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Microvascular and Macrovascular Complications of Diabetes: Editor's Note: This Article Is The 6th in A

This document summarizes the microvascular and macrovascular complications of diabetes, focusing on microvascular complications. It discusses diabetic retinopathy and nephropathy. For retinopathy, it outlines pathological mechanisms like the polyol pathway and discusses classification and features of background and proliferative retinopathy. For nephropathy, it defines microalbuminuria and discusses screening, progression to proteinuria, and treatment including controlling blood glucose and blood pressure.

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0% found this document useful (0 votes)
49 views6 pages

Microvascular and Macrovascular Complications of Diabetes: Editor's Note: This Article Is The 6th in A

This document summarizes the microvascular and macrovascular complications of diabetes, focusing on microvascular complications. It discusses diabetic retinopathy and nephropathy. For retinopathy, it outlines pathological mechanisms like the polyol pathway and discusses classification and features of background and proliferative retinopathy. For nephropathy, it defines microalbuminuria and discusses screening, progression to proteinuria, and treatment including controlling blood glucose and blood pressure.

Uploaded by

nadya
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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D i a b e t e s F o u n d a t i o n

Microvascular and Macrovascular Complications


of Diabetes
Michael J. Fowler, MD

Editor’s note: This article is the 6th in a Microvascular Complications of retinopathy. In animal models, sugar
12-part series reviewing the fundamentals Diabetes alcohol accumulation has been linked

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of diabetes care for physicians in training. to microaneurysm formation, thicken-
Previous articles in the series can be Diabetic retinopathy ing of basement membranes, and loss of
viewed at the Clinical Diabetes website Diabetic retinopathy may be the most pericytes. Treatment studies with aldose
(http://clinical.diabetesjournals.org). common microvascular complication of reductase inhibitors, however, have been
diabetes. It is responsible for ~ 10,000 disappointing.1,4,5
new cases of blindness every year in Cells are also thought to be injured
Diabetes is a group of chronic dis- the United States alone.1 The risk of by glycoproteins. High glucose concen-
eases characterized by hyperglycemia. developing diabetic retinopathy or other trations can promote the nonenzymatic
Modern medical care uses a vast array microvascular complications of diabetes formation of advanced glycosylated end
of lifestyle and pharmaceutical interven- depends on both the duration and the products (AGEs). In animal models,
tions aimed at preventing and controlling severity of hyperglycemia. Development these substances have also been associ-
hyperglycemia. In addition to ensuring of diabetic retinopathy in patients with ated with formation of microaneurysms
the adequate delivery of glucose to the type 2 diabetes was found to be related and pericyte loss. Evaluations of AGE
tissues of the body, treatment of diabetes to both severity of hyperglycemia and inhibitors are underway.1
attempts to decrease the likelihood that presence of hypertension in the U.K. Oxidative stress may also play an
Prospective Diabetes Study (UKPDS), important role in cellular injury from
the tissues of the body are harmed by
and most patients with type 1 diabetes hyperglycemia. High glucose levels
hyperglycemia.
develop evidence of retinopathy within can stimulate free radical production
The importance of protecting the
20 years of diagnosis.2,3 Retinopathy and reactive oxygen species formation.
body from hyperglycemia cannot be
may begin to develop as early as 7 Animal studies have suggested that
overstated; the direct and indirect effects
years before the diagnosis of diabetes in treatment with antioxidants, such as
on the human vascular tree are the major
patients with type 2 diabetes.1 There are vitamin E, may attenuate some vascular
source of morbidity and mortality in
several proposed pathological mecha- dysfunction associated with diabetes,
both type 1 and type 2 diabetes. Gener- nisms by which diabetes may lead to but treatment with antioxidants has not
ally, the injurious effects of hypergly- development of retinopathy. yet been shown to alter the develop-
cemia are separated into macrovascular Aldose reductase may participate in ment or progression of retinopathy or
complications (coronary artery disease, the development of diabetes complica- other microvascular complications of
peripheral arterial disease, and stroke) tions. Aldose reductase is the initial diabetes.1,6
and microvascular complications (dia- enzyme in the intracellular polyol Growth factors, including vascular
betic nephropathy, neuropathy, and reti- pathway. This pathway involves the con- endothelial growth factor (VEGF),
nopathy). It is important for physicians version of glucose into glucose alcohol growth hormone, and transforming
to understand the relationship between (sorbitol). High glucose levels increase growth factor β, have also been pos-
diabetes and vascular disease because the flux of sugar molecules through the tulated to play important roles in the
the prevalence of diabetes continues to polyol pathway, which causes sorbitol development of diabetic retinopathy.
increase in the United States, and the accumulation in cells. Osmotic stress VEGF production is increased in dia-
clinical armamentarium for primary and from sorbitol accumulation has been betic retinopathy, possibly in response to
secondary prevention of these complica- postulated as an underlying mechanism hypoxia. In animal models, suppressing
tions is also expanding. in the development of diabetic microvas- VEGF production is associated with less
cular complications, including diabetic progression of retinopathy.1,3,7

