissue (168–170) and gingival ecology of the mouth, in this case determined to a great extent by
crevicular fluid (171, 172), with alveolar bone resorption as the pH of saliva and competing non-cariogenic bacteria, is also
a consequence. Treatment with OPG, and thereby decreasing important. In the healthy situation, there is a balance between
the RANKL/OPG ratio, even reversed alveolar bone loss in the bacterial biofilm and the tooth minerals. If this balance is
diabetic mice. This suggests that this ratio is important for disturbed (often referred to as the ecological shift), bacteria in
the development or prevention of periodontitis in the presence the dental biofilm (including Streptococcus mutans, other closely
of DM (169). related Streptococci and some Lactobacilli) produce a sticky
We discussed before that patients with DM are susceptible polysaccharide matrix and acids, causing demineralization of
for opportunistic infections because of an impaired innate and the hard dental tissues. Ultimately, this leads to cavitation. As
adaptive immune response. In the case of periodontitis, especially human teeth are composed of non-shedding tissue, the aciduric
the PMN response seems to be impaired, characterized by bacteria can prolong this activity as long as they remain on
reduced chemotaxis (173, 174). This might cause opportunistic the surface and have sufficient nutrition, in particular sucrose.
pathogens in the biofilm to persist over time, thereby causing Thus, poor oral hygiene and very regular intake of sucrose-
the aberrant inflammation to retain, which enhances the rich or other fermentable carbohydrates-containing food, snacks,
progression of periodontitis (173–175). In that perspective, and soft-drinks—that also may be acidic—are cariogenic lifestyle
(severe) periodontitis in patients with DM can best be habits. The process of demineralization can be stopped or even
compared to the diabetic foot. Just as in this condition, the reversed, as there is a balance between demineralization and
exaggerated inflammatory response to the unresolved infection remineralization. This balance is influenced by the supply of
with opportunistic micro-organisms is retained, which—in calcium, phosphate, and fluoride, the composition and quantity
combination with poor wound healing—sometimes even results of saliva (which serves as a buffer), diet and of course the
in tooth loss (176, 177). presence of cariogenic bacteria in the dental plaque. In this way,
physical, biological, environmental, and behavioral risk factors
are involved in caries development (178).
Concluding Comments
Table 1 summarizes the studies on which the section above Relationship With Diabetes Mellitus: Epidemiology
was based. Both prevalence and incidence of periodontitis are Several literature reviews that discuss the association between
increased in patients with DM. There are many similarities diabetes and dental caries, point to the lack of solid evidence
to the pathogenesis of the well-known complications of DM. for a clear correlation (6, 93, 182–184). The majority of studies
Glycemic control seems to be particularly important in the have a cross-sectional design, investigating patients with T1DM.
development and severity of periodontitis. However, there In many studies, these patients showed an increased prevalence
are indications that other metabolic disturbances also play a of dental caries, compared to patients without DM (185–194).
role, such as dyslipidemia, insulin resistance, and especially However, a considerable number of studies could not replicate
immune dysfunction. these findings (195–201).

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TABLE 1 | Overview of studies investigating the association between diabetes mellitus and periodontal disease.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
Chavarry et al. (97) 49 cross-sectional studies (17 on T1DM [n = Systematic Yes T2DM increased the risk for development and
1,678], 26 on T2DM [n = 13,773] and 6 on both review with progression of periodontal disease. The
types [n = 17,427]). meta-analysis meta-analysis revealed statistically significant
8 longitudinal studies (total n = 644). mean differences in pocket depth (0.46, 95%
CI: 0.01–0.91) and clinical attachment loss
(1.00, 95% CI: 0.15–1.84) when comparing
patients with T2DM and healthy controls. The
positive mean differences indicated more
periodontitis. This could not be established for
patients with T1DM.
Chiu et al. (103) Group 1: Patients without DM (FPG <100 mg/dL) (n Prospective Yes After correcting for all possible confounding
= 4,033). cohort study factors, patients with (pre-diabetes had a
Group 2: Patients with pre-diabetes (FPG 100–125 higher incidence of periodontal disease
mg/dL) (n = 297). (community periodontal index [CPI] of 3 [a
Group 3: Patients with T2DM (medical history or 4–5 mm pocket] or 4 [a pocket ≥6 mm])
FPG ≥126 mg/dL) (n = 57). compared to subjects with normal FPG levels
All groups were periodontally healthy at baseline. at baseline.
Demmer et al. Group 1: Diabetes free subjects (n = 2,280). Prospective Yes Patients with uncontrolled T2DM had a
(106) Group 2: Incident patients with T2DM (n = 79). cohort study significant higher increase in pocket depth over
Group 3: Patients with controlled T2DM (HbA1c 5 years, compared to the healthy subjects.
6.5–7.0%) (n = 80). Patients with either uncontrolled T1DM or
Group 4: Patients with uncontrolled T2DM (HbA1c T2DM had significant higher increase in
>7.0%) (n = 72). attachment loss over 5 years, compared to
Group 5: Patients with controlled T1DM (HbA1c diabetes free subjects.
6.5-7.0%) (n = 43).
Group 6: Patients with uncontrolled T1DM (HbA1c
>7.0%) (n=72).
Jimenez et al. Group 1: Patients with T2DM (self-reported; n = Prospective Yes Patients with T2DM had an adjusted 29%
(104) 2,285; mean age = 54.7 ± 8.9 years). cohort study greater risk of developing periodontitis,
Group 2: Patients without DM (n = 32,962; mean compared to patients without DM (HR = 1.29;
age = 53.4 ± 9.6 years). 95% CI:1.13–1.47).
Löe (89) Group 1: Pima Indians with T2DM (n = 693; 261 Retrospective Yes Both prevalence and incidence were increased
males, 432 females). cohort study in patients with DM, compared to the control
Group 2: Pima Indians without DM (n = 1,487; 644 subjects. Furthermore, in the subjects with DM,
males, 843 females). a higher prevalence of edentulism was found,
which also increased with a longer duration of
the diabetic conditions.
Nelson et al. (101) Group 1: Pima Indians with T2DM (n = 720). Cohort study Yes Both incidence and prevalence of periodontal
Group 2: Pima Indians without DM (n = 1,553). disease was higher in patients with DM,
compared to subjects without DM, after
correction for age and gender. They conclude
that periodontal disease should be considered
as a non-specific complication of T2DM.
Taylor et al. (102) Group 1: Patients with poorly controlled T2DM Retrospective Yes Patients with poorly controlled DM had a
(HbA1c ≥9.0%) (n = 7; 4 males, 3 females; median cohort study greater risk for alveolar bone loss progression.
age = 26 years). Also, this progression was more severe in
Group 2: Patients with better controlled T2DM patients, compared to controls.
(HbA1c <9.0%) (n = 14; 3 males, 11 females;
median age = 27 years).
Group 3: Controls without DM (n = 338; 138 males,
200 females; median age = 21 years).
PATHOGENESIS
Hyperglycemia
Polyol pathway
Kador et al. (126) Group 1: Control rats (n = 5). Longitudinal Yes Injection of LPS resulted in significant bone loss
Group 2: Diabetic rats (n = 8). animal study in the control group and untreated diabetic
Group 3: Diabetic rats, treated with aldose rats. However, in the group treated with ARI,
reductase inhibitor (ARI) (n = 8). this was not observed. This might indicate that
Rats used: Sprague-Dawley rats (male, diabetes by obstructing a crucial step in the polyol
induced by Streptozotocin injection, experimental pathway, alveolar bone loss in a diabetic rat
periodontitis induced by injection of LPS from model was prevented.
Escherichia coli).
(Continued)

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TABLE 1 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Kador et al. (127) Group 1: Diabetic rats (n = 30; 8 on standard diet, Longitudinal Unclear Aldose reductase inhibitors indeed prevented
22 on ARI diet). animal study alveolar bone loss in diabetic rats, but in control
Group 2: Non-diabetic rats (n = 30, 8 on standard rats as well.
diet, 22 on ARI diet).
Rats used: Sprague-Dawley rats (male, diabetes
induced by Streptozotocin injection, experimental
periodontitis induced by injection of LPS from
Porphyromonas Gingivalis).
Advanced glycation endproducts
Chang et al. (122) Group 1: T1DM rats (n = 18). Longitudinal Yes Healing of bony defects was significantly lower
Group 2: Control rats (n = 18). animal study in diabetic rats, compared to healthy rats. The
Rats used: Sprague-Dawley rats (male, diabetes AGE-RAGE interaction was enhanced by both
induced by Streptozotocin injection, a inflammatory status and diabetic conditions,
tooth-associated osseous periodontal defect was indicating a role in the impaired periodontal
surgically created). wound healing seen in patients with DM.
Lalla et al. (125) Group 1: T1DM mice (n = 77; C57BL/6; subdivided Longitudinal Yes Blockade of RAGE reduced alveolar bone loss
into different groups by treatment dose). animal study and lowered levels of inflammatory cytokines
Group 2: Non-diabetic control mice (n = 12). such as TNF-α and IL-6. This indicates a link
between levels of RAGE and periodontal
destruction in patients with DM.
Schmidt et al. Animal Cross- Yes AGEs appeared to accumulate in the gingival
(123) Group 1: Diabetic mice (CD1 ) sectional tissue of both mice and humans with DM. In
Group 2: Non-diabetic control mice. human and parallel with this, enhanced oxidative stress
Human animal study was observed in patients with DM, compared
Group 1: Patients with T1DM (n = 1) or T2DM (n = to controls without DM, linking AGE
3) and periodontitis accumulation to periodontal destruction.
Group 2: Patients without DM, with periodontitis (n
= 5).
Takeda et al. (124) Group 1: Patients with T2DM and periodontitis (n = Cross- Yes AGEs were the only biomarker in serum that
69). sectional showed a significant relationship with
Group 2: Patients with T2DM without periodontitis study periodontal disease.
(n = 28).
Yoon et al. (120) Group 1: Patients with DM (n = 52; 26 males, 26 Cross- Yes Significantly more AGEs were found in saliva of
females; mean age = 57 ± 13 year). sectional patients with DM, indicating involvement in the
Group 2: Age-matched controls without DM (n = study pathogenesis of periodontal disease as a
47; 17 males, 30 females; mean age = 41 ± 14 complication of DM.
years).
Zizzi et al. (119) Group 1: Periodontally healthy subjects without DM Cross- Yes In patients with T1DM or T2DM and periodontal
(n = 16). sectional disease, gingival AGEs are increased. In this
Group 2: Patients with periodontitis, without DM (n study study, duration of DM could be a determining
= 16). factor for the accumulation of AGEs.
Group 3: Patients with T1DM and periodontitis (n =
16).
Group 4: Patients with T2DM and periodontitis (n =
16).
Protein kinase C
Karima et al. (128) Group 1: Patients with DM (n = 50; 12 T1DM, 38 Cross- Yes Neutrophils of patients with DM produced
T2DM; 30 males, 20 females; mean age = 50.9 sectional significantly higher levels of superoxide and
years) study displayed higher protein kinase C activity
Group 2: Healthy subjects without DM (n = 45, 30 compared to those of healthy controls. This
males and 15 females; mean age = 48.3 years). indicates a more pro-inflammatory state.
Furthermore, there was an association
between metabolic control and severity of
periodontal disease in patients with DM.
Insulin resistance
Demmer et al. Patients without DM (n = 3,616; 50% male, 50% Cross- Unclear An association between periodontal pocket
(129) female; mean age = 41 ± 0.4 years). sectional depth and insulin resistance was found.
study However, the cross-sectional design leaves the
association open for interpretation. Also, in the
regression analysis, insulin resistance was
considered as outcome variable, and pocket
depth as risk factor.

(Continued)

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 1 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Genco et al. (132) Group 1: Patients with obesity (BMI ≥27 kg/m2 ), Cross- Yes Multiple regression analysis showed that obese
without DM (n = 5,326; 45.0% male; mean age = sectional patients with high levels of insulin resistance
45.2 ± 0.2 years). study were more likely to suffer from severe
Group 2: Patients without obesity and DM (n = periodontitis, compared to obese patients with
7,041; 48.3% male; mean age = 42.2 ± 0.2 years). low levels insulin resistance.
Islam et al. (130) Group 1: Patients with periodontitis (n = 5,992; Cross- No There were no differences in insulin resistance
52.9% male; mean age = 55.4 ± 13.3 years) sectional between patients with or without periodontitis.
Group 2: Patients without periodontitis (n = 13,130; study However, patients with periodontitis had
38.7% male; mean age = 46.3 ± 16.4 years). decreased pancreatic β cell functioning,
compared to patients without periodontitis.
Lim et al. (131) Group 1: Men with periodontitis (n = 2,055; mean Cross- Yes An association was found only in
age = 47.2 ± 0.4 years). sectional post-menopausal women, who showed a
Group 2: Men without periodontitis (n = 5,005; study higher periodontitis prevalence when their
mean age = 41.3 ± 0.4 years). insulin resistance increased. This was not
Group 3: Pre-menopausal women with periodontitis found for pre-menopausal women or men.
(n = 641; mean age = 40.1 ± 0.4 years).
Group 4: Pre-menopausal women without
periodontitis (n = 3,801; mean age = 34.8 ± 0.2
years).
Group 5: Post-menopausal women with
periodontitis (n = 763; mean age = 59.4 ± 0.4
years).
Group 6: Post-menopausal women without
periodontitis (n = 2,487; mean age = 62.6 ± 0.3
years).
Mizutani et al. Group 1: Male Zucker Fatty rats (ZF-fa/fa) (n = 12). Cross- Yes The obesity induced insulin resistance resulted
(135) Group 2: Lean matched controls (ZL-fa/+) (n = 12). sectional in increased oxidative stress, activation of PKC,
animal study decreased gingival endothelial functioning and
increased inflammation, possibly contributing
to the progression of periodontitis.
Timonen et al. Adult subjects without diabetes (n = 157), divided Prospective Yes Insulin resistance predicted the formation of
(134) into three tertiles of insulin resistance: cohort study periodontal pockets (4 mm or deeper) over a
Group 1: Lowest tertile (n = 58; 20.7% male; mean period of 4 year (IRR = 1.7, 95% CI: 1.1–2.7)
age = 41.2 ± 8.3 years). after adjusting for confounders.
Group 2: Intermediate tertile (n = 55; 34.6% male;
mean age = 44.7 ± 9.5 years).
Group 3: Highest tertile (n = 44; 25.0% male; mean
age = 44.2 ± 10.7 years).
Timonen et al. Adult subjects without diabetes (n = 2,050), divided Cross- No There was a crude association between insulin
(133) into five quintiles, ranging from lowest to highest sectional resistance and periodontal infection (measured
insulin resistance levels. study by number of teeth with deepened pockets).
However, when corrected for BMI, this
association disappeared.
Dyslipidemia
Awartani and Group 1: Otherwise systemically healthy female Cross- Yes Mean probing pocket depth and attachment
Atassi (138) subjects with hyperlipidemia (n = 30; mean age = sectional loss was significantly higher in the
47.1 ± 5.0 years). study hyperlipidemic group, who also had a higher
Group 2: Systemically healthy female subjects (n = bleeding on probing index.
30; mean age = 46.3 ± 4.4 years).
Bastos et al. (142) Group 1: Patients with poorly controlled T2DM and Cross- Yes Markers for lipid peroxidation were significantly
dyslipidemia (n = 30; 12 males, 18 females; mean sectional increased in patients with T2DM. These
age = 48.0 ± 7.6 years) study increased values significantly correlated with
Group 2: Patients with well-controlled T2DM and periodontal parameters (% sites with bleeding,
dyslipidemia (n = 30; 10 males, 20 females; mean pocket depth ≥6 mm and pocket suppuration)
age = 50.3 ± 6.7 years) and several inflammatory markers (IL-6, IL-10,
Group 3: Patients without T2DM, with dyslipidemia TNF-α).
(n = 30; 13 males, 17 females; mean age = 49.0 ±
7.5 years)
Group 4: Patients without T2DM and dyslipidemia
(n = 30; 11 males, 19 females; mean age = 45.9 ±
5.9 years)

(Continued)

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TABLE 1 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Fentoglu et al. Group 1: Subjects with hyperlipidemia (n = 51; 16 Cross- Yes The hyperlipidemic group showed higher
(137) males, 35 females; mean age = 49.4 ± 6.0 years). sectional values of periodontal parameters (mean
Group 2: Normolipidemic subjects (n = 47; 27 study probing pocket depth, clinical attachment loss,
males, 20 females; mean age = 47.3 ± 8.1 years). bleeding on probing and plaque index).
Lee et al. (140) Adult subjects (n = 15,534; 49.8% males; mean Cross- Yes Multivariate logistic regression analyses
age = 44.9 years). sectional showed an association between dyslipidemia
study (hyper TC, hyper TG and hypo HDL-c) and
periodontitis, after correction for demographic
and general health characteristics (including
DM).
Sangwan et al. Group 1: Normolipidemic subjects (n = 46; 22 Cross- Yes Hyperlipidemic patients without statin treatment
(139) males, 24 females; mean age = 42.5 ± 9.9 years). sectional had increased probing pocket depth and
Group 2: Hyperlipidemic patients with statin study gingival index, compared to normolipidemic
treatment (n = 50; 29 males, 21 females; mean age subjects and hyperlipidemic patients with statin
= 45.6 ± 9.9 years). treatment. Pocket depth was associated with
Group 3: Hyperlipidemic patients without statin TC, TG and LDL-c, while clinical attachment
treatment (n = 44; 25 males, 19 females; mean age loss was associated with TC and LDL-c.
= 41.3 ± 10.0 years).
Hypertension
Araujo et al. (154) Group 1: Healthy Wistar albino rats (n = 10) Longitudinal Yes Anti-hypertensive treatment with TELM,
Group 2: Ligated Wistar rats, fed with water (n = 10) animal study especially the 10 mg/kg dose, resulted in
Group 3: Ligated Wister rats, treated with 1 mg/kg decreased levels of inflammatory markers
telmisartan (TELM) (n = 10) (IL-1β, TNF-α), reduced expression of markers
Group 4: Ligated Wister rats, treated with 5 mg/kg for bone loss (MMP-2, MMP-9, RANKL/RANK,
TELM (n = 10) OPG), and actually reduced alveolar bone loss.
Group 5: Ligated Wister rats, treated with 10 mg/kg It should be noted that normotensive rats were
TELM (n = 10) used in this study.
Bastos et al. (151) Group 1: Normotensive Wistar rats (n = 15) Longitudinal Yes In both treated and untreated hypertensive
Group 2: Spontaneously hypertensive rats (SHR), animal study rats, increased bone loss and decreased bone
treated (n = 15) density were observed, compared to the
Group 3: Spontaneously hypertensive rats, not normotensive rats.
treated (n = 15)
Castelli et al. (152) Group 1: Normotensive control rats (n = 5). Longitudinal Unclear Morphologic changes to the gingival blood
Group 2: Renovascular hypertensive rats (n = 20, 9 animal study vessels were observed in the hypertensive rats,
lost to follow up). Rats used: Sprague Dawley (male, but not in the control rats. However, alveolar
adult). arterioles and pulp tissues were not affected.
Leite et al. (153) Group 1: Normotensive Wistar rats (n = 6) Longitudinal Yes In the hypertensive rats, all ligated sites – where
Group 2: Spontaneously hypertensive rats (n = 6). animal study periodontitis was induced – showed moderate
In both groups, each rat had a site with to severe alveolar damage. In the normotensive
ligature-induced periodontitis and a control site. rats, only mild or even no damage was
observed at the ligated sites. Hypertension
possibly aggravates tissue damage in
periodontitis.
Immune dysfunction
Duarte et al. (163) Group 1: Periodontally healthy subjects without DM Cross- Yes Levels of IL-1β and IL-6 in periodontally
(n = 10; 40% male, 60% female; mean age = 39.57 sectional inflamed tissue of patients with DM were
± 2.85). study significantly higher than those in the control
Group 2: Patients without DM, with moderate- group.
to-severe chronic periodontitis (n = 20; 33% male;
67% female; mean age = 37.50 ± 4.11).
Group 3: Patients with T2DM and periodontitis (n =
20; 40% male; 60% female; mean age = 40.86 ±
3.37).
Duarte et al. (170) Group 1: Periodontally healthy subjects without DM Cross- Yes Lower levels of IL-10 (an anti-inflammatory
(n = 10; 40% male, 60% female; mean age = 39.57 sectional cytokine) and OPG (an anti-resorption
± 2.85). study molecule) are observed in patients with DM.
Group 2: Patients without DM, with moderate- Together with the increased levels of their
to-severe chronic periodontitis (n = 20; 33% male; antagonists (IL-6 and RANKL, respectively), the
67% female; mean age = 37.50 ± 4.11). balance between bone resorption and
Group 3: Patients with T2DM and periodontitis (n = formation is negatively influenced by the
20; 40% male; 60% female; mean age = 40.86 ± diabetic state, leading to a greater periodontal
3.37). breakdown.