Clinical Diabetes • Volume 26, Number 2, 2008 77


D i a b e t e s F o u n d a t i o n

Diabetic retinopathy is generally Microalbuminuria is defined as albumin treated to the lowest safe glucose level
classified as either background or prolif- excretion of 30–299 mg/24 hours. With- that can be obtained to prevent or control
erative. It is important to have a general out intervention, diabetic patients with diabetic nephropathy.9,11,12 Treatment
understanding of the features of each to microalbuminuria typically progress to with angiotensin-converting enzyme
interpret eye examination reports and proteinuria and overt diabetic nephropa- (ACE) inhibitors has not been shown to
advise patients of disease progression thy. This progression occurs in both type prevent the development of microalbu-
and prognosis. 1 and type 2 diabetes. minuria in patients with type 1 diabetes
Background retinopathy includes As many as 7% of patients with type but has been shown to decrease the risk
such features as small hemorrhages in 2 diabetes may already have microalbu- of developing nephropathy and cardio-
the middle layers of the retina. They minuria at the time they are diagnosed vascular events in patients with type 2
clinically appear as “dots” and therefore with diabetes.9 In the European Diabetes diabetes.9,13

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are frequently referred to as “dot hemor- Prospective Complications Study, the In addition to aggressive treatment
rhages.” Hard exudates are caused by cumulative incidence of microalbumin- of elevated blood glucose, patients
lipid deposition that typically occurs at uria in patients with type 1 diabetes was with diabetic nephropathy benefit from
the margins of hemorrhages. Microaneu- ~ 12% during a period of 7 years.9,10 In treatment with antihypertensive drugs.
rysms are small vascular dilatations that the UKPDS, the incidence of microalbu- Renin-angiotensin system blockade
occur in the retina, often as the first sign minuria was 2% per year in patients with has additional benefits beyond the
of retinopathy. They clinically appear type 2 diabetes, and the 10-year preva- simple blood pressure–lowering effect
as red dots during retinal examination. lence after diagnosis was 25%.9,11 in patients with diabetic nephropathy.
Retinal edema may result from micro- The pathological changes to the Several studies have demonstrated
vascular leakage and is indicative of kidney include increased glomerular renoprotective effects of treatment with
compromise of the blood-retinal barrier. basement membrane thickness, micro- ACE inhibitors and antiotensin receptor
The appearance is one of grayish retinal aneurysm formation, mesangial nodule blockers (ARBs), which appear to be
areas. Retinal edema may require inter- formation (Kimmelsteil-Wilson bod- present independent of their blood pres-
vention because it is sometimes associ- ies), and other changes. The underlying sure–lowering effects, possibly because
ated with visual deterioration.8 mechanism of injury may also involve of decreasing intraglomerular pressure.
Proliferative retinopathy is charac- some or all of the same mechanisms as Both ACE inhibitors and ARBs have
terized by the formation of new blood diabetic retinopathy. been shown to decrease the risk of pro-
vessels on the surface of the retina and Screening for diabetic nephropathy gression to macroalbuminuria in patients
can lead to vitreous hemorrhage. White or microalbuminuria may be accom- with microalbuminuria by as much
areas on the retina (“cotton wool spots”) plished by either a 24-hour urine as 60–70%. These drugs are recom-