(Continued)

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 1 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Engebretson et al. Patients with T2DM (n = 45; 45% male, 55% Cross- Yes Higher levels of HbA1c were associated with
(162) female; mean age = 54.0 ± 9.8 years). sectional higher levels of the pro-inflammatory cytokine
study IL-1β in GCF. This was on its turn correlated
with worse clinical periodontal measures
(pocket depth, clinical attachment loss,
bleeding).
Engebretson et al. Group 1: Patients with T2DM (n = 45; 45% female, Cross- Yes Patients with DM showed an insufficient PMN
(175) 55% male; mean age = 54.2 years). sectional response in the crevice (measured in GCF),
Group 2: Control group without DM (n = 32; 47% study which may (partly) contribute to the
female; mean age = 42.0 years). development and severity of periodontal
disease.
Gyurko et al. (155) Group 1: Chronic hyperglycemia mice (Akita; n = Longitudinal Yes Mice with hyperglycemia had an exaggerated
28). animal study inflammatory response as their leukocytes were
Group 2: Age- and gender matched control mice primed for marginalization and superoxide
(wild-type C57BL/6; n = 28). production. However, transmigration was
impaired. This could contribute to periodontal
tissue damage by a weakened immune
response to periodontal pathogens as well as
by increased local production of free radicals.
Kardeşler et al. Group 1: Patients with periodontitis and T2DM (n = Cross- Unclear The researchers did find increased levels of
(165) 17; 5 males, 12 females; mean age = 47.35 ± 8.3) sectional certain cytokines associated with inflammation
Group 2: Patients with periodontitis, without DM study in the GCF of patients with DM, compared to
(n = 17; 9 males, 8 females; mean age = 49.12 ± the healthy control subjects. However, there
6.6) were no differences between group 1 (patients
Group 3: Systemically & periodontally healthy with DM and periodontitis) and group 2
controls (n = 17; 3 males, 14 females; mean age = (systemically healthy patients with
40.65 ± 6.7) periodontitis).
Kardeşler et al. Group 1: Patients with periodontitis and T2DM (n = Cohort study Yes After initial periodontal treatment, both groups
(164) 20; 13 males, 7 females; mean age = 53.6 ± 6.0 showed clinical improvement. However, after 1
years). month the situation in the group with DM
Group 2: Patients with periodontitis, without DM worsened, reflected by an increase in cytokines
(n = 22; 10 males, 12 females; mean age = 49.6 ± associated with increased inflammation,
8.2 years). measured in the GCF (IL-6, tPA, and PAI-2).
Lappin et al. (168) Patients with T1DM (n = 63; 30 males, 33 females), Cross- Yes Patients with DM displayed lower RANKL:OPG
divided as: sectional ratio, which would suggest that they are not
Group 1: “Low HbA1c ” (n = 30; mean age = 34 study susceptible for increased bone resorption via
years). that specific pathway. However, lower levels of
Group 2: “High HbA1c ” (n = 33; mean age = 40 osteocalcin (a marker for bone formation) were
years). also observed in patients with DM. It is
Group 3: Controls without DM (n = 38; 16 males, suggested that this causes an insufficient repair
22 females; mean age = 40 years). response following bone loss, explaining the
susceptibility for periodontal disease
progression often seen in patients with DM.
Liu et al. (160) Group 1: Diabetic rats (type-2 Zucker diabetic fatty Longitudinal Yes There was a significant difference in retention of
(ZDF)). animal study the inflammatory infiltrate (PMNs and
Group 2: Normoglycemic control rats. Periodontitis mononuclear cells) between diabetic and
was induced by tying silk ligatures soaked with non-diabetic rats after inducing experimental
Porphyromonas gingivalis around the maxillary periodontitis. Consequently, a greater
second molars or mandibular first molars, periodontal destruction was found in diabetic
rats.
Mahamed et al. Group 1: Diabetic mice (T1DM model, NOD/LtJ). Longitudinal Yes Diabetic mice presented higher alveolar bone
(169) Group 2: Normoglycemic mice. animal study breakdown compared to normoglycemic mice.
Periodontitis was induced by oral inoculation with The expression of RANKL by t-cells seemed to
Actinobacillus Actinomycetemcomitans. play an important role, and treatment with OPG
prevented alveolar bone loss.
Manouchehr-Pour Group 1: Patients with T1DM and severe Cross- Yes Patients with DM suffering from severe
et al. (173) periodontitis (n = 8). sectional periodontitis exhibited a significant decrease in
Group 2: Patients with T1DM and mild periodontal study neutrophil chemotaxis, compared to patients
disease (n = 6). with DM and mild periodontal

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 1 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Group 3: Patients without DM, with severe disease and patients without DM. Impaired
periodontitis (n = 7). PMN chemotaxis might contribute to the
Group 4: Patients without DM, with mild periodontal severity of periodontitis in patients with DM.
disease (n = 11).
McMullen et al. Group 1: Patients with a family history of diabetes, Cross- Yes Patients with a family history of DM had
(174) without overt DM themselves and with severe sectional impaired PMN chemotaxis, compared to
generalized alveolar bone loss (n = 24; 10 males, study patients without a family history of DM. They
14 females; mean age = 35.9 years). suggest that this impaired PMN function or
Group 2: Patients diagnosed with adult number predisposes a diabetes patient to
periodontitis, without family history of diabetes (n = develop more severe periodontal disease.
20; 10 males, 10 females; mean age = 41.8 years).
Group 3: Age- and gender matched healthy control
subjects.
Naguib et al. (161) Group 1: Diabetic mice (Db/db, n = 6). Longitudinal Yes Diabetic mice that were inoculated with a
Group 2: Normoglycemic mice (Db/+). animal study periodontal pathogen (Porphyromonas
gingivalis) presented a prolonged infiltration of
PMNs in the inflamed tissue, compared to the
non-diabetic mice.
Ross et al. (166) Group 1: Patients without DM and periodontitis (n = Cross- Yes There were significant differences in periodontal
8; 1 male, 7 females; mean age = 59 ± 15 years). sectional expression of IL-6 between all groups. Patients
Group 2: Patients without diabetes, with study with both periodontal disease and DM had the
periodontitis (n = 17; 11 males, 6 females; mean highest levels, the controls showed the lowest
age = 50 ± 13 years). expression.
Group 3: Patients with DM and periodontitis (n =
10; 6 males, 4 females; mean age = 57 ± 12 years).
Salvi et al. (158) Group 1: Patients with T1DM (n = 32; aged 22-81 Cross- Yes Patients with DM showed a significant higher
years). sectional monocytic TNF-α secretion in the presence of a
Group 2: Control subjects without DM (n = 17; study periodontal pathogen (Porphyromonas
aged 30-75 years). gingivalis), which is associated with an
increased periodontal disease severity.
Salvi et al. (157) Group 1: Patients with T1DM (n = 39; aged 22-81). Cross- Yes Concentrations of prostaglandin E2 (PGE2 ) and
Group 2: Healthy control subjects (n = 64; aged sectional IL-1β in the GCF of patients with DM was
20-73). study significantly higher compared to the
concentrations in subjects without DM.
Furthermore, as a response to exposure to
periodontal pathogens, monocytes in diabetic
produced more PGE2 and IL-1β than those in
controls.
Santos et al. (172) Group 1: Patients with well-controlled T2DM (n = Quasi- Yes Overall, RANKL/OPG ratios were higher in
18; 8 males, 10 females; mean age = 51.2 ± 9.9 experiment patients with poorly controlled DM.
years). Furthermore, after initial treatment, these ratios
Group 2: Patients with poorly controlled T2DM (n = decreased in the well-controlled patients, but
20; 9 males, 11 females; mean age = 53.4 ± 8.0 not in the poorly controlled. Therefore,
years). metabolic control seems to play a role in
periodontal bone resorption.
Sima et al. (156) Group 1: Diabetic mice (Akita). Cross- Yes The elevated blood glucose levels in diabetic
Group 2: Healthy mice (wild-type C57BL/6). sectional mice resulted in increased leukocyte
animal Study marginalization and macromolecule
extravasation in the gingival vasculature. This
represented a pro-inflammatory state, which
might contribute to periodontal disease.
Vieira Ribeiro et al. Group 1: Patients with T2DM and chronic Cross- Yes Higher levels of OPG, sRANKL, IFN-γ, IL-17,
(171) periodontitis (n = 37; 16 males; 21 females; mean sectional and IL-23 (pro-inflammatory) and lower levels
age = 52.5 ± 8.7). study of IL-4 (anti-inflammatory) were observed in the
Group 2: Systemically healthy subjects with chronic GCF of patients with DM, compared to control
periodontitis (n = 20; 8 males, 12 females; mean subjects.
age = 51.5 ± 8.3 years).

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; FPG, Fasting Plasma Glucose; LPS, Lipopolysaccharide; ARI, Aldose Reductase Inhibitor; (R)AGE, (Receptor for)
Advanced Glycation End Products; TNF-α, Tumor Necrosis Factor Alpha; IL, Interleukin (e.g., IL-1β or IL-6); PKC, Protein Kinase C; IRR, Incidence Rate Ratio; TC, Total Cholesterol;
TG, Triglycerides; LDL-c, Low-density Lipoprotein Cholesterol; HDL-c, High-density Lipoprotein Cholesterol; TELM, Telmisartan; MMP, Matrix Metalloproteinase; (s)RANK(L), (soluble)
Receptor Activator of Nuclear factor Kappa B (Ligand); OPG, Osteoprotegerin; GCF, Gingival Crevicular Fluid; PMN, Polymorphonuclear Neutrophil; tPA, Tissue Plasminogen Activator;
PAI-2, Plasminogen Activator Inhibitor-2; PGE2 , Prostaglandin E2 ; IFN-γ , Interferon Gamma.

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Verhulst et al. Oral Complications of Diabetes Mellitus

There is limited research available on the epidemiology of that an increased number of decayed teeth was associated with
caries and T2DM. Some papers found an increased prevalence of higher HbA1c levels (217, 218). A large Asian adult cohort
dental caries (202–206), which was supported by investigations investigated the relationship between dental caries and metabolic
using diabetic animal models (207–209). On the contrary, several syndrome (219). Metabolic syndrome is defined by having
studies did not find a significant association between T2DM and three of the following five components: hyperglycemia, elevated
caries (197, 210–212). triglycerides, lowered HDL levels, hypertension, and central
Longitudinal research with children and adults into the effect obesity. Multivariate analysis on these individual components
of DM on the development of dental caries is very rare. A revealed a significant association between dental caries and
prospective cohort study reported that poor glycemic control hyperglycemia (219). Another study also found a significant
was associated with increased caries incidence within T1DM association between dental caries and metabolic syndrome, but
children (192). No longitudinal studies are available on patients no relationships with the individual components were observed
with T2DM. (220). Reports about the downstream pathways of hyperglycemia
In general, the cross-sectional design of most studies, varying (polyol, AGEs, PKC, hexosamine) and upstream effects (ROS
definitions of dental caries that limit generalizability, and possible production) in relation to caries are lacking.
differences between the mostly young T1DM and the generally Interestingly, hyperglycemia results in increased levels of
older T2DM population, make it difficult to establish a clear glucose in saliva of patients with DM (221). This could be
epidemiologic association between DM and dental caries. It important, as glucose might serve as a source of nutrition for the
is worth noting that some studies even report a decreased cariogenic bacteria in the dental biofilm. Indeed, some studies
prevalence of dental caries in patients with DM (213, 214). It found an association between these increased salivary glucose
can be speculated that this remarkable finding could be ascribed levels and dental caries in patients with DM (192, 222), however,
to proper diabetes care management. As we know, lifestyle others did not (193, 196). Therefore, at this point, there is
adjustment and losing weight are important in diabetes care, inconclusive evidence that salivary hyperglycemia is associated
especially for T2DM. Nutritional management (i.e., restrictions with increased dental caries.
of carbohydrate intake) is a crucial part of the strategy to lose
weight. For T1DM, restrictions in carbohydrate intake could be a Insulin resistance
strategy to achieve reduction in insulin doses. The relatively low, One study compared the decayed, missing, and filled teeth
and/or more infrequent, intake of fermentable carbohydrates (DMFT) index—a marker for experienced and current caries—
might reduce the risk for developing dental caries (93). between obese, insulin-resistant (OB-IR) patients and healthy
controls. The DMFT index, as well as one of its components
Relationship With Diabetes Mellitus: Pathogenesis (decayed teeth), were increased in patients with insulin
In contrast to periodontal disease, less is known about biologic resistance (223).
explanations for the possible association between DM and dental
caries. Nevertheless, we will review the same five pathologic Dyslipidemia
mechanisms we discussed before. However, it is important Research into the involvement of dyslipidemia in dental caries is
to note several complicating factors. First, adult and elderly limited to those studies we mentioned above, which investigated
individuals with DM often suffer from periodontitis as discussed dyslipidemia as a component of metabolic syndrome. None
before. This is associated with gingival recession (i.e., receding of those found a relationship, as only hyperglycemia was
gums), which exposes dental root surfaces that then become significantly associated with decayed teeth (219, 220).
susceptible to root caries (183). As we will discuss in section
Dry Mouth below, patients with DM also often suffer from Hypertension
decreased salivary flow rates and altered saliva composition. A recent study with indigenous Brazilian adolescents revealed
Since saliva acts as a buffer against the acidic by-products that hypertension was significantly associated with dental caries
from the bacterial fermentation of carbohydrates, a change in (OR = 1.95, 95% CI: 1.03–3.66) (224). Another study found
mere quantity (i.e., hyposalivation) or composition of saliva a significant association between and dental caries—measured
could therefore influence that protective function against dental as DMFT and DMFS (Decayed, Missing due to caries, Filled
caries (203). For example, low salivary calcium and phosphate teeth/Surface)—and self-reported hypertension (225).
levels are associated with higher caries experience (215). Two
studies indeed found lower calcium and phosphate levels in Immune dysfunction: impaired immune response and
patients with DM, which was associated with higher caries proinflammatory state
prevalence (203, 204). There is no evidence that inflammation plays a role in dental
caries, as is the case for periodontitis or the chronic systemic
Hyperglycemia complications of DM. However, the impaired immune defense
Only a limited number of studies investigated the direct effect against opportunistic pathogens might influence the number
of hyperglycemia on dental caries. One animal study with of cariogenic bacteria in saliva and dental biofilm. Increased
diabetic rats showed that prevention of hyperglycemia by insulin counts of streptococci and lactobacilli were observed in the
treatment prevented the progression of dental caries (216). supragingival plaque (the biofilm on teeth along and above the
Studies with human subjects with either T1DM or T2DM found gum margins) of patients with DM, which was associated with