can be a sign of impending proliferative collection or a spot urine measurement mended as the first-line pharmacological
retinopathy. If proliferation continues, of microalbumin. Measurement of the treatment of microalbuminuria, even in
blindness can occur through vitreous microalbumin-to-creatinine ratio may patients without hypertension.9
hemorrhage and traction retinal detach- help account for concentration or dilu- Similarly, patients with macroalbu-
ment. With no intervention, visual loss tion of urine, and spot measurements minuria benefit from control of hyper-
may occur. Laser photocoagulation can are more convenient for patients than tension. Hypertension control in patients
often prevent proliferative retinopathy 24-hour urine collections. It is important with macroalbuminuria from diabetic
from progressing to blindness; therefore, to note that falsely elevated urine protein kidney disease slows decline in glomeru-
close surveillance for the existence or levels may be produced by conditions lar filtration rate (GFR). Treatment with
progression of retinopathy in patients such as urinary tract infections, exercise, ACE inhibitors or ARBs has been shown
with diabetes is crucial.8 and hematuria. to further decrease the risk of progres-
Initial treatment of diabetic nephrop- sion of kidney disease, also independent
Diabetic nephropathy athy, as of other complications of diabe- of the blood pressure–lowering effect.
Diabetic nephropathy is the leading tes, is prevention. Like other microvas- Combination treatment with an ACE
cause of renal failure in the United cular complications of diabetes, there inhibitor and an ARB has been shown to
States. It is defined by proteinuria > 500 are strong associations between glucose have additional renoprotective effects.
mg in 24 hours in the setting of diabetes, control (as measured by hemoglobin It should be noted that patients treated
but this is preceded by lower degrees A1c [A1C]) and the risk of developing with these drugs (especially in combina-
of proteinuria, or “microalbuminuria.” diabetic nephropathy. Patients should be tion) may experience an initial increase

78 Volume 26, Number 2, 2008 • Clinical Diabetes


D i a b e t e s F o u n d a t i o n

in creatinine and must be monitored for peripheral sensation are > 87% sensitive with increased risk of silent myocardial
hyperkalemia. Considerable increase in in detecting the presence of neuropathy. ischemia and mortality.18
creatinine after initiation of these agents Patients also typically experience loss There is no specific treatment of
should prompt an evaluation for renal of ankle reflex.16 Patients who have lost diabetic neuropathy, although many
artery stenosis.9,14 10-g monofilament sensation are at drugs are available to treat its symptoms.
considerably elevated risk for developing The primary goal of therapy is to control
Diabetic neuropathy foot ulceration.17 symptoms and prevent worsening of
Diabetic neuropathy is recognized by the Pure sensory neuropathy is relatively neuropathy through improved glycemic
American Diabetes Association (ADA) rare and associated with periods of poor control. Some studies have suggested
as “the presence of symptoms and/or glycemic control or considerable fluctua- that control of hyperglycemia and
signs of peripheral nerve dysfunction in tion in diabetes control. It is character- avoidance of glycemic excursions may
people with diabetes after the exclusion improve symptoms of peripheral neurop-
ized by isolated sensory findings without
of other causes.”15 As with other micro- athy. Amitriptyline, imiprimine, parox-

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signs of motor neuropathy. Symptoms
vascular complications, risk of develop- etine, citalopram, gabapentin, pregablin,
are typically most prominent at night.16
ing diabetic neuropathy is proportional carbamazepine, topiramate, duloxetine,
Mononeuropathies typically have a
to both the magnitude and duration of tramadol, and oxycodone have all been
more sudden onset and involve virtu-
hyperglycemia, and some individuals used to treat painful symptoms, but only
ally any nerve, but most commonly the
may possess genetic attributes that affect duloxetine and pregablin possess official
median, ulnar, and radial nerves are
their predisposition to developing such indications for the treatment of painful
affected. Cranial neuropathies have been
complications. peripheral diabetic neuropathy.16 Treat-
described but are rare. It should be noted
The precise nature of injury to the ment with some of these medications
that nerve entrapment occurs frequently
peripheral nerves from hyperglycemia may be limited by side effects of the
in the setting of diabetes. Electrophysi-
is not known but likely is related to medication, and no single drug is univer-
ological evaluation in diabetic neu-
mechanisms such as polyol accumula- sally effective. Treatment of autonomic
tion, injury from AGEs, and oxidative ropathy demonstrates decreases in both
amplitude of nerve impulse and conduc- neuropathy is targeted toward the organ
stress. Peripheral neuropathy in diabetes system that is affected, but also includes
may manifest in several different forms, tion but may be useful in identifying the
location of nerve entrapment. Diabetic optimization of glycemic control.
including sensory, focal/multifocal, and
autonomic neuropathies. More than amyotrophy may be a manifestation Macrovascular Complications
80% of amputations occur after foot of diabetic mononeuropathy and is of Diabetes
ulceration or injury, which can result characterized by severe pain and muscle The central pathological mechanism in
from diabetic neuropathy.16 Because of weakness and atrophy, usually in large macrovascular disease is the process of
the considerable morbidity and mortality thigh muscles.16 atherosclerosis, which leads to nar-
that can result from diabetic neuropathy, Several other forms of neuropathy rowing of arterial walls throughout the
it is important for clinicians to under- may mimic the findings in diabetic sen- body. Atherosclerosis is thought to result
stand its manifestations, prevention, and sory neuropathy and mononeuropathy. from chronic inflammation and injury
treatment. Chronic inflammatory polyneuropathy, to the arterial wall in the peripheral or
Chronic sensorimotor distal sym- vitamin B12 deficiency, hypothyroidism, coronary vascular system. In response
metric polyneuropathy is the most and uremia should be ruled out in the to endothelial injury and inflamma-
common form of neuropathy in diabetes. process of evaluating diabetic peripheral tion, oxidized lipids from LDL particles
Typically, patients experience burning, neuropathy.16 accumulate in the endothelial wall of
tingling, and “electrical” pain, but some- Diabetic autonomic neuropathy also arteries. Angiotensin II may promote
times they may experience simple numb- causes significant morbidity and even the oxidation of such particles. Mono-
ness. In patients who experience pain, it mortality in patients with diabetes. cytes then infiltrate the arterial wall and
may be worse at night. Patients with sim- Neurological dysfunction may occur in differentiate into macrophages, which
ple numbness can present with a painless most organ systems and can by manifest accumulate oxidized lipids to form foam
foot ulceration, so it is important to by gastroparesis, constipation, diarrhea, cells. Once formed, foam cells stimulate
realize that lack of symptoms does not anhidrosis, bladder dysfunction, erectile macrophage proliferation and attraction
rule out presence of neuropathy. Physi- dysfunction, exercise intolerance, resting of T-lymphocytes. T-lymphocytes, in
cal examination reveals sensory loss to tachycardia, silent ischemia, and even turn, induce smooth muscle proliferation
light touch, vibration, and temperature. sudden cardiac death.16 Cardiovascular in the arterial walls and collagen accu-
Abnormalities in more than one test of autonomic dysfunction is associated mulation. The net result of the process is