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Verhulst et al. Oral Complications of Diabetes Mellitus

increased caries incidence (213, 226). Another study showed undergoing bone marrow transplantation, HIV infection, and
that, especially in persons with poorly controlled DM, the renal failure (236).
presence of caries was associated with high levels of lactobacilli
and Streptococcus mutans, compared to patients with well- Relationship With Diabetes Mellitus: Epidemiology
controlled DM (199). One study proposed that elevated levels The experience of a dry mouth is one of the most frequently
of salivary glucose—presumably caused by obesity or DM— mentioned oral complaints by patients with DM. In a way, this
favors a relative abundance of aciduric bacteria that increases the is not surprising, considering the fact that the population with
risk for developing dental caries (227). Others did not find any T2DM generally consists of relatively older individuals, and we
differences in cariogenic bacteria in saliva between patients with now know that the prevalence of xerostomia and hyposalivation
and without DM (210). increases with age. Also, many patients with DM suffer from
one or more complications and/or comorbidities, for which
Concluding Comments they possibly receive medication that increases the risk for oral
Summarizing the findings of the studied literature in Table 2, dryness (e.g., anti-cholinergic and anti-hypertensive medication).
it becomes clear that several studies observe an increased Varying definitions and methods of diagnosing hyposalivation
prevalence of dental caries in patients with DM. Although and xerostomia make it difficult to establish a direct association
it is conceivable that caries and DM are associated, the with DM. Nevertheless, many cross-sectional studies reported a
lack of longitudinal research prevents us from making causal diminished salivary flow rate in patients with DM, compared to
assumptions. Moreover, it is not clear whether the increased control subjects without DM. This finding applies for patients
prevalence is a direct result of DM, or that other factors with T1DM (237–243), as well as for individuals with T2DM
contribute to the association. For example, certain lifestyle (204, 206, 239, 241, 244–252). However, it should be noted that
aspects, such as an unhealthy diet with high carbohydrates intake, in several of these studies, the measured decrease in salivary flow
increases the risk for DM as well as for dental caries. rate did not necessarily fulfill the earlier mentioned criteria to be
classified as hyposalivation. This could be one of the reasons why
Dry Mouth some studies did not find an increased prevalence of xerostomia
Background in patients with T1DM (237, 253) or T2DM (243, 244, 253).
The term “dry mouth” can be interpreted in several ways. Usually, This is supported by the suggestion that in general, a salivary
two distinctive phenomena are referred to in literature when flow rate above the threshold of 0.1–0.3 mL/min is sufficient
speaking of dry mouth. The first is the objective measurement to prevent xerostomia in most individuals (254). Still, there
of reduced salivary flow rate, called hyposalivation or salivary is sufficient literature that reports an increased prevalence of
gland hypofunction. This is usually defined as “an unstimulated xerostomia in patients with T1DM (240, 241, 243, 255–257) and
whole saliva flow rate of <0.1 mL/min, collected for 5 to 15 min, T2DM (206, 247, 248, 257, 258).
or chewing-stimulated whole saliva flow rate of <0.7 mL/min,
collected for 5 min” (228). The second condition often referred Relationship With Diabetes Mellitus: Pathogenesis
to as “dry mouth” is xerostomia, which addresses the subjective Although many cross-sectional studies report an increased
experience of a dry mouth by the patient (229). Even though these prevalence of xerostomia and a decreased salivary flow rate in
conditions are closely related, patients with hyposalivation do patients with DM, the mechanisms underlying these observations
not necessarily suffer from xerostomia. And vice versa, although remain unclear. Secretion of saliva by the parotid gland—the
many patients with xerostomia do actually have underlying largest salivary glands—is regulated by the autonomic nervous
hyposalivation, this is not always the case. This suggests that system, which led to the hypothesis that diabetic neuropathy
other mechanisms could partly explain the dry mouth sensation might somehow be involved in the development of dry mouth
in some patients, such as a change in saliva composition, a experience. However, studies investigating this theory present
sensory dysfunction or a cognitive problem (230–232). contradictory results. Decreased (240, 259), comparable (241,
When defining hyposalivation as an unstimulated whole saliva 260), or even increased (261) salivary flow rates are observed in
flow rate of <0.1 mL/min, research showed that approximately patients with DM, having peripheral or autonomic neuropathy,
20% of individuals across all ages were affected, while the compared to subjects without DM and/or patients with DM
prevalence was ∼3% when using the stimulated whole saliva without neuropathy. It should be noted that tricyclic anti-
flow rate definition (<0.7 mL/min) (233). The prevalence of depressants, sometimes prescribed to relieve neuropathic pain,
xerostomia is subject of discussion, as estimations in literature are associated with the development of dry mouth and therefore
range from 1 to 65% (234). This wide range is mainly the is another xerogenic drug (235).
result of high variation in defining xerostomia and methods of There are a few studies that actually observed structural
diagnosis, and implies that there is need for large population- changes in the salivary glands of patients with DM, in
based research. However, it is clear that the prevalence of both particular in the parotid glands. Vacuolization of acini (the
conditions increases with age (234). Furthermore, medication use saliva secretory cells) in the parotid gland was observed, which
is one of the major causes of both xerostomia and hyposalivation indicated an early form of degeneration (262). Another study
(235), as well as Sjögren syndrome and radiation therapy of also showed atrophy of the acini, lipid droplets in epithelial
the head and neck region (229). Xerostomia is also associated cells of the acini and ducts, and adipose infiltration in the
with several autoimmune diseases, graft-vs.-host disease after stromae (263). On the contrary, a study into the submandibular

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 2 | Overview of studies investigating the association between diabetes mellitus and dental caries.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
Alves et al. (195) Group 1: Patients with T1DM (n = 51; 56% male, 44% Cross- No No significant difference was found in DMFT
female; mean age = 11.3 ± 3.4 years). sectional and def-t between patients with DM and
Group 2: Control subjects without DM (n = 51; 37% study controls.
male, 63% female; mean age = 11.9 ± 3.4 years).
Arheiam and Omar Group 1: T1DM children (n = 70; 45 males, 25 females; Cross- Yes Children with DM showed higher means for the
(185) mean age = 11.66 ± 1.44 years). sectional amount of decayed teeth and missing teeth,
Group 2: Control subjects without DM (n = 70; 45 study compared to healthy controls.
males, 25 females; mean age = 11.63 ± 1.54 years).
Saes Busato et al. Group 1: Patients with T1DM (n = 51; 24 males, 27 Cross- Yes A significantly higher DMF index was observed
(194) females; mean age = 17 years, range 14–19 years). sectional in patients with DM, compared to controls. No
Group 2: Age- and gender matched control subjects study influence of metabolic control was found,
without DM (n = 51). possibly caused by the small sample size.
Cherry-Peppers Group 1: Patients with T2DM (n = 11; mean age = 67.9 Cross- Yes More coronal caries were present in patients
and Ship (186) ± 11.1 years). sectional with DM compared to the other groups.
Group 2: Patients with impaired glucose tolerance (n = study
32; mean age = 60.7 ± 19.1 years).
Group 3: Control subjects without DM (n = 43; mean
age = 60.2 ± 16.8 years).
Collin et al. (210) Group 1: Patients with T2DM (n = 25; 3 males, 22 Cross- No No difference in prevalence of root and coronal
females; mean age = 67 years, range 58–76 years). sectional caries was observed in patients, compared to
Group 2: Control subjects without DM (n = 40; 21 males, study controls.
19 females; mean age = 66 years, range 59–77 years).
Edblad et al. (187) Group 1: Young adults with T1DM (n = 41; 15 males, 26 Cross- Yes Patients with DM showed more initial buccal
females; mean age = 21 ± 1.6 years). sectional caries, compared to the healthy controls.
Group 2: Age- and gender matched healthy controls study
(n = 41).
Gómez-Díaz et al. Patients with T1DM (n = 69; 36 males, 33 females; Cross- Yes More buccodental conditions were found in
(188) range 6–17 years old), subdivided in: sectional patients with poorly controlled DM (HbA1c
Group 1: Well controlled (HbA1c ≤7.0%). study >8.5%).
Group 2: Moderately controlled (HbA1c 7.1–8.5).
Group 3: Poorly controlled (HbA1c >8.5%).
Hintao et al. (202) Group 1: Patients with T2DM (n = 105; 50.5% female; Cross- Yes Patients had a higher prevalence of root
mean age = 54.3 ± 8.7 years). sectional surface caries and a higher number of decayed
Group 2: Control subjects without DM (n = 103; 50.5% study or filled root surfaces compared with subjects
female; mean age = 53.3 ± 7.6 years). without DM.
Jawed et al. (204) Group 1: Patients with T2DM (n = 400; mean age = Cross- Yes A higher DMFT score was observed in patients,
41.0 ± 9.7 years). sectional compared to controls. The role of glycemic
Group 2: Age- & gender matched controls without DM study control, salivary flow and salivary calcium level
(n = 300; mean age = 41.6 ± 11.3 years). were pointed out.
Jawed et al. (203) Group 1: Patients with T2DM (n = 398; 198 males, 200 Cross- Yes A higher DMFT score was seen in patients,
females; mean age = 40.2 ± 9.0 years). sectional compared to controls. Also, a role of glycemic
Group 2: Healthy controls without DM (n = 395; 194 study control was observed.
males, 201 females; mean age = 39.9 ± 10.6 years).
Johnston and 1,281 subjects, aged 6–94 years (mean age = 47.71 Cross- Yes Cross-sectional analysis of the subjects
Vieira (225) years). No data about the number of subjects with DM. sectional regarding caries experience and systemic
study diseases revealed a significant association
between dental caries and DM.
Jones et al. (205) Group 1: Adults with non-specified DM (n = 642; 78% Cross- Yes Patients suffered from a higher rate of caries
dentate). sectional than controls.
Group 2: “General population”, represented by the Adult study
Dental Health Survey (ADHS) (n = 916; 77% dentate).
Kodama et al. Group 1: Type 1 diabetic rats (type: WBN/KobSlc). Longitudinal Yes The diabetic conditions in the rats lead to
(208) Group 2: Age- and gender matched non-diabetic rats animal study elevated and more advanced caries
(type: F344). development, compared to the non-diabetic
rats.
Lin et al. (212) Group 1: Patients with T2DM (n = 24; 10 males, 14 Cross- No After correction for the available teeth surfaces,
females; mean age = 71 years, range 54–85 years). sectional the prevalence of coronal and root-surface
Group 2: Controls without DM (n = 18; 10 males, 8 study caries was not increased in patients with DM.
females; mean age = 73 years, range 57–86 years).

(Continued)

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TABLE 2 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Marín et al. (197) Group 1: Patients with T1DM (n = 35; HbA1c of 6.5–7%). Cross- No No differences between patients with DM and
Group 2: Patients with T1DM (n = 35; HbA1c >7%). sectional controls were found with regard to dental
Group 3: Controls without T1DM (n = 35). study caries.
Group 4: Patients with T2DM (n = 35).
Group 5: Controls without T2DM (n = 35).
Miko et al. (189) Group 1: Patients with T1DM (n = 259; aged 14–19 Cross- Yes A higher DMFT and an increased number of
years old). sectional filled teeth were found in patients with T1DM,
Group 2: Age- and gender matched control subjects study compared to the control group. The number of
without DM (n = 259). decayed teeth was lower in patients with DM,
which the authors ascribe to early dentist
consultation and treatment of caries in that
group.
Miralles et al. (190) Group 1: Patients with T1DM, (n = 90; aged 18–50 Cross- Yes DM patients showed a higher prevalence
years old). sectional (authors incorrectly report incidence) of caries
Group 2: Matched controls without DM (n = 90). study (measured as CAO index). Poor metabolic
control (HbA1c >7.5%), disease duration and
the presence of other complications were not
associated with caries.
Moore et al. (196) Group 1: Patients with T1DM (n = 390; 199 males, 191 Cross- No Patients with DM did not show higher DFS
females; mean age = 32.6 ± 0.4 years). sectional compared to controls. A slightly increased
Group 2: Controls (n = 202; 76 males, 126 females; study RDFS was observed, which was associated
mean age = 33.0 ± 0.5 years). with periodontal disease at older age.
Rai et al. (191) Group 1: T1DM children (n = 100, aged 6–12 years). Cross- Yes A higher caries prevalence (authors incorrectly
Group 2: Matched children without DM (n = 100). sectional report incidence) was seen in patients with DM,
study compared to healthy controls.
Sandberg et al. Group 1: Patients with T2DM (n = 102; 64 males, 38 Cross- Yes Patients with DM displayed an increase in initial
(206) females; mean age = 64.8 ± 8.4 years). sectional caries lesions compared to the controls without
Group 2: Control subjects without DM (n = 102; 64 study DM, as well as a larger need for caries
males, 38 females; mean age = 64.9 ± 8.5 years). prevention.
Sano et al. (209) Group 1: Type 2 diabetic mice (db/db, 9 males, 11 Cross- Yes The diabetic mice showed a higher prevalence
females). sectional of dental caries, compared to the control mice.
Group 2: Non-diabetic mice (db/+, 9 males, 9 females). animal study
Swanljung et al. Group 1: Patients with T1DM (n = 85; mean age = 15.1 Cross- No The patients with DM did not show a
(198) ± 1.5 years). sectional significantly higher DMF, DMFS or initial caries
Group 2: Age- & gender matched controls (n = 85; study lesions compared to the controls. Important
mean age = 15.1 ± 1.6 years). note: all patients with DM were well regulated.
Tagelsir et al. (200) Group 1: Patients with T1DM (n = 52; 29 males, 23 Cross- No There was no significant difference in caries
females; aged 3–16 years). sectional experience between patients and controls.
Group 2: Matched healthy controls (n = 50; 28 males study
and 22 females; aged 2–16 years).
Tavares et al. (201) Group 1: Patients with T1DM (n = 88; 61.1% male, Cross- No No significant differences in numbers of buccal
38.9% female; mean age = 55.7 ± 7.1). sectional surface sites with gingival recession or in
Group 2: Controls without DM (n = 185; 47.6% male, numbers of root caries were found between the
52.4% female; mean age = 56.3 ± 5.2). patients with DM and the control subjects.
Yeh et al. (207) Group 1: Type 1 diabetic mice (Ins2 Akita mice, i.e., Longitudinal Yes A strong link between glycemic control and
Akita–/–). animal study salivary dysfunction was found. The
Group 2: Age- and gender matched wild-type control combination of hyperglycemia and
mice (Akita +/+). hyposalivation had a negative influence on
enamel mineralization, increasing the risk for
tooth decay.
PATHOGENESIS
Hyperglycemia
Bakhshandeh Dentate patients with DM (both T1DM and T2DM; n = Cross- Yes An association between metabolic control
et al. (218) 299; mean age = 49 ± 7.6 years). sectional (HbA1c >8.5%). and duration of DM (≥ 7
study years) and mean DMFT was found in men, not
in women.
Cao et al. (219) Group 1: Patients with MetS (n = 3,571; 70.9% male, Cross- Yes After adjustment for multiple confounders,
29.1% female; mean age = 53.7 ± 5.9 years). sectional stratified regression analysis showed an
Group 2: Patients without MetS (n = 10,427; 55.4% study association between dental caries and
male, 44.6% female; mean age = 52.4 ± 5.8 years). hyperglycemia as part of MetS (OR = 1.14,
95% CI: 0.98–1.34).

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 2 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Siudikiene et al. Group 1: Patients with T1DM (n = 68, aged 10–15 years Cross- Unclear In the total population, patients with DM even
(213) old). sectional showed fewer caries compared to the controls.
Group 1a: Patients with well-to-moderately controlled study However, amongst patients with DM,
T1DM (n = 39; HbA1c <9%). well-to-moderately regulated patients had
Group 1b: Patients with poorly controlled T1DM (n = 29; fewer caries, compared to poorly regulated
HbA1c ≥9.0%). patients.
Group 2: Age- & gender matched controls (n = 68).
Syrjälä et al. (199) Patients with T1DM (n = 149; 87 males, 62 females; Cross- No HbA1c levels were not directly associated with
mean age = 34.1 ± 12.4 years). sectional caries prevalence. However, in poorly regulated
study patients (HbA1c >8.5%), a positive association
of mutans streptococci and lactobacilli with
dental caries was found.
Timonen et al. Group 1: Patients with MetS (n = 337; 50.7% male, Cross- No Despite a significant association between MetS
(200) 49.3% female; mean age = 48.5 ± 0.5 years). sectional as a whole and dental caries, no independent
Group 2: Subjects without MetS (n = 1,713; 37% male, study association was found between hyperglycemia
63% female; mean age = 45.5 ± 0.2 years) . (as a component of MetS) and caries after
multiple adjustments.
Twetman et al. Children with T1DM (n = 64; 32 males, 32 females; Prospective Yes Children with poor glycemic control (HbA1c
(192) mean age = 11.2 years, range 8–15 years). cohort study >8.0%) showed a higher 3-year incidence of
caries, compared to children who were well
controlled (HbA1c ≤8.0%). Other risk factors
included: poor oral hygiene, previous caries
experience and high levels of salivary
lactobacilli.
Yonekura et al. Group 1: Patients with well-controlled T2DM (n = 24; 15 Cross- Yes The prevalence of decayed teeth (DT) was
(217) males, 9 females; mean age = 64.5 years). sectional higher in patients with poorly controlled T2DM.
Group 2: Patients with poorly controlled T2DM (n = 84; study Logistic regression analysis showed significant
48 males, 36 females; mean age = 59.0 years). association between HbA1c levels and the
absolute number of DT.
Insulin resistance
Loyola-Rodriguez Group 1: Patients with obesity and insulin resistance (n = Cross- Yes Obese patients with insulin resistance showed
et al. (223) 50; 23 males, 27 females; mean age = 13.0 ± 1.2 sectional a higher DMFT index and number of decayed
years). study teeth, compared to the control group. A
Group 2: Healthy controls (n = 50; 21 males, 29 multivariate regression analysis revealed odds
females; mean age = 13.1 ± 1.1 years). ratios for insulin resistance of 3.1 for DMFT
index and 3.3 for decayed teeth.
Timonen et al. Group 1: Patients with MetS (n = 337; 50.7% male, Cross- No Despite a significant association between MetS
(200) 49.3% female; mean age = 48.5 ± 0.5 years). sectional as a whole and dental caries, no independent
Group 2: Subjects without MetS (n = 1713; 37% male, study association was found between insulin
63% female; mean age = 45.5 ± 0.2 years) . resistance (as a component of MetS) and
caries after multiple adjustments.
Dyslipidemia
Cao et al. (219) Group 1: Patients with MetS (n = 3,571; 70.9% male, Cross- No After adjustment for multiple confounders,
29.1% female; mean age = 53.7 ± 5.9 years). sectional stratified regression analysis showed no
Group 2: Patients without MetS (n = 10,427; 55.4% study association between dental caries and
male, 44.6% female; mean age = 52.4 ± 5.8 years). dyslipidemia (OR=1.01 for hypertriglyceridemia
[95% CI: 0.85–1.19] and 0.84 for low HDL-c
[95% CI: 0.70–1.00]).
Timonen et al. Group 1: Patients with MetS (n = 337; 50.7% male, Cross- No Despite a significant association between MetS
(200) 49.3% female; mean age = 48.5 ± 0.5 years). sectional as a whole and dental caries, no independent
Group 2: Subjects without MetS (n = 1713; 37% male, study association was found between dyslipidemia
63% female; mean age = 45.5 ± 0.2 years) . (as a component of MetS) and caries after
multiple adjustments.
Hypertension
Cao et al. (219) Group 1: Patients with MetS (n = 3,571; 70.9% male, Cross- No After adjustment for multiple confounders,
29.1% female; mean age = 53.7 ± 5.9 years). sectional stratified regression analysis showed no
Group 2: Patients without MetS (n = 10,427; 55.4% study association between dental caries and
male, 44.6% female; mean age = 52.4 ± 5.8 years). hypertension (OR=0.96; 95% CI: 0.86–1.13).

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 2 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Johnston and 1,281 subjects, aged 6–94 years (mean age = 47.71 Cross- Yes Both primary (DMFT) and secondary (DMFS)
Vieira (225) years). No data about the number of subjects with DM. sectional caries experience were independently
study associated with hypertension.
Ribeiro et al. (224) Adult subjects (n = 225, 101 males, 124 females; 60.9% Cross- Yes Patients with hypertension (n = 54) had a
aged 19–34, 39.1% aged ≥35). sectional higher prevalence of dental caries (55.6%),
study compared to subjects without hypertension
(n = 171, 38.6%). Logistic regression analysis
revealed an independent association between
hypertension and dental caries (OR = 1.95;
95% CI: 1.03–3.66)
Timonen et al. Group 1: Patients with MetS (n = 337; 50.7% male, Cross- No Despite a significant association between MetS
(200) 49.3% female; mean age = 48.5 ± 0.5 years). sectional as a whole and dental caries, no independent
Group 2: Subjects without MetS (n = 1713; 37% male, study association was found between hypertension
63% female; mean age = 45.5 ± 0.2 years) . (as a component of MetS) and caries after
multiple adjustments.
Immune dysfunction
Collin et al. (210) Group 1: Patients with T2DM (n = 25; 3 males, 22 Cross- No There was no difference in cariogenic
females; mean age = 67, range 58–76). sectional microorganisms and yeasts between patients
Group 2: Control subjects without DM (n = 40; 21 study with or without DM. It should be noted that
males, 19 females; mean age = 66, range 59–77). they also did not find a higher prevalence of
dental caries.
Goodson et al. Adolescents (n = 8,173; 38.9% male, 61.1% female; Cross- Yes Increasing salivary glucose levels—presumably
(227) mean age = 10.0 ± 0.7 years). sectional caused by obesity and/or DM—reduced the
study total bacterial load in saliva. The authors
hypothesize that glucose metabolism by
acidogenic bacteria lowers the salivary pH,
which disturbs the oral microbiome and favors
cariogenic bacteria species.
Kampoo et al. Group 1: Patients with T2DM (n = 20; 5 males, 15 Cross- Yes Patients with DM showed higher numbers of
(226) females; mean age = 56.4 years). sectional total streptococci and lactobacilli in
Group 2: Control subjects without DM (n = 11; 4 males, supragingival plaque, compared to the control
7 females; mean age = 37.1 years). subjects. Lactobacillus numbers were also
increased in saliva and supragingival plaque of
patients with DM and active caries, compared
to patients with DM, without active caries.
Siudikiene et al. Group 1: Patients with T1DM (n = 68, aged 10-15 years Cross- Yes Patients with DM showed more frequent
(213) old). sectional presence of yeasts, and poorly controlled
Group 2: Age- & gender matched controls (n = 68). study patients also had higher numbers of mutans
streptococci.
Syrjälä et al. (199) Patients with T1DM (n = 149; 87 males, 62 females; Cross- Yes In poorly regulated patients (HbA1c ≥8.5%), a
mean age = 34.1 ± 12.4) sectional positive association of mutans streptococci
study and lactobacilli with dental caries was found.

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; DMF(T/S), Decayed, Missing, Filled (Teeth/Surfaces); Def-t, Decayed, extracted, filled tooth index; CAO, Caried, Absent
and Obturated teeth index; (R)DFS, (Root) Decayed and Filled Surfaces; MetS, Metabolic Syndrome; DT, Decayed Teeth.

gland of patients with T2DM observed enlargement of the Hyperglycemia

acini, independent of impaired glandular function or metabolic In general, patients with poor glycemic control present
control. This might indicate a compensatory mechanism to significantly lower salivary flow rate and higher prevalence of
counteract hyposalivation (264). Asymptomatic enlargement of xerostomia, compared to subjects with well-controlled DM (240,
the parotid gland is also frequently observed in patients with 241, 244, 245). This suggests that, again, hyperglycemia is a
DM, which could indicate similar compensatory mechanisms driving force in the pathogenic association between DM and dry
against hyposalivation or xerostomia (265). The pathological mouth. However, the downstream pathways of hyperglycemia
mechanisms of how DM contributes to these structural changes (polyol, AGEs, PKC, and hexosamine) are completely unexplored
are still matter of discussion, and solid research is scarce. Below, in human study subjects, as well as the common upstream
we summarize possible mechanisms of action how DM might effect of increased oxidative stress. One animal study suggests
induce xerostomia or hyposalivation, again via the established that the expression of AGEs and RAGE in the lacrimal glands
pathological mechanisms of diabetic complications. (which secrete the aqueous layer of the tear film) might cause

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Verhulst et al. Oral Complications of Diabetes Mellitus

eye dryness (266). Theoretically, that could also account for Immune dysfunction: impaired immune response and
the salivary glands, causing oral dryness. Indeed, submandibular proinflammatory state
salivary glands of diabetic rats also showed increased expression As described above, DM and its metabolic disturbances could be
of RAGE, which resulted in an inflammatory upregulation associated with dry mouth, sometimes mediated by inflammatory
through NF-κB activation (267). However, this hypothesis processes. However, this remains rather speculative, since most
has not been studied in humans so far and demands of those studies investigated diabetic animal models. Moreover,
further research. the inflammatory state observed in some studies did not
Hyperglycemia in patients with DM can cause polyuria necessarily affect salivary flow rate, xerostomia or salivary
and osmotic diuresis, possibly leading to dehydration, which gland morphology.
is associated with hyposalivation (268, 269). Also, a fairly Some studies suggest that Sjögren syndrome—an
novel class of antidiabetic drugs (SGLT-2 inhibitor) prevents autoimmune disease affecting the salivary glands—could
reabsorption of glucose in the kidneys, and thereby increases be the underlying cause of dry mouth in patients with DM
urinary glucose excretion (i.e., glycosuria). This could lead to (277, 278). However, there is no convincing evidence for
dehydration and increased thirst, both associated with oral this hypothesis.
dryness (270). Other xerogenic medications that patients with
DM often need (e.g., anti-hypertensives) might also partly explain Concluding Comments
the association between DM, hyperglycemia and reduced salivary Dry mouth is a very often heard complaint by patients with DM,
flow or xerostomia (241). and the majority of epidemiological studies indeed report an
increased prevalence of xerostomia and a decreased salivary flow
Insulin resistance rate. Especially poor glycemic control negatively impacts both the
prevalence and severity of dry mouth. Older age, dehydration
Research into the role of insulin resistance in the pathogenesis
and medication use also seem to be important determinants
of hyposalivation and xerostomia is limited to a few animal
in this association. However, there is hardly any research into
studies. Increased ROS production, an upregulated inflammatory
other pathogenic pathways that could explain the association
response (271) and an altered lipid profile (272) were observed in
between DM and dry mouth, and longitudinal studies are also
the submandibular and parotid salivary gland of insulin resistant
lacking. Table 3 summarizes the literature on which this section
rats. The pro-inflammatory state observed in salivary glands did
was based.
not alter their structural morphology (273).
Oral Mucosal Lesions
Dyslipidemia Background
As we mentioned earlier, some studies observed an accumulation The name oral mucosal lesion is used as an umbrella term
of lipid droplets in epithelial cells of the salivary glands (263, for any abnormal change to the mucosal surface in the oral
264). This might be the consequence of the excess flux of free cavity. This concerns numerous different types of lesions, and
fatty acids (FFAs), resulting from insulin resistance (see section it is beyond the scope of this review to discuss them all
Insulin Resistance). In several tissue types, accumulation of lipids individually. Often, oral mucosal lesions are classified based on
induces lipotoxicity, which can lead to cell apoptosis (274). It is the pathology, morphology, or location of the lesion. Shulman
hypothesized that these processes could also affect the salivary et al. classify: “candida-related lesions, tobacco-related lesions,
glands and thereby cause hyposalivation, but this theory has acute conditions, tongue conditions, red/white conditions, raised
not been investigated yet (264). As a matter of fact, to the conditions, and other conditions.” Possible locations where
best of our knowledge, the independent role of dyslipidemia mucosal lesions can be observed are: the hard palate, gingiva,
in the association between xerostomia/hyposalivation and lip, tongue, buccal mucosa, vestibule, labial mucosa, commissure,
DM has not been investigated in humans. One animal floor of the mouth, and the soft palate (279).
study showed that saturated fatty acids (SFAs) induced an Despite the heterogeneity of oral mucosal lesions, several
inflammatory response, reflected by increased production studies tried to estimate their prevalence. A large epidemiologic
of IL-6 through NF-κB activation in the salivary glands study from the U.S. (17,235 individuals >17 years old) concluded
epithelial cells (275). that 27.9% of the population had at least one lesion (279). In a
German population, 33.8% of adults aged 35–44 years and 33.9%
Hypertension of adults aged 65–74 years were without any oral mucosal lesion
One study showed that patients with hypertension and without (280). Somewhat similar figures were reported in a Slovenian
DM had reduced submandibular and sublingual salivary flow population aged 25–75 years, where 38.4% had no oral mucosal
rates, compared to healthy controls. The salivary flow rates of lesions (281). A Chilean study showed a prevalence of 53% for
the hypertensive patients were comparable with those of patients one or more oral mucosal lesions, although in this study, only
with DM, while stimulated parotid and unstimulated whole individuals older than 65 years were included (282). From the
salivary flow did not differ across the groups. However, it was majority of studies, it can be concluded that tobacco use seems
not clear whether these differences were a consequence of the to be the most important risk factor for having any type of
hypertension itself, possible anti-hypertensive medication use, oral mucosal lesions, followed by (ill-fitting) removable dentures.
or both (276). The prevalence of oral mucosal lesions increases with age and

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 3 | Overview of studies investigating the association between diabetes mellitus and dry mouth.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
Ben-Aryeh et al. Group 1: Patients with T1DM (n = 35; 20 males, 15 Cross- Yes Patients with DM showed significantly lower salivary
(237) females; mean age = 31.2 ± 7.4 years). sectional flow. Also, higher glucose, potassium and protein
Group 2: Control subjects without DM (n = 31; 17 study levels were seen in saliva of patients with DM,
males, 14 females; mean age = 29.0 ± 6.2 years). indicating affected salivary gland. No differences in
xerostomia experience were observed.
Ben-Aryeh et al. Group 1: Patients with T1DM (n = 20; mean age = Cross- No Patients with T1DM showed a significantly lower
(253) 38.9 ± 13.7 years). sectional salivary flow compared to patients with T2DM, but
Group 2: Patients with T2DM (n = 19; mean age = study not compared to controls. Potassium and IgA
45.9 ± 11.2 years). concentrations were different between the groups.
Group 3: Healthy controls (n = 35; mean age = No difference in the complaint of xerostomia was
40.4 ± 12.0 years). observed between the groups.
Busato et al. (255) Group 1: Patients with T1DM (n = 51; 24 males, 27 Cross- Yes DM appeared to be associated with a high
females; mean age = 17 ± 1.4, range 14–19). sectional prevalence of xerostomia, which in turn was
Group 2: Age- and gender matched controls study predictive of a poor oral health related quality of life.
without DM (n = 51).
Carda et al. (258) Group 1: Patients with T2DM (n = 17; 10 males, 7 Cross- Yes Xerostomia was observed more often in patients
females; mean age = 68, range 26–86 years). sectional with DM. Increased levels of urea and proteins were
Group 2: Control subjects (n = 16; 8 males, 8 study found in saliva of patients with DM, while albumin
females; mean age = 48, range 26–86 years). was decreased. Increased levels of salivary glucose
were associated with poor metabolic control.
Ivanovski et al. Group 1: Patients with T1DM (n = 60). Cross- Yes The authors conclude that patients with DM have
(256) Group 2: Control subjects without DM (n = 60). sectional significantly higher salivary levels of urea and
Both males and females (proportion not given), study glucose. Also, they claim diabetes causes
aged 30–70 years. xerostomia, and a significant correlation exists
between the degree of xerostomia and the salivary
glucose concentrations.
Jawed et al. (204) Group 1: Patients with T2DM (n = 400; mean age = Cross- Yes Patients with DM had a lower salivary pH, flow rate,
40.9 ± 9.7 years). sectional and calcium levels compared to controls. Fasting
Group 2: Age- and gender matched controls (n = study blood glucose, HbA1c , and DMFT score were
300; mean age = 41.6 ± 11.3 years). significantly increased in patients with DM.
Kao et al. (246) Group 1: Patients with T2DM and xerostomia (n = Cross- Yes Patients with DM and xerostomia (group 1) showed
20; 13 males, 7 females; mean age = 54.2 ± 14.5 sectional significantly lower saliva production and excretion,
years). study compared to the other two groups.
Group 2: Patients with T2DM, without xerostomia
(n = 20; 13 males, 7 females; mean age = 55.2 ±
13.4 years).
Group 3: Healthy age- and gender matched
controls (n = 36; 23 males, 13 females; aged 56.2
± 13.3 years).
Karjalainen et al. Group 1: Newly diagnosed T1DM children (n = 14; Cross- Yes At initial T1DM diagnosis, hyperglycemia was
(242) 7 boys, 7 girls; mean age = 11 ± 2.4 years). sectional reflected as increased levels of salivary glucose and
Group 1: Patients with long-term T1DM (n = 50; 30 a decreased salivary flow. Patients with long-term
males, 20 females; mean age = 14.4 ± 1.7 years). diabetes did not show such a clear relationship.
Khovidhunkit et al. Group 1: Patients with T2DM (n = 154; 37 males, Cross- Yes A significantly higher prevalence of xerostomia and
(247) 117 females; mean age = 63 ± 10 years). sectional hyposalivation was observed in patients with DM,
Group 2: Control subjects without DM (n = 50; 12 study compared to the subjects without DM.
males, 38 females; mean age = 65 ± 10 years).
Lasisi and Group 1: Patients with T2DM (n = 20; 10 males, 10 Cross- Yes Patients with DM showed reduced salivary flow, and
Fasanmade (252) female; mean age = 58.4 years). sectional increased salivary concentrations of glucose and
Group 2: Controls without DM (n = 20; 11 males, 9 study potassium. Total protein, Na+ , Ca2+ , Cl− , and
female; mean age = 50.2 years). HCO− 3 concentrations did not differ.
Lin et al. (248) Group 1: Patients with T2DM and xerostomia (n = Cross- Yes Salivary scintigraphy revealed that salivary function
36; 23 males, 13 females; mean age = 56.3 ± 14.2 sectional (expressed as production and secretion) was
years). study significantly lower in patients with DM and
Group 2: Patients with T2DM, without xerostomia xerostomia, compared to patients with DM, without
(n = 36; 23 males, 13 females; mean age = 56.0 ± xerostomia and healthy controls.
13.9 years).
Group 3: Healthy controls (n = 36; 23 males and 13
females; mean age = 56.2 ± 13.3 years).

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TABLE 3 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

López et al. (238) Group 1: Children with T1DM (n = 20; 9 males, 11 Cross- Yes Children with diabetes showed a lower salivary pH,
females; mean age = 9.4 ± 3.9 years). sectional a decreased flow, higher concentrations of sugars,
Group 2: Clinically healthy children (n = 21; 9 males, study glucose, urea, and total proteins and decreased
12 females; mean age = 8.3 ± 1.8 years). levels of calcium, compared to the controls.
Malicka et al. (243) Group 1: Patients with T1DM (n = 34; 16 males, 18 Cross- Yes A significantly decreased salivary flow and increased
females; mean age = 37.5 years). sectional prevalence of xerostomia were observed in patients
Group 2: Patients with T2DM (n = 59; 31 males, 28 study with T1DM compared to controls. For patients with
females; mean age = 65 years). T2DM, these differences were not significant, but a
Group 3: Healthy, age- and gender matched trend was observed.
controls (n = 63).
Mata et al. (239) Group 1: Patients with T1DM (n = 30; age range Cross- Yes Patients with DM showed a significant decrease in
20–30 years) and patients with T2DM (n = 30; age sectional salivary flow and secretion capacity, while protein
range 40–55). study and Ca2+ levels were increased. Levels of Mg2+ ,
Group 2: Two groups of age matched controls (2 Zn2+ , and K+ were significantly lower compared to
times n = 30). the control group.
Montaldo et al. Group 1: Patients with T2DM (n = 134; 56 males, Cross- Yes Mean salivary flow appeared to be lower in the
(251) 78 females; mean age = 47.9 ± 2.9 years). sectional diabetes group, compared to the control group.
Group 2: Healthy controls (n = 111; 49 males, 62 study
females; mean age = 44.9 ± 5.8 years).
Quirino et al. (249) Group 1: Patients with controlled T2DM (n = 35; Cross- Yes Hyposalivation was observed more often in patients
80% female, 20% male). sectional with DM, compared to controls.
Group 2: Patients with uncontrolled T2DM (n = 35, study
68.7% female, 31.4% male).
Sandberg et al. Group 1: Patients with T2DM (n = 102; 64% males, Cross- Yes Xerostomia was significantly more prevalent in
(260) 36% females; mean age = 64.8 ± 8.4 years). sectional patients with DM (53.5%) compared to the control
Group 2: Age- & gender matched control subjects study group (28.4%).
without DM (n = 102).
Silveira Lessa et al. Group 1: Patients with T1DM and T2DM (combined Systematic Yes The prevalence of xerostomia in patients with DM
(257) n = 1,979). review and was higher (37.4% for T1DM and 46.1% for T2DM),
Group 2: Control subjects without DM (n = 1,225). meta-analysis compared to the control subjects without DM
(24.2%). Furthermore, a significant association
between DM and xerostomia was found when
analyzing case-control studies (OR=3.15, 95% CI:
2.11–4.70), indicating an increased risk for
xerostomia when diabetes is present).
Vasconcelos et al. Group 1: Patients with T2DM (n = 40; 20 males, 20 Cross- Yes Both resting and stimulated salivary flow was lower
(250) females; mean age = 57.7 ± 8.9 years). sectional in patients with DM, compared to the control group.
Group 2: Control subjects without DM (n = 40; 20 study However, no significant difference in the prevalence
males, 20 females; mean age = 50.2 ± 12.3 years). of xerostomia was found.
PATHOGENESIS
Hyperglycemia
Chávez et al. (244) Group 1: Patients with better controlled T2DM Prospective Yes Patients with poorly controlled diabetes showed
(HbA1c ≤9%) (n = 10; 5 males, 5 females; 6 ≤71 cohort study lower stimulated parotid saliva flow rates, both at
year old, 4 >71 years old). baseline and after 1 year follow-up. Also, patients
Group 2: Patients with poorly controlled T2DM with DM reported more complaints of thirst, though
(HbA1c >9%) (n = 14; 5 males, 9 females; 6 ≤71 not of xerostomia. No changes over 1 year of
year old, 8 >71 years old). follow-up were observed.
Group 3: Controls without DM (n = 15; 9 males, 6
females; 5 ≤71 year old, 10 >71 years old).
Chavez et al. (245) Group 1: Patients with well controlled T2DM (HbA1c Cross- Yes Patients with poorly regulated diabetes displayed a
≤9%) (n = 11; 8 males, 3 females; 6 ≤71 year old, sectional significant decrease in stimulated parotid salivary
5 >71 years old). study flow rates compared to well-controlled patients and
Group 2: Patients with poorly controlled T2DM subjects without DM.
(HbA1c >9%) (n = 18; 8 males, 10 females; 8 ≤71
year old, 10 >71 years old).
Group 3: Patients without DM (n = 23; 9 males, 14
females; 9 ≤71 year old, 14 >71 years old).