Clinical Diabetes • Volume 26, Number 2, 2008 79


D i a b e t e s F o u n d a t i o n

the formation of a lipid-rich atheroscle- in this setting of multiple risk factors, There has not been a large, long-
rotic lesion with a fibrous cap. Rupture type 2 diabetes acts as an independent term, controlled study showing
of this lesion leads to acute vascular risk factor for the development of isch- decreases in macrovascular disease
infarction.19 emic disease, stroke, and death.27 Among event rates from improved glycemic
In addition to atheroma formation, people with type 2 diabetes, women control in type 2 diabetes. Modifica-
there is strong evidence of increased may be at higher risk for coronary heart tion of other elements of the metabolic
platelet adhesion and hypercoagulability disease than men. The presence of syndrome, however, has been shown to
in type 2 diabetes. Impaired nitric oxide microvascular disease is also a predictor very significantly decrease the risk of
generation and increased free radical of coronary heart events.28 cardiovascular events in numerous stud-
formation in platelets, as well as altered Diabetes is also a strong independent ies. Blood pressure lowering in patients
calcium regulation, may promote platelet predictor of risk of stroke and cerebro- with type 2 diabetes has been associated
aggregation. Elevated levels of plas- vascular disease, as in coronary artery with decreased cardiovascular events and
minogen activator inhibitor type 1 may disease.29 Patients with type 2 diabetes mortality. The UKPDS was among the

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also impair fibrinolysis in patients with have a much higher risk of stroke, with first and most prominent study demon-
diabetes. The combination of increased an increased risk of 150–400%. Risk of strating a reduction in macrovascular
coagulability and impaired fibrinolysis stroke-related dementia and recurrence, disease with treatment of hypertension
likely further increases the risk of vascu- as well as stroke-related mortality, is in type 2 diabetes.32,33
lar occlusion and cardiovascular events elevated in patients with diabetes.20 There is additional benefit to lower-
in type 2 diabetes.20 Patients with type 1 diabetes also ing blood pressure with ACE inhibitors
Diabetes increases the risk that an bear a disproportionate burden of or ARBs. Blockade of the renin-
individual will develop cardiovascular coronary heart disease. Studies of have angiotensin system using either an ACE
disease (CVD). Although the precise shown that these patients have a higher inhibitor or an ARB reduced cardio-
mechanisms through which diabetes mortality from ischemic heart disease at vascular endpoints more than other
increases the likelihood of atheroscle- all ages compared to the general popula- antihypertensive agents.13,20,34 It should
rotic plaque formation are not com- tion. In individuals > 40 years of age, be noted that use of ACE inhibitors and
pletely defined, the association between women experience a higher mortality ARBs also may help slow progression of
the two is profound. CVD is the primary from ischemic heart disease than men.21 diabetic microvascular kidney disease.
cause of death in people with either type Observational studies have shown that Multiple drug therapy, however, is gener-
1 or type 2 diabetes.21,22 In fact, CVD the cerebrovascular mortality rate is ally required to control hypertension in
accounts for the greatest component of elevated at all ages in patients with type patients with type 2 diabetes.
health care expenditures in people with 1 diabetes.30 Another target of therapy is blood
diabetes.22,23 The increased risk of CVD has led lipid concentration. Numerous studies
Among macrovascular diabetes to more aggressive treatment of these have shown decreased risk in macrovas-
complications, coronary heart disease conditions to achieve primary or second- cular disease in patients with diabetes
has been associated with diabetes in ary prevention of coronary heart disease who are treated with lipid-lowering
numerous studies beginning with the before it occurs. Studies in type 1 dia- agents, especially statins. These drugs
Framingham study.24 More recent studies betes have shown that intensive diabetes are effective for both primary and sec-
have shown that the risk of myocardial control is associated with a lower resting ondary prevention of CVD, but patients
infarction (MI) in people with diabetes heart rate and that patients with higher with diabetes and preexisting CVD may
is equivalent to the risk in nondiabetic degrees of hyperglycemia tend to have receive the highest benefit from treat-
patients with a history of previous MI.25 a higher heart rate, which is associated ment. Although it is beyond the scope of
These discoveries have lead to new rec- with higher risk of CVD.22 Even more this article to review all relevant studies,
ommendations by the ADA and Ameri- conclusively, the Diabetes Control and it should be noted these beneficial effects
can Heart Association that diabetes be Complications Trial/Epidemiology of of lipid and blood pressure lowering are
considered a coronary artery disease risk Diabetes Interventions and Complica- relatively well proven and likely also
equivalent rather than a risk factor.26 tions Study demonstrated that during 17 extend to patients with type 1 diabetes.
Type 2 diabetes typically occurs in years of prospective analysis, intensive In addition to statin therapy, fibric acid
the setting of the metabolic syndrome, treatment of type 1 diabetes, including derivates have beneficial effects. They
which also includes abdominal obe- lower A1C, is associated with a 42% risk raise HDL levels and lower triglyceride
sity, hypertension, hyperlipidemia, and reduction in all cardiovascular events concentrations and have been shown
increased coagulability. These other fac- and a 57% reduction in the risk of nonfa- to decrease the risk of MI in patients
tors can also act to promote CVD. Even tal MI, stroke, or death from CVD.31 with diabetes in the Veterans Affairs