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 3 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Fukuoka et al. Group 1: Control rats (n = 11). Longitudinal Yes The diabetic rats showed an upregulated
(267) Group 2: Diabetic rats (n = 9). animal study AGE/RAGE expression in the salivary glands, which
Group 3: Diabetic rats, treated with low-power laser resulted in an inflammatory response through
irradiation (n = 10). Diabetes was induced with activation of the NF-κB pathway. Therapy with the
Streptozotocin. low-power laser irradiation suppressed this
inflammatory state, and reduced apoptosis caused
by diabetes.
Moore et al. (240) Group 1: Patients with T1DM (n = 406; 204 males, Cross- Yes Patients with DM complained more often of dry
202 female; mean age = 33.0 ± 0.4 years). sectional mouth and had decreased salivary flow rates
Group 2: Healthy controls (n = 268; 108 males, 160 study compared to controls. Furthermore, decreased
female; mean age = 31.8 ± 0.5 years). salivary flow rates were associated with increased
fasting glucose levels.
Sreebny et al. Group 1: Patients with T1DM (n = 15) and T2DM Cross- Yes Patients with DM showed a decreased salivary flow
(241) (n = 25) sectional compared to the control subjects. Also, an inverse
Group 2: Age- and gender matched healthy control study relationship between metabolic control (HbA1c ) and
subjects without DM (n = 40). salivary flow was observed.
Insulin resistance
Ittichaicharoen Group 1: Normal diet fed Wistar rats (n = 8). Longitudinal Yes Rats fed with a high-fat diet developed
et al. (271) Group 2: High-fat diet fed Wistar rats, vehicle animal study obese-insulin resistance, with increased apoptosis,
treated (n = 8). ROS production, inflammation and mitochondrial
Group 3: High-fat diet fed Wistar rats, vildagliptin dysfunction in their salivary glands as a result. When
treated (n = 8). treated with the anti-diabetic drug, these changes
were reduced.
Matczuk et al. Group 1: Normal diet fed rats (n = 8) Longitudinal Yes A high-fat diet, inducing insulin resistance and
(272) Group 2: High-fat diet fed rats (n = 8). animal study obesity, resulted in a changing lipid composition in
rat salivary glands. Phospholipids and
triacylglycerols were increased; FFAs and
diacylglycerols were not.
Mozaffari et al. Group 1: Obese rats (n = 7). Cross- Unclear The obese rats develop insulin resistance, which
(273) Group 2: Lean rats (n = 9). Rats used: male, obese sectional resulted in an increased expression of ICAM-1 and
(OBZ) and lean Zucker rats. animal study an upregulation of the NF-κB pathway in the salivary
glands. However, morphological changes were not
observed.
Dyslipidemia
Shikama et al. Human parotid and submandibular salivary gland Ex vivo Yes Treatment with saturated (not unsaturated) fatty
(275) epithelial cell lines, treated with various types of experiment acids (SFA) activates the NF-κB and MAPK
FFAs to mimic dyslipidemic conditions. pathway, resulting in increased IL-6 production in
human parotid and submandibular salivary gland
epithelial cell lines.
Hypertension
Dodds et al. (276) Group 1: Healthy controls (n = 240; 134 males, 116 Cross- Yes Patients with hypertension had lower unstimulated
females; mean age = 55.6 years). sectional submandibular/sublingual (US) and stimulated
Group 2: Patients with hypertension (n = 227; 91 study submandibular/sublingual (SS) salivary flow rates,
males, 136 females; mean age = 63.7 years). compared to healthy controls. US flow rates were
Group 3: Patients with DM (n=233; 120 males, 113 also comparable with patients with DM.
females; mean age = 62.6 years).

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; IgA, Immunoglobulin A; DMFT, Decayed, missing, filled teeth; (R)AGE, (Receptor for) Advanced Glycation End Products;
NF-κB, Nuclear Factor Kappa B; FFA, Free Fatty Acids; ICAM-1, Intercellular Adhesion Molecule 1; MAPK, Mitogen-Activated Protein Kinase; IL-6, Interleukin 6.

is higher in males (279). Ethnicity might also play a role. For Relationship With Diabetes Mellitus: Epidemiology
example, non-Hispanic whites in the US had increased odds of (Candida-Related Oral Lesions)
having a lesion, compared to non-Hispanic blacks and Mexican- Candida is a genus of yeasts, with Candida albicans as the
Americans (279). most common species, and it can be found on the skin and
The large majority of studies investigating the association on all mucosal surfaces. It exists in healthy individuals as a
between DM and oral mucosal lesions focus on Candida-related commensal organism, but causes opportunistic infections in
lesions. For this reason, we will also focus especially on these susceptible patients, such as patients with HIV/AIDS, persons
forms of mucosal lesions, while we will only briefly discuss using immunosuppressive medication and individuals with
non-candidal oral mucosal lesions at the end of this section. poorly controlled DM (283). Oral candidal infection (candidiasis)

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Verhulst et al. Oral Complications of Diabetes Mellitus

has several clinical manifestations, including median rhomboid Dyslipidemia

glossitis (redness and loss of papillae on the dorsal side of Two animal studies observed an increased systemic infection
the tongue), angular cheilitis (inflammation of the corners of with C. albicans after inducing hyperlipidemia, with increased
the mouth) and denture stomatitis (inflammation and redness LDL or VLDL levels in particular (297, 298). It should be further
underneath a denture). Assessment of the association between elucidated whether this is the case for humans as well, and if this
DM and Candida-related lesions is hampered by the complexity is also applicable specifically for the oral cavity.
of the lesions, variations in study populations and interaction
with other local risk factors (284). Moreover, there are no Insulin resistance and hypertension
longitudinal studies investigating a possible causal relationship Currently, there are no studies that investigated the effect of
between DM and Candida-related lesions. However, cross- insulin resistance or hypertension on Candida colonization or
sectional studies investigating the previously mentioned candidal Candida-related oral lesions.
manifestations showed a higher prevalence of median rhomboid
glossitis (285), denture stomatitis (286, 287), and angular cheilitis Immune dysfunction: impaired immune response and
(288) in patients with T1DM or T2DM, compared to healthy proinflammatory state
controls. In one study, the overall prevalence of Candida-related As we discussed before, patients with DM are susceptible for
lesions was 15% in patients with DM, compared to 3% in healthy hyposalivation. Saliva has several innate immune defensive
controls (285). One study found an increased overall prevalence mechanisms to protect the oral mucosa against microorganisms
of fungal infections—including candidiasis—in patients with DM such as Candida. Examples are mechanical washing, its buffering
(289), while another study in complete denture wearers did capacity and the presence of antifungal components such
not find an increased prevalence (290). Furthermore, one study as histatins and mucins (299). If patients with DM develop
found increased counts of Candida pseudohyphae in patients hyposalivation, these mechanisms are impaired, and as such,
with T1DM, compared to healthy controls (285). This might hyposalivation is an important risk factor for oral candidiasis
partly explain the increased prevalence of candidal infections the (300). This was confirmed in a study, where patients with both
latter authors observed. However, other studies show conflicting DM and hyposalivation had higher counts of Candida species in
results, as they did not find an increased colonization of Candida their saliva (247). One study showed that both hyposalivation
in individuals with T1DM and T2DM (291, 292). and the presence of DM were independent predictors of oral
candidiasis (299).
Relationship With Diabetes Mellitus: Pathogenesis We discussed before that the impaired innate immune
(Candida-Related Oral Lesions) response makes patients with DM susceptible to infections.
This section will discuss the pathogenesis of candidal lesions The decreased phagocytosis and killing capabilities of the
in relation to DM, again by means of the previously utilized PMNs might cause overgrowth of Candida, eventually causing
pathologic phenomena related to DM: hyperglycemia, insulin candidal infection (301). Furthermore, we mentioned that
resistance, dyslipidemia, hypertension, and immune dysfunction. patients with DM have increased adhesion of microorganisms
to several cell types. Adhesion to epithelial cells of the oral
cavity is a prerequisite for Candida colonization; interestingly,
Hyperglycemia buccal and palatal epithelial cells from patients with DM
Several studies found that the increased prevalence of Candida- showed increased adhesion capacities for Candida in ex vivo
related oral lesions was associated with poor metabolic control, experiments (287, 302).
indicating that hyperglycemia is important for this association
(285, 293, 294). However, besides these observational studies, Relationship With Diabetes Mellitus (Non-candida
very little is known about its exact pathogenic role. There are Related Lesions)
no studies investigating the downstream effects of hyperglycemia Several studies investigated only one non-candida related
that are involved in the well-known complications of DM (polyol, mucosal lesions (303, 304), while others studied several types
AGE/RAGE, PKC, and hexosamine pathways). Interestingly, one of mucosal lesions (289, 305–309), but none of those studies
study showed that inhibition of AGE formation in diabetic rats investigated possible underlying biologic mechanisms. For this
improved the microbicidal activity of PMNs against C. albicans reason, all individual lesion types that might be associated with
(295). However, it should be noted that this study concerned DM are presented separately in Table 4, together with their
peritoneal PMNs and Candida infection, but AGEs might be clinical signs. This concerns: traumatic ulcer, actinic cheilitis,
involved in oral candidal lesions as well. This has not been melanin pigmentation, fissured tongue, benign migratory
confirmed or investigated yet. glossitis (geographic tongue), leukoplakia, lichen planus, and
As we have discussed before, salivary glucose levels are often other lichenoid lesions. The (pre)malignant mucosal lesions will
increased in patients with DM due to hyperglycemia. Similar to be discussed in more detail in section Oral Cancer.
the suggestions for cariogenic oral streptococci, glucose can also
act as a source of nutrition for yeast species such as Candida. Concluding Comments
Indeed, several studies found an association between increased From an epidemiologic point of view, the prevalence of candida-
glucose levels in saliva and the growth of Candida in the oral related oral mucosal lesions is increased in patients with DM.
cavity of patients with DM (292, 296). However, longitudinal studies are lacking, and not much is

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 4 | Overview of non-candidal lesions that are possibly associated with diabetes mellitus.

Lesion type Clinical signs Association with diabetes

Traumatic ulcer Damaged mucosa caused by mechanical, thermal, Guggenheimer et al. (305) found an increased prevalence in patients with T1DM, but
chemical, electrical or irradiation trauma. could not find an explanation for this in their data. Perhaps impaired wound healing
seen in patients with DM might play a role.
Actinic cheilitis Premalignant disorder of the lip characterized by Silva et al. (306) and de Souza Bastos et al. (289) found a high prevalence in patients
inflammation, caused by exposure to sunlight. with T1DM or T2DM, compared to controls, but their data could not explain this
difference.
Melanin Pigmentation of oral mucosa with a broad range of Conflicting results, as some found an increased prevalence in patients with T1DM or
pigmentation clinical signs, caused by both exo- and endogenous T2DM (289), but others did not (307).
factors.
Fissured tongue Deep grooves on the dorsal side of the tongue. A few studies observe an increase in prevalence, and hypothesize that fissured
tongue might be the result of aging and a dry mouth (289, 305, 307).
Benign migratory An inflammatory condition of the dorsal mucosal surface Several studies reported a significant increase in the prevalence of geographic tongue
glossitis of the tongue, with loss of lingual papillae as a result. in patients with T1DM or T2DM (288, 293). Guggenheimer et al. (305) also found
(geographic This is visible as a red, smooth surface, with a shifting more subjects with geographic tongue amongst patients with T1DM, but this
tongue) positioning. difference was not significant.
Leukoplakia Literally: white patch. It is a “predominantly white Studies investigating the relationship between leukoplakia and DM show
(premalignant) lesion of the oral mucosa that cannot be contradictory results. Some found an association (308–310), whereas others did not
characterized as any other definable lesion.” (288, 289, 307).
Lichen planus and An inflammatory condition with varying clinical Again, there is no consensus in the literature, as some report an increased prevalence
lichenoid lesions appearances, affecting the skin, the oral mucosa, or of lichen planus (303, 308) whereas others did not find a difference between patients
both. It might cause white patches, red and swollen with DM and healthy controls (304, 305, 307). As the name suggests, oral lichenoid
tissue, pain in varying degrees and a burning sensation. lesions resemble oral lichen planus, but have a different pathogenesis, such as
It can be considered as a premalignant disorder. medication use, contact allergies and graft-vs.-host disease. In case of DM,
medication use, such as hypoglycemic drug or anti-hypertensives, increases the risk
for oral lichenoid lesions (311). Sometimes, this is referred to as “Grinspan syndrome”
(312).

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2.

known about the pathogenesis behind the increased prevalence. and 90% for cancers of the lip (313). As we mentioned in section
It is highly likely that the impaired immune response enables Dry Mouth, radiation therapy of cancer in the head and neck
Candida species to act as opportunistic organisms. Table 5 region can cause dry mouth (229).
provides an overview of the literature that discusses the
association between Candida-related lesions. As for non-candida
related mucosal lesions, the evidence is too limited to establish a Relationship With Diabetes Mellitus: Epidemiology
relationship with DM. Patients with DM have an increased risk for developing cancer
in several organs and tissues, as well as an increase in cancer
mortality, compared to subjects without DM (316). A recent
Oral Cancer meta-analysis showed that this is also the case for oral cancer
Background (317). One cross-sectional Hungarian study showed an increased
This section focuses on cancers of the lip, tongue, oral cavity, and prevalence of oral cancer in patients with T2DM or T1DM
oropharynx. Oral and oropharyngeal cancers together are ranked compared to controls, as well as an over-representation of T2DM
as the sixth most common type of cancer, but prevalence and in individuals with oral cancer (310). A Brazilian cross-sectional
incidence vary greatly between countries and regions (313). The study, which we also discussed in the previous section, revealed
global incidence was estimated to be 263,900 in 2008, causing an increased prevalence of potentially malignant mucosal lesions
128,000 deaths worldwide (314). Many possible risk factors (actinic cheilitis, lichen planus, leukoplakia, and nicotinic
have been identified, including: smoking, tobacco and betel stomatitis) in patients with T2DM (289). A similar study from
nut chewing, alcohol abuse, snuff dipping, sunlight, radiation, Malaysia showed contradicting results, as no association between
viruses, and immune dysfunction (313). Many risk factors are DM and precancerous lesions was found (288). However, a large
culture dependent, hence the varying epidemiologic figures cross-sectional study from the US also observed that DM was an
across regions. For example, 75% of all cases in the US could be independent predictor for oral leukoplakia, which is considered
attributed to alcohol and tobacco use (315), while in Taiwan and as a pre-malignant lesion (318). The same was found in a cross-
neighboring countries, betel nut chewing was the main risk factor sectional study from India, but only for women (309). Two case-
(314). Survival rates also vary between countries, age groups, and control studies from Italy presented contradicting results, as one
types of cancer, but in general, the 5-year survival is estimated to did find an increased risk for cancer of the oral cavity in patients
be ∼50% for cancers of the tongue, oral cavity, and oropharynx, with DM (319), while the other did not (320).