80 Volume 26, Number 2, 2008 • Clinical Diabetes


D i a b e t e s F o u n d a t i o n

High-Density Lipoprotein Cholesterol of painful peripheral neuropathy may monitored closely for possible adverse
Intervention Trial.20,26,35–39 be effective in improving quality of life reactions of therapy.15
in patients but do not appear to alter the Aspirin therapy (75–162 mg/day)
Practice Recommendations natural course of the disease. For this is indicated in secondary prevention
Patients with type 1 diabetes of > 5 reason, patients and physicians should of CVD and should be used in patients
years’ duration should have annual continue to strive for the best possible with diabetes who are > 40 years of
screening for microalbuminuria, and glycemic control. age and in those who are 30–40 years
all patients with type 2 diabetes should In light of the above strong evidence of age if other risk factors are present.
undergo such screening at the time of linking diabetes and CVD and to control Patients < 21 years of age should not
diagnosis and yearly thereafter. All and prevent the microvascular complica- receive aspirin therapy because of the
patients with diabetes should have serum tions of diabetes, the ADA has issued risk of Reye’s syndrome. Patients who
creatinine measurement performed cannot tolerate aspirin therapy because
practice recommendations regarding the
annually. Patients with microalbuminuria of allergy or adverse reaction may be

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prevention and management of diabetes
or macroalbuminuria should be treated considered for other antiplatelet agents.15
complications.
with an ACE inhibitor or ARB unless In addition to the above pharmaco-
Blood pressure should be mea-
they are pregnant or cannot tolerate the logical recommendations, patients with
sured routinely. Goal blood pressure is
medication. Patients who cannot tolerate diabetes should be encouraged to not
< 130/80 mmHg. Patients with a blood
one of these medications may be able to begin smoking or to stop smoking to
pressure ≥ 140/90 mmHg should be
tolerate the other. Potassium should be decrease their risk of CVD and benefit
treated with drug therapy in addition to
monitored in patients on such therapy. their health in other ways. It should also
diet and lifestyle modification. Patients
Patients with a GFR < 60 ml/min or with be noted that statins, ACE inhibitors, and
with a blood pressure of 130–139/80–89
uncontrolled hypertension or hyper- ARBs are strongly contraindicated in
mmHg may attempt a trial of lifestyle
kalemia may benefit from referral to a pregnancy.
and behavioral therapy for 3 months and
nephrologist.15
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Boyle PJ: Diabetes mellitus and macrovascu- treated diabetes. Stroke 34:418–421, 2003 Michael J. Fowler, MD, is an assistant
lar disease: mechanisms and mediators. Am J Med
120:S12–S17, 2007
31
Nathan DM, Cleary PA, Backlund JY, professor of medicine in the Division of
Genuth SM, Lachin JM, Orchard TJ, Raskin P,
20
Beckman JA, Creager MA, Libby P: Zinman B: Intensive diabetes treatment and cardio- Diabetes, Endocrinology, and Metabo-
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physiology, and management. JAMA 287:2570– N Engl J Med 353:2643–2653, 2005
2581, 2002 at Vanderbilt University Medical Center
32
U.K. Prospective Diabetes Study Group:
21
Laing SP, Swerdlow AJ, Slater SD, Burden Efficacy of atenolol and captopril in reducing risk in Nashville, Tenn. He is an associate
AC, Morris A, Waugh NR, Gatling W, Bingley PJ, of macrovascular and microvascular complications editor of Clinical Diabetes.

82 Volume 26, Number 2, 2008 • Clinical Diabetes

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