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 5 | Overview of studies investigating the association between diabetes mellitus and oral candidal lesions.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
Bremenkamp et al. Group 1: Patients with T1DM (n = 39; 20 males, 19 Cross- No There were no differences in the frequency of
(291) females; aged 9–27 years). sectional Candida spp. between the diabetic group and the
Group 2: Control group 1 (n = 50; age- and gender study matched control groups.
matched with group 1).
Group 3: Patients with T2DM (n = 37; 8 males, 29
females; aged 37–78 years).
Group 4: Control group 2 (n = 36 age- and gender
matched with group 3).
Darwazeh et al. Group 1: Patients with DM (n = 41; 17 T1DM, 24 Cross- No Patients with DM did not show higher Candida
(292) T2DM; mean age = 52 ± 16 years). sectional isolation compared to the controls. However,
Group 2: Control subjects without DM (n = 34; study patients with DM and oral candidal colonization had
mean age = 52 ± 18 years). significant higher levels of salivary glucose,
compared to non-colonized patients.
de Lima et al. (290) Group 1: Patients with T2DM (n = 30; 11 males, 19 Cross- No There were no significant differences in oral mucosal
females; mean age = 60 ± 9 years). sectional lesions, including Candida-related lesions, between
Group 2: Healthy controls (n = 30; 9 males, 21 study patients with DM and healthy controls.
females; mean age = 63 ± 12 years).
de Souza Bastos Group 1: Patients with T2DM (n = 146; 56 males, Cross- Yes A significantly higher prevalence of total fungal
et al. (289) 90 females; mean age = 53.10 ± 7.9 years). sectional infections was observed in patients with DM,
Group 2: Age- and gender matched controls (n = study compared to the control subjects.
111; 53 males, 58 females; mean age = 51.4 ±
10.3 years).
Dorocka- Group 1: Patients with T2DM (n = 110, 47 males; Cross- Yes The prevalence of denture stomatitis and its
Bobkowska et al. 63 females; 63.2 ± 10.5 years). sectional associated oral complaints, angular cheilitis, glossitis
(286) Group 2: Control subjects without DM (n = 50; 21 study and oral dryness were significantly increased in
males, 29 females; mean age = 66.9 ± 8.8 years). patients with DM, compared to the controls.
Guggenheimer Group 1: Patients with T1DM (n = 405; 204 males, Cross- Yes The prevalence of several manifestations of candidal
et al. (285) 201 females; mean age = 33.0 ± 0.4). sectional lesions (median rhomboid glossitis, denture
Group 2: Matched controls without DM (n = 268; study stomatitis and atrophy of the tongue papilla) was
108 males, 160 females; mean age = 31.8 ± 0.49). increased in patients with DM, compared to
controls.
Saini et al. (288) Group 1: Patients with DM (n = 420; 29 T1DM, 309 Cross- Yes The prevalence of denture stomatitis and angular
T2DM; 185 males, 235 females; mean age = 53.0 sectional cheilitis was increased in patients with DM,
± 10.5 years). study compared to the controls.
Group 2: Control subjects without DM (n = 420;
167 males, 253 females; mean age = 51.8 ± 11.6
years).
PATHOGENESIS
Hyperglycemia
Al Mubarak et al. Patients with T2DM (n = 42; 18 males, 24 females; Cross- Yes Patients with poor metabolic control (HbA1c >9%)
(294) mean age = 47.3 ± 14.4 years). sectional had more candidal infections, compared to
study well-controlled patients (HbA1c <6%).
Al-Maweri et al. Group 1: Patients with T2DM (n = 391; 43.5% male, Cross- Yes The prevalence of denture stomatitis and angular
(293) 56.5% female; mean age = 54.71 ± 8.48 years). sectional cheilitis was increased in patients with DM,
Group 2: Control subjects without DM (n = 391; study compared to the controls. Within the group with
38.9% males, 61.1% females; mean age = 53.04 ± DM, poor glycemic control was associated with
12.06 years). increased prevalence of the same conditions.
Guggenheimer Group 1: Patients with T1DM (n = 405; 204 males, Cross- Yes The presence of Candida pseudohyphae was
et al. (285) 201 females; mean age = 33.0 ± 0.4). sectional significantly increased in patients with DM, which
Group 2: Matched control subjects without DM (n = study was associated with glycemic control.
268; 108 males, 160 females; mean age = 31.8 ±
0.49).
Sashikumar and Group 1: Well-controlled diabetic subjects (n = 50; Cross- Yes Colony-forming units of Candida were higher in
Kannan (296) aged 40–60 years). sectional patients with DM, and this was significantly
Group 2: Patients with poorly controlled T2DM (n = study correlated with levels of salivary glucose.
50; age- and gender matched).
Group 3: Age- and gender matched non-diabetic
controls (n = 50).

(Continued)

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 5 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

de Souza Ferreira Group 1: Control rats, no AMG treatment (n = 8). Cross- Yes Microbicidal activity of the PMNs against Candida
et al. (295) Group 2: Control rats, + AMG treatment (n = 8). sectional significantly increased in the rats that were treated
Group 3: Diabetic rats, no AMG treatment (n = 8). animal study with AMG, which inhibits the formation of AGEs.
Group 4: Diabetic rats, + AMG treatment (n = 8). This implicates that there is a relationship between
Rats used: Wistar rats (male, 280 ± 50 g). AGE formation and the host immune response
against opportunistic infections. It should be noted
that it concerned peritoneal PMNs and peritoneal
Candida infection in this study.
Dyslipidemia
Netea et al. (297) Group 1: Low-density-lipoprotein-receptor-deficient Longitudinal Yes The Ldlr –/– mice developed 7–9 times higher LDL
mice (type: Ldl–/–). animal study levels, compared to the control rats. These
Group 2: Wild type control mice (type: 57BL/6J). increased levels made them more susceptible for
systemic Candida infection, which resulted in higher
levels of inflammatory markers and a higher
mortality rate.
Vonk et al. (298) Group 1: Apolipoprotein E-deficient mice (Apoe–/–). Cross- Yes VLDL levels were 8 times higher in Apoe-/- mice,
Group 2: Weight matched control mice (Apoe+/+). sectional compared to the matched controls. This resulted in
animal study higher mortality due to candidemia and higher levels
of C. Albicans in plasma and kidney tissue. VLDL
particles might serve as nutrition for Candida, and
neutralize candidacidal properties of human serum.
Immune dysfunction
Darwazeh et al. Group 1: Patients with DM (n = 50; 27 males, 23 Cross- Yes There was increased adhesion of C. albicans to the
(302) females; mean age = 53.7 ± 14.5 years). sectional buccal mucosa of patients with DM, who also more
Group 2: Control subjects without DM (n = 50; 23 study and frequently suffered from Candida infection.
males, 27 females; 56.3 ± 17.3 years). ex-vivo
experiment
Dorocka- Group 1: T2DM denture-wearing patients (n = 70; Cross- Yes Not only did they found an increased prevalence of
Bobkowska et al. 29 males, 41 females; mean age = 57 ± 8.8 years). sectional denture stomatitis in the diabetic group, but also an
(287) Group 2: Denture-wearing control subjects without study and increased adherence of C. albicans to palatal
DM (n = 58; 27 males, 31 females; mean age = 58 ex-vivo epithelial cells. This indicates a predisposition for
± 7.3 years) experiment Candida infection in patients with DM.
Ueta et al. (301) Group 1: Patients with symptomatic oral candidiasis Cross- Yes White blood counts, levels of CRP and erythrocyte
and DM (n = 8). sectional sedimentation rates were all increased in patients
Group 2: Patients with symptomatic oral study with DM and oral candidiasis. Oral PMNs in these
candidiasis, without DM (n = 64). patients produced less ROS and showed impaired
phagocytosis and intracellular killing of Candida
cells. This might indicate that the neutrophil
suppression plays an important role in the
predisposing state of DM for opportunistic
infections.

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; AMG, Aminoguanidine; PMN, Polymorphonuclear Neutrophil; VLDL, Very Low-Density Lipoprotein; CRP, C-reactive
Protein.

There are also several longitudinal studies investigating the after matching the patients and prolonging the follow-up
incidence of—and risk for—oral cancer in diabetic cohorts. One period in their second study, they showed an increased
Danish population-based cohort study compared the incidence risk for oral cancer and oropharyngeal cancer in patients
of several types of cancer in a large diabetic population (n with T2DM (323).
= 109,581) with expected incidences based on a national Besides its effect on cancer incidence, DM also negatively
cancer registry record. They found that the incidence of affects the prognosis of patients with oral squamous cell
“cancer of the mouth” was increased 2-fold in the diabetic carcinoma (OSCC). In another Taiwanese study, overall survival,
population younger than 50 years (321). Two large Taiwanese recurrence-free survival, and cancer-specific survival were all
cohort studies from the same group also investigated the decreased in patients with OSCC and DM, compared to patients
risk for head and neck cancer in patients with T2DM, with with OSCC without DM (324). This was also observed in a large
oral cancer specifically. The first did not find an increased prospective cohort study from the US, where DM was associated
risk, possibly due to a relatively short follow-up period (2 with an increased risk for mortality from cancer of the oral cavity
years), and no matching of study subjects (322). However, or pharynx (325).

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Verhulst et al. Oral Complications of Diabetes Mellitus

Relationship With Diabetes Mellitus: Pathogenesis oral cancer is increased in patients with DM. Considering the
The pathogenesis behind the epidemiologic association between potentially devastating and even fatal effects of oral cancer, these
DM an oral cancer is complex and remains to be fully elucidated. findings are worrying. There is a lack of research into possible
In an attempt to explain the increased risk for oral cancer by pathogenic pathways that explain the association between DM
means of the pathological mechanisms that we have been using and oral cancer. As long as it remains unknown why patients
throughout this review, it appears that only hyperglycemia and with DM are at higher risk for oral cancer, targeted prevention
dyslipidemia have been studied, albeit very limited. There is no and treatment programs are unlikely to succeed.
data available on the role of hypertension, insulin resistance and
immune dysfunction. Taste Disturbance
Background
Hyperglycemia Gustatory dysfunction (i.e., taste disturbance) is generally
Although it is likely that hyperglycemia is important for classified into three major types: dysgeusia, a distortion or
the increased risk of oral cancer in patients with DM, alteration in taste sensation; hypogeusia, a partial loss of taste
there is only limited evidence for that hypothesis. In one and ageusia, a complete loss of taste (334). Compared to for
study, elevated levels of HbA1c were associated with an example olfactory dysfunction, gustatory dysfunction is relatively
increased risk for oral leukoplakia, a pre-malignant oral mucosal rare. Estimations of the prevalence of any disturbance of taste
lesion (326). The downstream pathways of hyperglycemia in the adult population range from 0.93% in the US (335) to
(polyol, AGE/RAGE, PKC, hexosamine) are largely unexplored. 2.5% in Sweden (336). The prevalence of severe hypogeusia or
Interestingly, inhibition of the polyol pathway in a diabetic ageusia is lower, with 0.83% of a study population that attended a
animal model significantly lowered the number of premalignant chemosensory clinic. In the general population, this will probably
lesions in the colon (327). It would be interesting to investigate be even lower (337). As is the case for other sensory functions,
whether this is the case for animal and human oral mucosal such as hearing or smell, the risk for gustatory dysfunction
tissues as well. increases with age (338). The prevalence is doubled in individuals
One in vitro study observed increased cell migration when aged 45–65, and even tripled in those aged 66 and older,
oral cancer cell lines were treated with AGEs. This was probably compared to subjects aged 18–44 (335). Especially women aged
the result of increased expression of RAGE, MMP-2, and MMP-9 50 years or older seem to be susceptible for taste disturbances
(328). Increased migration of cancer cells is one of the important (336). Besides older age, many other risk factors have been
characteristics of cancer malignancy. In another in vitro study, proposed in literature, including physiological changes, oral and
oral cancer cells were again treated with AGEs, which resulted systemic diseases, iatrogenic causes, nutritional deficiencies, and
in a decreased p53 expression. P53 is an important tumor lifestyle behavior (338).
suppressor, regulating cell survival and cell death; decreased
expression usually promotes cell survival and inhibits cell death. Relationship With Diabetes Mellitus: Epidemiology
Therefore, AGEs are probably involved in the survival rate of Epidemiologic research into the association between DM and
oral cancer cells through p53 suppression, and might worsen taste disturbances is limited to a few cross-sectional studies.
the prognosis of oral cancer in patients with DM (329). This Nevertheless, both hypogeusia and ageusia were observed more
poor prognosis was confirmed in patients with oral squamous frequently in patients with T1DM (339, 340) and T2DM (340,
cell carcinoma, where increased RAGE expression in tumors 341), compared to healthy controls. Another way of defining taste
decreased disease-free survival (330). One study found that one disturbances is by measuring detection thresholds for certain
specific RAGE gene polymorphism significantly increased the tastes (e.g., sweet or salty), after exposure to certain taste stimuli
risk for oral cancer in patients with DM (331). RAGE also seems (e.g., chemical or electrical), with higher thresholds indicating
to be important for the invasiveness of oral mucosal tumor reduced taste sensation. In both patients with T1DM (339, 340,
cells, since metastatic tumor cells showed a higher expression of 342) and patients with T2DM (340, 343–345), these thresholds
RAGE. Suppression of RAGE in oral squamous carcinoma cell were generally elevated, compared to healthy controls. One
lines decreased the invasive activity (332). study did not find an association (346). Taste disturbances can
have important consequences, especially for patients with DM.
Dyslipidemia Research has shown that diminished taste perception resulted
One study had a closer look at the individual components of in a tendency toward consumption of beverages with a higher
the metabolic syndrome (hyperglycemia, elevated triglycerides, sucrose concentration with a higher sweet taste intensity. This
lowered HDL levels, hypertension, and central obesity), which might indicate a preference for sweeter foods or beverages that
revealed that subjects with hypertriglyceridemia had a higher risk probably are higher in carbohydrates and calories (347). Besides
for developing oral pre-malignancies (333). a possible increase in glucose supplies, this could also increase
the risk to develop obesity, a major risk factor for T2DM and
Concluding Comments its complications.
Table 6 presents an overview of the literature that discusses the
association between DM and oral cancer. As is the case for other Relationship With Diabetes Mellitus: Pathogenesis
types of cancer, epidemiologic research seems to indicate that the Unfortunately, there is no literature available that investigated
prevalence and even incidence of oral premalignant lesions and the same pathogenic pathways we have been using throughout

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 6 | Overview of studies investigating the association between diabetes mellitus and oral cancer.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
Bosetti et al. (319) Group 1: Patients with cancer of the oral Integrated Yes The risk for oral and pharyngeal cancer was
cavity/pharynx (n = 1,468; 1,190 males, 278 case-control increased in patients with DM, compared to the
females; median age = 58, self-reported DM: n = studies group without DM (OR = 1.58, 95% CI=1.15–2.18),
98). after adjustment for gender, age, study center, year
Group 2: Cancer-free controls (n = 3,761; 2553 of interview, education, alcohol drinking, tobacco
males, 1,208 female; median age = 58, smoking, and BMI.
self-reported DM n = 181).
Campbell et al. Subjects free of cancer at baseline (n = 1,053,831), Prospective Yes After multivariable adjustment, diabetes was
(325) followed from 1982 to 2008. cohort study associated with an increased mortality from cancer
of the oral cavity and pharynx in men (RR = 1.44,
95% CI: 1.07–1.94).
de Souza Bastos Group 1: Patients with T2DM (n = 146; 56 males, Cross- Yes The prevalence of potentially malignant disorders
et al. (289) 90 females; mean age = 53.10 ± 7.9 years). sectional (actinic cheilitis, lichen planus, leukoplakia and
Group 2: Age- and gender matched controls (n = study nicotinic stomatitis) was significantly increased in
111; 53 males, 58 females; mean age = 51.4 ± patients with T2DM.
10.3 years).
Dietrich et al. (318) Group 1: Patients with oral leukoplakia (n = 65; 12 Cross- Yes Oral leukoplakia was more prevalent in patients with
with DM, 53 without DM; 69.2% male, 30.8% sectional DM (0.92%), compared to patients without DM
female; mean age = 57.5 years). study (0.37%). Besides smoking, age, and
Group 2: Controls (n = 15,746; 1,289 with DM, socio-economic status, DM was found to be an
14,457 without DM; 47.4% male, 52.6% female; independent predictor for the development of oral
mean age = 47.9 years). leukoplakia (OL). Patients with DM were 3 times
more likely to develop OL (weighed OR = 3.03,
95% CI: 1.28–7.21).
Dikshit et al. (309) Group 1: Patients with leukoplakia (n = 927) or Case-control Yes In women, DM was an independent risk factor for
erythroplakia (n = 100). study oral leukoplakia (OR = 2.0, 95% CI: 1.4–2.9) and
Group 2: Healthy controls (n = 47,773). erythroplakia (OR = 3.2, 95% CI: 1.3–7.9). For men,
no such association was found.
Gong et al. (317) 13 epidemiological studies on the association Systematic Yes Analysis of 4 case-control studies and 9 cohort
between oral cancer and DM (4 case-control and 9 review with studies revealed a significant association between
cohort studies, combined n >4.8 million; 6,456 meta-analysis oral cancer (SRR = 1.15, 95% CI: 1.02–1.29) and
patients with oral cancer). 4 case-control studies on oral cancer related mortality (SRR = 1.41, 95% CI:
the association between oral precancerous lesions 1.16–1.72) and T2DM. Meta-analysis of the
and DM (1,407 patients with oral precancerous case-control study revealed a positive association
lesions). between T2DM and the risk for precancerous
lesions (SRR = 1.85, 95% CI: 1.23–2.80).
La Vecchia et al. Group 1: Patients with histologically confirmed Integrated No There was no significant increase in the risk for
(320) incident cancer (n = 9,991). case-control cancer of the oral cavity (RR=0.50, 95% CI:
Group 2: Healthy control subjects (n = 7.834). studies 0.2–1.1) in patients with DM.
Saini et al. (288) Group 1: Patients with DM (n = 420; 29 T1DM, 309 Cross- No There was no association between the presence of
T2DM; 185 males, 235 females; mean age = 53.0 sectional DM and the prevalence of oral precancerous lesions.
± 10.5 years). study
Group 2: Control subjects without DM (n = 420;
167 males, 253 females; mean age = 51.8 ± 11.6
years).
Tseng (322) Group 1: Patients with T2DM (n = 115,692; 45.3%, Retrospective No After multivariable adjustment, there was no
male, 54.7% female). cohort study significant association between T2DM and
Group 2: Patients without T2DM (n = 882,849; 50.1 incidence oral cancer after 2-year follow-up (RR =
males, 49.9% female). 1.195, 95% CI: 0.892–1.601).
Tseng et al. (323) Group 1: Patients with DM (n = 89,089; 52.9% Retrospective Yes The risk for developing oral cancer and
male, 47.1% female; mean age = 55.4 ± 15.1 cohort study oropharyngeal cancer was significantly higher in
years). patients with DM, compared to the matched
Group 2: Matched patients without DM (n = controls (adjusted HR = 1.74, 95% CI 1.47–2.06 for
89,089; 52.9% male, 47.1% female; mean age = oral cancer and 1.53, 95% CI: 1.01–2.31 for
55.4 ± 15.1 years). oropharyngeal cancer).

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 6 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Ujpál et al. (310) First analysis: Cross- Yes The first cross-sectional analysis showed an
Group 1: Patients with DM (n = 200; 82 T1DM, 118 sectional increased prevalence of benign tissue
T2DM; 69 males, 131 females; mean age = 45.8 study accumulations (14.5%) and precancerous lesions
years). (8%) in patients with T1DM or T2DM, compared to
Group 2: Control subjects without DM (n = 280; control subjects without DM (6.4% and 3.2%
109 males, 171 females; mean age = 47.2 years). respectively). The second cross-sectional analysis
Second analysis: showed an increased prevalence of diabetes in the
Group 1: Patients with malignant oral tumors (n = oral cancer patient group, compared to the
610; 435 males, 175 females; mean age = 56 cancer-free controls.
years).
Group 2: Tumor- and complaint free controls (n =
574; 351 males, 223 females; mean age = 51
years).
Wideroff et al. Group 1: Patients diagnosed with diabetes (n = Population- Yes The observed numbers of incident cancers of the
(321) 109,581). based cohort mouth in the diabetic population were compared
Group 2: National cancer registry records. study with the expected incidence, based on the national
cancer registry records. Even after adjustment for
multiple variables, the relative incidence ratios
remained significantly increased (1.8, 95% CI:
1.2–2.6).
Wu et al. (324) Group 1: Patients with OSCC and DM (n = 71; 62 Retrospective Yes OSCC patients with DM showed a decreased
males, 9 females; mean age = 58.9 ± 12.4 years). cohort study overall survival (HR = 2.22, 95% CI: 1.27–3.88),
Group 2: Patients with OSCC, without DM (n = 301; recurrence-free survival (HR = 2.42, 95% CI:
270 males, 31 females; mean age = 51.2 ± 12.6 1.49–3.92), and cancer-specific survival (HR =
years). 2.16, 95% CI: 1.17–3.97), compared to the OSCC
patients without DM, even after multivariable
adjustment.
PATHOGENESIS
Hyperglycemia
Meisel et al. (326) Group 1: Patients with leukoplakia (n = 123; 68 Cross- Yes Conditional regression analysis revealed a higher
males, 55 females; mean age = 55.2 ± 15.5 years). sectional probability for leukoplakia with increasing HbA1c
Group 2: Patients without leukoplakia (n = 246; 136 study levels (OR = 1.51, 95% CI: 1.08–2.12). When
males, 110 females; mean age = 55.2 ± 15.6 correcting for the interaction with smoking status,
years). the OR for never-smokers was 1.96 (95% CI:
1.15–3.37), and for ever-smokers 1.29 (95% CI:
0.80–2.09).
Advanced glycation endproducts
Bhawal et al. (332) Analysis 1: In vitro Yes The number of cells expressing RAGE was
Group 1: Oral primary tumors and tumor-containing experiment significantly higher in metastatic tumors, compared
metastatic lymph nodes. to normal mucosal cells. Also, suppressing the
Group 2: The corresponding normal oral mucosa. expression of RAGE in oral squamous cell
Analysis 2: carcinoma cell lines resulted in a decreased invasive
Oral squamous cell carcinoma cell lines. activity and absolute number of invasive cells. This
suggests that RAGE expression is involved in the
invasiveness of oral malignant tumors.
Ko et al. (328) Oral cancer cell lines (SAS), treated with AGEs or In vitro Yes Increased cell migration was observed when the
BSA (negative control). experiment oral cancer cells were treated with AGEs. This was
probably the result of increased expression of
RAGE, MMP-2 and MMP-9. The authors suggest
that this increases the invasiveness of oral cancer
cells, since migration is an important feature of
malignancy.
Ko et al. (329) Oral cancer cell lines (SAS), treated with AGEs or In vitro Yes The oral cancer cells that were treated with AGEs,
BSA (negative control). experiment showed a decreased p53 expression. A decreased
expression of p53 usually promotes cell survival and
suppresses cell death. The authors therefore
conclude that AGEs are probably involved in the
survival rate of oral cancer cells, which might worsen
the prognosis of oral cancer in patients with DM.
Sasahira et al. Group 1: Patients with OSCC and high expression Prospective Yes High expression of RAGE in OSCCs was associated
(330) of RAGE (n = 30). cohort study with the depth of invasion and local recurrence of
Group 2: Patients with OSCC without high the cancer. Disease-free survival was negatively
expression of RAGE (n = 44). impaired by high expression of RAGE.

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 6 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Su et al. (331) Group 1: Patients with oral cancer (n = 618; 96.4% Cross- Yes Patients with a specific RAGE polymorphism had an
male, 3.6% female; mean age = 54.3 ± 11.3) sectional increased risk for oral cancer (aOR = 2.053, 95%
Group 2: Cancer-free control subjects (n = 592; study CI: 1.269–3.345), even after correction for multiple
81.9% male, 18.1% female; mean age = 51 ± 15). confounders (age, gender, betel nut chewing, and
tobacco consumption).
Polyol pathway
Saxena et al. (327) Group 1: Control diabetic mice (n = 6). Longitudinal Yes By inhibiting the polyol pathway, significantly fewer
Group 2: Diabetic mice with AOM-induced colon animal study premalignant lesions were observed in the colons of
carcinogenesis (n = 6). diabetic mice. This indicates that the polyol pathway
Group 3: Diabetic mice with AOM-induced colon is involved in the development of
carcinogenesis, treated with a polyol pathway diabetes-associated colon cancer. Perhaps the
inhibitor (n = 6). C57BL/KsJ-db/db obese mice same accounts for oral cancer as well.
were used.
Dyslipidemia
Meisel et al. (326) Group 1: Patients with leukoplakia (n = 123; 68 Case-control Yes Besides HbA1c , LDL and total cholesterol levels
males, 55 females; mean age = 55.2 ± 15.5 years). study were also increased in patients with leukoplakia.
Group 2: Patients without leukoplakia (n = 246; 136 The conditional regression analysis for
males, 110 females; mean age = 55.2 ± 15.6 LDL-cholesterol revealed an OR of 3.01 in “never
years). smokers” and an OR of 1.47 in “ever
smokers.”
Yen et al. (333) Group 1: Patients with metabolic syndrome (n = Cross- Yes The prevalence of at least one oral premalignant
17,206) sectional lesion was significantly higher in the group with
Group 2: Patients without metabolic syndrome (n = study metabolic syndrome, compared to the control
60,564) group. Multivariate logistic regression analysis
revealed that hyperglycemia (aOR = 1.30, 95% CI:
1.02–1.67) and hypertriglyceridemia (aOR = 1.43,
95% CI: 1.17–1.75) independently increased the
risk for an oral premalignant lesion.

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; BMI, Body Mass Index; OL, Oral Leukoplakia; SRR, Standardized Relative Risk; OSCC, Oral Squamous Cell Carcinoma;
(R)AGE, (Receptor for) Advanced Glycation Endproducts; MMP, Matrix Metalloproteinase; LDL, Low Density Lipoprotein.

this report. However, a few explanations why patients with Concluding Comments
DM more frequently suffer from taste impairment have been Studies investigating the association between taste impairments
proposed. For example, the increased susceptibility for dry and DM can be found in Table 7. Although it remains a relatively
mouth we discussed in section Dry Mouth, might increase rare condition, patients with DM seem to be susceptible for
the risk for taste disturbances. One study found that, of all certain forms and gradations of taste impairment. However, there
patients with a subjective complaint of taste disturbance, 63% is a lack of solid longitudinal research, and many common risk
also had a sensation of oral dryness, often regardless of the actual factors can obscure a possible association. Besides a few careful
salivary flow (336). Another study showed that hyposalivation suggestions that neural and vascular degeneration might play a
was indeed associated with hypogeusia in a general elderly role, the pathogenesis remains largely unexplored.
population (348). Furthermore, since gustation is a sensory
function with neural involvement, it is conceivable that the Other Oral Complications
typical neuropathy associated with DM is one of the causative The following conditions affecting the oral cavity have been
factors for impaired gustatory function in patients with DM. mentioned in the literature as possible complications of DM,
Three studies from the same research group showed that but evidence for an epidemiologic or pathologic association is
taste impairment in individuals with T1DM was significantly too scarce to dedicate a separate section. Table 8 provides an
associated with peripheral neuropathy (339, 349, 350). One overview of the literature that discusses the associations between
animal study observed decreased innervation of taste buds each of these oral conditions and DM.
in diabetic rats, compared to non-diabetic control rats (351).
Another study with diabetic rats showed increased cell apoptosis Temporomandibular Disorders (TMD)
in their taste buds (352). Humans with T1DM also had decreased Temporomandibular disorder (TMD) is an umbrella term that
vascularization of the tip of the tongue (353). The above findings comprises several conditions affecting the temporomandibular
indicate that the tongue, with the taste buds in particular, is region. The principal clinical feature of TMD is pain during
susceptible for vascular and neuronal damage. mastication, often accompanied by joint sounds and/or limited

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 7 | Overview of studies investigating the association between diabetes mellitus and taste impairment.

Study Study population Study Relationship? Authors’ conclusions

design

EPIDEMIOLOGY
De Carli et al. (345) Group 1: Patients with T2DM (n = 25; 72% male, Cross- Yes Thresholds for sweet, salt, sour, and bitter taste
28% female; mean age = 56.8 ± 6.7 years). sectional recognition were increased in patients with T2DM,
Group 2: Healthy controls (n = 25; 72% male, 28 study compared to the controls.
female; mean age = 56.2 ± 4.9 years).
Gondivkar et al. Group 1: Patients with well controlled T2DM (n = Cross- Yes Patients with either well or poorly controlled
(341) 40; 21 males, 19 females; mean age = 40.97 ± sectional diabetes suffered from hypogeusia and ageusia
5.35 years). study more often, compared to healthy controls.
Group 2: Patients with poorly controlled T2DM (n = Especially sweet taste was impaired, followed by
40; 25 males, 15 females; mean age = 43.52 ± sour and salt. They hypothesize that the impaired
6.32 years). taste for sweet might result in increased
Group 3: Control subjects without DM (n = 40; 23 consumption of sweet food, and beverages, (mostly
males, 17 females; mean age = 40.10 ± 5.18 high in sugar) worsening the hyperglycemia.
years).
Khobragade et al. Group 1: Patients with T1DM (n = 70; 38 males, 32 Cross- Yes The taste thresholds for sweet, salt, sour and bitter
(342) females; age range 20–45 years). sectional was significantly increased in the patients with DM,
Group 2: Age and weight matched control subjects study which indicates an impaired taste sensation.
without DM (n = 70; 40 males, 30 females).
Le Floch et al. Group 1: Patients with T1DM (n = 57; 29 males, 28 Cross- Yes Hypogeusia was observed in significantly more
(339) females; mean age = 40.9 ± 2.0 years). sectional patients with DM than in control subjects without
Group 2: Control subjects without DM (n = 38; 17 study DM. This concerned all four primary tastes, and the
males, 21 females; mean age = 45.5 ± 1.6 years). taste impairment was significantly associated with
other diabetic complications. The association with
peripheral neuropathy was the strongest.
Naka et al. (346) Group 1: Patients with uncomplicated DM (n = 29; Cross- No There was no significant difference in gustatory
20 males, 9 females; mean age = 46.3 ± 15.7 sectional function (for the four basic tastes) between patients
years). study with DM and control subjects without DM, assessed
Group 2: Patients with DM and vascular by using impregnated taste strips.
complications (n = 24; 9 males, 15 females; mean
age = 57.9 ± 15.6 years).
Group 3: Patients with DM and complicating
diseases (n = 23; 12 males, 11 females; mean age
= 54.7 ± 16.0 years).
Group 4: Control subjects without DM (n = 29; 20
males, 9 females; mean age = 45.6 ± 15.3 years).
Perros et al. (343) Group 1: Patients with newly diagnosed T2DM (n = Cross- Yes The patients with newly-diagnosed diabetes had
20). sectional increased EGT, detection threshold for glucose, and
Group 2: Age-, BMI- and gender matched control study recognition threshold for glucose and salt. This
subjects without DM (n = 20). might indicate a preference for sweet nutrients,
Group 3: Patients with DM (n = 11; 5 T1DM, 6 increasing the risk for elevated blood glucose levels.
T2DM), with a disease duration of >10 years.
Stolbova et al. Group 1: Patients with T2DM (n = 73; 26 males, 47 Cross- Yes The gustometric threshold was significantly higher in
(340) females; mean age = 57.7 ± 14.0 years). sectional the diabetic and obese subject, compared to the
Group 2: Patients with T1DM (n = 11; 4 males, 7 study controls. Also, hypogeusia and ageusia were
females; mean age = 47.6 ± 16.1 years). observed in patients with T1DM or T2DM, as well as
Group 3: Obese control subjects without DM (n = in obese patients, but not in the control subjects.
12; 4 males, 8 females; mean age = 49.7 ± 12.0
years).
Group 4: Control subjects (n = 29; mean age =
25.6 ± 9.5 years).
Wasalathanthri Group 1: Control subjects without DM (n = 34; 11 Cross- Yes The patients with T2DM had impaired sweet taste
et al. (344) males, 23 females; mean age = 45.1 ± 8.9 years). sectional sensitivity, compared to the controls. Furthermore,
Group 2: Patients with pre-diabetes (n = 40; 17 study even though the taste sensitivity of the patients with
males, 23 females; mean age = 45.9 ± 9.4 years). pre-diabetes lay in between those of patients with
Group 3: Patients with T2DM (n = 40; 22 males, 18 DM and controls, this could not be statistically
females; 45.7 ± 8.4 years). proven.

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 7 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

PATHOGENESIS
Cheng et al. (352) Group 1: Diabetic rats (induced with high-fat diet Cross- Yes The diabetic rats showed increased cell apoptosis
and streptozotocin injection). sectional of the taste buds, compared to the non-diabetic
Group 2: Non-diabetic rats Rats used: male, Wistar, animal study rats. Further analysis seems to hint that the
8–10 weeks old, 180–200 g. apoptosis of the cells in the taste buds is mediated
by the intrinsic mitochondrial pathway through
increased BCL2 and decreased BAX expression.
Le Floch et al. Group 1: Patients with DM (n = 73). Prospective Yes The EGT, which is an indicator for taste loss,
(350) Group 2: Age- and gender matched control cohort study significantly increased in both groups, but was
subjects without DM (n = 25). higher in the patients with DM. Moreover, this
increase was significantly associated with other
degenerative complications, especially neuropathy,
which indicates a similar biologic mechanism.
Le Floch et al. Group 1: Patients with T1DM (n = 50; 26 males, 24 Cross- Yes The EGT was significantly higher in the diabetic
(349) females; mean age = 29.1 ± 3.3 years). sectional group, compared to the control subjects without
Group 2: Age- and gender matched control study DM. The increased EGT was significantly associated
subjects without DM (n = 50; 26 males, 24 females; with diabetic peripheral neuropathy and
29.2 ± 3.3). nephropathy, suggesting that taste impairment is
another degenerative complication of DM.
Pai et al. (351) Group 1: Diabetic rats (induced by streptozotocin Cross- Yes The number of nerve fibers in the papillae and taste
injection). sectional cells in the taste buds were decreased in the
Group 2: Non-diabetic control rats. rats used: adult, animal study diabetic rats after 20 weeks of streptozotocin
male, Sprague-Dawley rats, weighing 300–350 g. injection. After this period, the diabetic rats also had
fewer numbers of these fibers and cells, compared
to the control rats. This might indicate that taste
impaired in patients with DM is caused by
neuropathic damage and/or morphological changes
in the taste buds
Pavlidis et al. (353) Group 1: Patients with T1DM (n = 14; 6 males, 8 Cross- Yes Patients with DM had increased taste thresholds,
females; mean age = 48 ± 3.2 years) and patients sectional measured by EGM. Furthermore, differences in
with T2DM (n = 22; 7 males; 15 females; mean age study gustatory anatomical structures were observed
= 46 ± 2.6 years). between the two groups. The patients with DM had
Group 2: Control subjects without DM (n = 36; 13 a decreased density of fungiform papillae and
males, 23 females; mean age = 47 ± 2.3 years). worsened vascularization of the tongue tip,
measured by contact endoscopy.

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; EGT, Electrogustometric Threshold; BCL2, B-cell lymphoma 2; BAX, Bcl-2-Associated X Protein; STZ, Streptozotocin;
EGM, Electrogustometry.

opening of the jaw. It is estimated that ∼10% of the adult microvascular damage. Research into the pathogenic pathways
population suffers from TMD (375). Earlier in this report, (hyperglycemia, insulin resistance, dyslipidemia, hypertension,
we mentioned that patients with DM are susceptible for joint and immune dysfunction) should confirm this hypothesis.
disorders, primarily through the damaging effects of AGEs on
connective tissue. From that perspective, the temporomandibular Burning Mouth Syndrome
joint could be affected as well. One study found that the Burning mouth syndrome (BMS) is a chronic pain syndrome.
prevalence of temporomandibular joint (TMJ) dysfunction was Usually, two types are distinguished: primary (i.e., idiopathic)
increased in patients with DM (354). More interestingly, the BMS if there are no underlying diseases that can explain
latter investigators also found that within the diabetic group, the complaints, and secondary BMS, when there is an oral
peripheral diabetic neuropathy was an independent risk factor or systemic disorder that could explain the condition. In the
for TMJ dysfunction. In a recent animal study, morphologic literature, many synonyms for BMS are used (e.g., glossodynia,
changes in the TMJ and the capillaries of the retrodiscal sore tongue, or stomatodynia), which complicates estimations
tissue were compared between diabetic rats and normal rats. regarding epidemiology. BMS rarely affects individuals younger
In the diabetic rats, the articular disc of the TMJ was than 30, and estimations of the total prevalence range from 0.7
significantly thinner at several sites, compared to the control rats. to 4.6% (376). A prospective cohort study from the US found
Also, the capillaries of the retrodiscal tissue were significantly an incidence rate of 11.4 per 100,000 person-years, and showed
decreased in diameter (355). These findings suggest that TMD a strong association with female gender and age (377). Despite
might be associated with DM, possibly with involvement of the major impact BMS has on quality of life, the pathogenesis

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 8 | Overview of studies investigating the association between diabetes mellitus and other oral complications.

Study Study population Study Relationship? Authors’ conclusions

design

TEMPOROMANDIBULAR JOINT DYSFUNCTION

Collin et al. (354) Group 1: Patients with T2DM (n = 45; 32 males, 13 Cross- Yes Severe temporomandibular joint (TMJ) dysfunction
females; mean age = 68 ± 5.9 years). sectional was significantly more prevalent in the diabetic
Group 2: Control subjects without DM (n = 77; 32 study group (27.3%), compared to the control group
males, 45 females; mean age = 67 ± 5.2 years). (15.8%). Also, peripheral diabetic neuropathy
emerged as independent risk factor for TMJ
dysfunction.
Uemura et al. (355) Group 1: Diabetic rats (n = 10; diabetes induced by Cross- Yes The thickness of the articular disk of the TMJ was
streptozotocin (STZ) injection). sectional significantly lower in the diabetic rats, compared to
Group 2: Non-diabetic control rats (n = 10). Rats animal study the healthy controls. Also, in the retrodiscal tissue,
used in both groups: adult, male, Wistar rats (n = 5) the diameter of the capillaries was significantly
and adult, male Goto-Kakizaki (GK) rats (n = 5]). decreased, possibly indicating microangiopathy.
BURNING MOUTH SYNDROME
Collin et al. (354) Group 1: Patients with T2DM (n = 45; 32 males, 13 Cross- Yes The prevalence of glossodynia (burning sensation of
females; mean age = 68 ± 5.9 years). sectional the tongue) was significantly higher in the diabetic
Group 2: Control subjects without DM (n = 77; 32 study group (18%) than in the control group (7%).
males, 45 females; mean age = 67 ± 5.2 years).
Eltas et al. (356) Group 1: Patients with DM (n = 22; 41% male, 59% Cross- Yes BMS was significantly more prevalent in the diabetic
female; mean age = 44.6 years). sectional group (40.9%), compared to the control group
Group 2: Control subjects without DM (n = 27; 44% study (11.1%).
male, 56% female; mean age = 40.4 years).
Moore et al. (357) Group 1: Patients with T1DM (n = 371; 50.4% Cross- Yes The prevalence of BMS without any apparent
male, 49.7% female; mean age = 33.4 ± 0.4 years). sectional pathology did not differ between the groups.
Group 2: Control subjects without DM (n = 233; study However, within the diabetic group, BMS was
37.3% male, 62.7% female; mean age = 33.1 ± significantly associated with diabetic peripheral
0.5 years). neuropathy.
Vesterinen et al. Group 1: Patients with DM and chronic kidney Cross- No There were no statistical significant differences in
(358) disease (n = 51; 37 males, 14 females; mean age = sectional the prevalence of BMS between the patients with
52 ± 13.5 years). study chronic kidney disease and diabetes, compared to
Group 2: Patients with only chronic kidney disease the control patients with only chronic kidney
(n = 87; 57 males, 30 females; mean age = 54 ± disease.
12.6 years).
PULP NECROSIS AND APICAL PERIODONTITIS
Arya et al. (359) Group 1: Patients with T2DM (n = 21; 12 males, 9 Prospective Yes Periapical healing after endodontic treatment was
females; mean age = 51 years). cohort study significantly lower in patients with DM (43%),
Group 2: Patients without DM (n = 25; 10 males, 15 compared to the group without DM (80%).
females; mean age = 34).
Catanzaro et al. Group 1: Healthy control rats (n = 8). Longitudinal Yes Several inflammatory markers were elevated in the
(360) Group 2: 30-days diabetic rats (n = 10, induced by animal study pulp of diabetic rats compared to the controls, such
streptozotocin injection) as nitrite concentrations, kallikrein and
Group 3: 90-days diabetic rats (n = 10, induced by myeloperoxidase activity and alkaline phosphatase
streptozotocin injection) Rats used: male, Wistar, concentration. Collagen concentration was
200–250 g. decreased in diabetic rats.
Fouad and Group 1: Patients with T1DM (n = 58) and T2DM Prospective Yes Of the included subjects, 540 non-surgically treated
Burleson (361) (n = 184). cohort study endodontic patients (of which 73 with DM)
Group 2: Control subjects without DM (n = 5,002). completed follow-up. Multivariate analysis revealed
that a history of DM in patients with preoperative
periradicular lesions (indicating endodontic infection)
decreased the success of endodontic treatment.
Garber et al. (362) Group 1: Healthy control rats (n = 11). Cross- Yes Inflammation was observed significantly more often
Group 2: Diabetic rats (n = 11, induced by sectional in dental pulp of diabetic rats, compared to controls.
streptozotocin injection) animal study Also, the formation of dentin bridges, which
indicates healing, was impaired more often in
diabetic rats.
Lopez-Lopez et al. Group 1: Patients with T2DM (n = 50; 20 males, 30 Cross- Yes AP was more prevalent in patient with T2DM (74%)
(363) females; mean age = 60.7 ± 10.3 years). sectional than in the control group (42%, p = 0.002). Also,
Group 2: Healthy controls (n = 50; 22 males, 28 study after multivariate regression analysis, adjusting for
females; mean age = 61.6 ± 10.4 years). several confounders, the association between AP
(OR = 3.3; 95% CI: 1.4–8.0) and the number of
root-filled teeth (OR = 1.7; 95% CI: 1.2–2.4) and
DM remained significant.

(Continued)

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 8 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Marotta et al. (364) Group 1: Patients with T2DM (n = 30; 12 males, 18 Cross- Yes Patients with DM had significantly more teeth
females; mean age = 58.2 ± 8.2 years). sectional affected by AP (15%), compared to the control
Group 2: Age- and gender matched controls (n = study subjects (12%, p=0.05).
60; mean age = 58.3 ± 8.0 years).
Nakajima et al. Experiment 1 Experiment 1: Yes Expression of RAGE and several inflammatory
(365) Group 1: Diabetic rats (n = 7, rats used: Otsuka cross- pathway markers (S100A8, S100A9, and IL-1β)
Long-Evans Tokushima Fatty Rats). sectional were increased in pulp of diabetic rats, compared to
Group 2: Control rats (n = 7, rats used: animal study the control rats. The dental pulp cell lines were
age-matched Long-Evans Tokushima Otsuka rats). Experiment 2: treated with AGE, which resulted in increased
Experiment 2 Ex vivo expression of the same inflammatory pathways.
Dental pulp cells from 8-week-old male Wistar rats experiment
were derived and cultured.
Sanchez- Group 1: Patients with poorly regulated T2DM (n = Cross- Yes In a multivariate logistic regression analysis, the
Dominguez et al. 59; 29 males, 30 females; mean age = 65.5 ± 10.6 sectional presence of AP in at least 1 tooth was significantly
(366) years; HbA1c ≥6.5%). study associated with poor metabolic control (HbA1c
Group 2: Patients with well-regulated T2DM (n = ≥6.5%).
24; 12 males, 12 females; 67.2 ± 10.8 years;
HbA1c <6.5%).
Segura-Egea et al. Group 1: Patients with T2DM (n = 32; 12 males, 20 Cross- Yes The prevalence of AP in at least one teeth was
(367) females; mean age = 63.1 ± 8.3 years). sectional higher in the diabetic group 81.3%), compared to
Group 2: Control subjects without DM (n = 38; 16 study the control group (58%, p=0.040). Also, in patients
males, 22 females; mean age = 59.6 ± 7.4 years). with DM, 7% of the teeth was affected by AP,
compared to 4% in the control group (p = 0.007).
Segura-Egea et al. 7 epidemiological studies, including patients with Systematic Yes In patients with DM, the prevalence of periapical
(368) root canal treatment (total n = 1,593; 582 patient review and radiolucent lesions was significantly increased,
with DM, 1,011 control subjects without DM). meta-analysis compared to the control subjects (OR = 1.42; 95%
CL: 1.11–1.80; p = 0.006)
Smadi (369) Group 1: Patients with T2DM (n = 145; 82 Cross- Yes The prevalence of teeth with AP and teeth with
well-controlled T2DM [HbA1c <7%], 63 sectional endodontic treatment were both increased in
poor-controlled [HbA1c >7%]; 49% male, 51% study patients with T2DM. Patients with poorly controlled
female; mean age = 49.6 ± 8.9 years) T2DM had a higher prevalence of AP and teeth with
Group 2: Patients without DM (n = 146; 51% male, endodontic treatment, compared to well-controlled
49% female; mean age = 52.0 ± 9.0 years). subjects.
PERI-IMPLANTITIS
Al-Sowygh et al. Group 1: Patients with HbA1c 6.1–8% (n = 25; 13 Cross- Yes Plaque index, bleeding on probing, pocket depth
(370) males, 12 females; mean age = 51.5 years). sectional and jaw bone loss were all increased in the diabetic
Group 2: Patients with HbA1c 8.1–10% (n = 25; 15 study groups, compared to the control group. Especially
males, 10 females; mean age = 53.7 years). the poorly controlled groups (2 and 3) showed
Group 3: Patients with HbA1c >10% (n = 17; 10 higher values. AGEs measured in peri-implant
males, 7 females; mean age = 55.9 years). sulcular fluid showed a significant correlation with
Group 4: Control subjects without DM with HbA1c pocket depth and jaw bone loss.
<6% (n = 26; 13 males, 13 females; mean age =
50.1 years).
Daubert et al. (371) Patients with dental implants (n = 96; 48 males, 48 Retrospective Yes Having DM at baseline (placement of dental
females; mean age at follow-up = 67.6 ± 10.6 cohort study implants) increased the risk for developing
years), of which 5 had DM at implant placement, with cross- peri-implantitis (RR = 3.0, 95% CI: 1.2–7.7) and for
and 8 had DM at follow-up. sectional implant loss (RR = 4.8, 95%: 1.8–12.9)
analysis
Ferreira et al. (372) Group 1: Patients with DM (unspecified type, n = Cross- Yes The prevalence of peri-implantitis was significantly
29) sectional increased in patients with DM (24%) compared to
Group 2: Patients without DM (n = 183). study the patients without DM (7%).
Gomez-Moreno Group 1: Patients with HbA1c ≤6% (n = 21; 9 Cross- Unclear Bleeding on probing was significantly different
et al. (373) males, 12 females; mean age = 60 ± 7.2 years). sectional between the groups, with the lowest values in group
Group 2: HbA1c 6.1–8% (n = 24; 11 males, 13 study 1 and the highest values in group 4. Jaw bone loss
females; mean age = 59 ± 8.1 years). and pocket depth did not significantly differ between
Group 3: HbA1c 8.1–10% (n = 11; 6 males, 5 the groups.
females; mean age = 62 ± 6.8 years).
Group 4: HbA1c ≥10.1 (n = 11; 7 males, 4 females;
mean age = 64 ± 5.6 years).

(Continued)

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Verhulst et al. Oral Complications of Diabetes Mellitus

TABLE 8 | Continued

Study Study population Study Relationship? Authors’ conclusions

design

Monje et al. (374) 7 epidemiological studies—including 2 prospective Systematic Yes Patients with hyperglycemia had an almost 50%
cohort studies, 1 retrospective cohort study and 4 review and higher risk for developing peri-implantitis, compared
cross-sectional studies—were found suitable for meta-analysis to normoglycemic controls (RR = 1.46, 95% CI:
meta-analysis (patients with DM: combined n = 1.21–1.77).
348, patients without DM: combined n = 1,165).

T1DM, Diabetes Mellitus Type 1; T2DM, Diabetes Mellitus Type 2; TMJ, Temporomandibular Joint; BMS, Burning Mouth Syndrome; AP, Apical Periodontitis; AGE, Advanced Glycation
Endproducts.

is unknown to a large extent. The general complaint of patients individuals older than 60 years suffer from at least one AP
with BMS is pain, more specifically a burning, scalding, tingling, lesion, but it is often asymptomatic (380). Similar to the marginal
or numb feeling at one or more sites in the mouth, such as form of periodontitis as discussed before (section Periodontal
the tongue, lip, and hard palate (376). Although pain is the Diseases), the driving force of AP is the inflammatory response
principle complaint, patients with BMS also often experience to microbial pathogens, which—in the case of AP—find their
xerostomia, dysgeusia, and other sensory disorders in the oral way beyond the tooth apex. Considering the pathologic similarity
region. Also, candidiasis is more prevalent in individuals with between AP and periodontitis, it is highly conceivable that AP
BMS, and often causes a burning sensation of the oral mucosa is also associated with DM. Several narrative reviews conclude
(376). Apparently, there is significant overlap with other oral that DM is a risk factor for developing AP, and negatively
conditions and complaints that are associated with DM as well. influences endodontic treatment success (378–382). Multiple
This overlap, together with a lack of a uniform definition of cross-sectional studies also show an increased prevalence of AP
BMS, complicates epidemiologic research into the association and an increased number of teeth affected by AP in patients
with DM. Increased prevalence of BMS in patients with DM with DM, compared to healthy controls (363, 364, 366–369).
compared to healthy subjects has been reported (354, 356), while Interestingly, two prospective treatment studies showed that
others did not find any differences in prevalence of BMS (358). In treatment of AP is less successful in patients with T2DM,
one study, within the people suffering from both DM and BMS, compared to healthy controls (359, 361). Considering the high
a significant association of BMS with peripheral neuropathy was prevalence of AP, and its similarities to periodontitis, it is rather
observed (357). This could indicate that BMS is another symptom surprising that so little is known about a possible relationship
of neuropathy in patients with DM, although this theory remains with DM. Longitudinal studies investigating this relationship
to be confirmed. should confirm whether DM is a risk factor for the development
and severity of AP.
Pulp Necrosis and Apical Periodontitis
Dental pulp necrosis is the death of cells and tissue inside the Peri-implant Disease
root canals and pulp chamber, which can be either symptomatic Peri-implant diseases are inflammatory lesions in the tissues
or asymptomatic. The effect of DM on the dental pulp has around dental implants. As in periodontal diseases, two entities
mainly been investigated in animal studies. Both acute and of the condition are recognized: peri-implant mucositis and
chronic effects of hyperglycemia on dental pulp were observed peri-implantitis (383). Peri-implant mucositis can be compared
in diabetic rats, characterized by increased inflammation and with gingivitis, affecting the soft tissues surrounding the
damage to structural components of the dental pulp (360). This implant, while peri-implantitis corresponds with periodontitis,
was confirmed in another study, where hyperglycemia in rats also affecting the supporting jaw bone (384). Among individuals
resulted in increased inflammation in the dental pulp, which with dental implants, the prevalence of peri-implantitis over a
impaired healing after pulp capping (362). Expression of RAGE 5–15 year period is estimated to range from 15 to 28% (383, 385–
was also increased in diabetic rats, while treatment of cultured 388). There is limited epidemiological evidence for an association
dental pulp cells of diabetic rats with AGEs also resulted in between DM and peri-implant diseases. Several recent review
increased inflammatory pathways (365). This generally observed articles assessed the influence of systemic conditions, among
inflammatory response increases the risk for pulp necrosis (378). which DM, on the development of peri-implant diseases (389–
However, the clinical relevance of these findings are questionable, 392). Despite limited evidence of often low quality, it is suggested
since well-designed studies with human subjects are lacking. that poorly controlled DM increases the risk for peri-implantitis,
Closely related to pulp necrosis is periapical or apical while well-controlled DM is not associated. A systematic review
periodontitis (AP), a condition in which the periodontal ligament confirmed this, as the meta-analysis of seven studies revealed
and surrounding alveolar bone around the apex of the tooth that patients with hyperglycemia had an almost 50% higher risk
is affected. AP is the result of an inflammatory response to an for peri-implantitis, compared to normoglycemic subjects (RR
infection of the pulp canals, often caused by caries, trauma, = 1.46, 95% CI: 1.21–1.77) (374). On the contrary, one study
or attrition (379). It is estimated that more than 60% of did not find any differences in jaw bone loss and pocket depth

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Verhulst et al. Oral Complications of Diabetes Mellitus

around dental implants between patients with well-controlled pathways that cause microvascular complications of DM also
and poorly controlled DM. However, it should be noted that the seem to be involved in oral complications. Even though this
bleeding tendency of the mucosa around implants was associated is not so evident for all oral complications we discussed, their
with higher HbA1c levels (373). A cross-sectional analysis showed generally increased prevalence cannot be ignored. Often, there
a higher prevalence of peri-implantitis in patients with DM, is a lack of decent research that prevents us from establishing
compared to subjects without DM (372). This finding was or rejecting clear associations between DM and oral diseases
confirmed in another study, where the researchers found an and conditions. Therefore, thorough, well-designed research
increased risk for peri-implantitis in patients that suffered from is necessary.
DM at the time of implant placement, compared to patients Considering the major impact of oral complications on quality
without DM (RR = 3.0, 95% CI: 1.2–7.7) (371). Interestingly, of life, prevention and early management of oral pathologies
one study observed a significant correlation between AGEs in diabetes care practice will be crucial. Although this review
concentration—measured in peri-implant sulcular fluid and has provided some insight, recognizing signs and symptoms of
increased in the groups with DM—and pocket depth and jaw oral complications will remain a major challenge for diabetes
bone loss around implants (370). care professionals. Therefore, as is already the case for the
well-known diabetic complications, we strongly encourage an
CONCLUDING COMMENTS interdisciplinary approach of DM care professionals together
with the dental field professionals, to manage potential
Prevention and management of well-known complications of oral complications.
DM, such as retinopathy, nephropathy, and neuropathy, are
crucial aspects of modern diabetes care. In order to achieve the
same for oral complications, this review has provided diabetes
AUTHOR CONTRIBUTIONS
care professionals with extensive background knowledge about MV, BL, VG, and WT contributed to the conception and drafting
potential oral complications that can occur in patients with of the review. MV and WT reviewed the literature.
DM. A considerable body of evidence suggests that several oral
complications are more prevalent in patients with DM, including
periodontitis, dry mouth, dental caries, oral candida infections, FUNDING
oral cancer, and taste disorders. In the case of periodontitis
and oral cancer, there are even longitudinal studies that show a This work is part of the Ph.D. track of MV, which is funded by
temporal association. Some studies suggest that the pathogenic Sunstar Suisse SA.

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a systematic review. Int J Oral Maxillofac Implants (2016) 31:111–8. Conflict of Interest Statement: The authors declare that the research was
doi: 10.11607/jomi.4149 conducted in the absence of any commercial or financial relationships that could
390. Naujokat H, Kunzendorf B, Wiltfang J. Dental implants and be construed as a potential conflict of interest.
diabetes mellitus-a systematic review. Int J Implant Dent. (2016) 2:5.
doi: 10.1186/s40729-016-0038-2 Copyright © 2019 Verhulst, Loos, Gerdes and Teeuw. This is an open-access article
391. Renvert S, Quirynen M. Risk indicators for peri-implantitis. A distributed under the terms of the Creative Commons Attribution License (CC BY).
narrative review. Clin Oral Implants Res. (2015) 26(Suppl. 11):15–44. The use, distribution or reproduction in other forums is permitted, provided the
doi: 10.1111/clr.12636 original author(s) and the copyright owner(s) are credited and that the original
392. Guobis Z, Pacauskiene I, Astramskaite I. General diseases influence on peri- publication in this journal is cited, in accordance with accepted academic practice.
implantitis development: a systematic review. J Oral Maxillofac Res. (2016) No use, distribution or reproduction is permitted which does not comply with these
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