Biennial Review of Pain

Diabetic neuropathy and neuropathic pain: a (con)

fusion of pathogenic mechanisms?
Nigel A. Calcutt

1. Introduction lesions similar to those reported in other organs during diabetes

Neuropathy will afflict over half of the estimated 460 million people are also an early feature.222 Biopsy studies have identified
worldwide who have diabetes,303 of whom approximately one- segmental demyelination in large fibers and axonal degeneration
third will also develop neuropathic pain.2 The pathogenesis of of all fiber classes96 with clusters of regenerating fibers,222 but
diabetic neuropathy is uncertain, and attaining and maintaining regeneration is clearly insufficient to overcome ongoing distal
close glycemic control remains the only universal recommenda- degenerative processes. It is now widely accepted that diabetes
damages all components of the nervous system, not just
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tion for preventing or slowing progression of the condition.

Although there has been considerable progress in b-cell, stem peripheral nerves. Historical autopsy evidence of demyelination
cell, and whole pancreas transplantation230 and ongoing re- and neuronal degeneration in the spinal cord328 has been
finement of continuous glucose monitors for maintaining consis- supported by more recent noninvasive imaging studies,311 and
tent euglycemia,281 these advanced bioengineering solutions are there is an emerging recognition of structural and functional
unlikely to become available for the majority of the diabetic impairments in the higher central nervous system (CNS).27,312,323
population worldwide in the foreseeable future.65 Although the Around one-third of patients with diabetic neuropathy report
intermittent or continuous paresthesias and/or pain.2 The most
mechanisms driving degenerative neuropathy and pain are likely
intertwined, the unpredictability of which patients with neuropa- frequent descriptors are of numbness, tingling, burning, pins and
thy also exhibit pain suggests as yet ill-defined pathways unique needles, electric shock, and pain to cold.357 Pain may develop
for pain generation. Treatment of painful diabetic neuropathy is during the prediabetic period329,336 or relatively early after
limited to analgesics,9,18 with efficacy of any given agent limited to diagnosis of diabetes132 but tends to be associated with
unpredictable subpopulations of patients.112 This somewhat advanced degenerative neuropathy.348 A separate and distinct
bleak landscape has prompted extensive investigation of the pain condition, historically termed insulin neuritis, can also
pathogenic consequences of hyperglycemia and, more recently, develop after instigation of tight glycemic control.121
glucose-independent neurotoxic mechanisms as downstream
sites for therapeutic intervention. 2. Discussion
The most common presentation of diabetic neuropathy is as
a distal symmetrical polyneuropathy with numbness in the distal 2.1. Mechanistic implications from clinical observations
extremities. Loss of sensation can lead to unattended wounds A number of deductions made from the clinical presentation of
that, when combined with peripheral vascular disease and diabetic neuropathy have guided the development of mechanistic
impaired wound healing, may lead to infection and ultimately hypotheses and both clinical and preclinical investigations:
amputation.160 Indications of motor and autonomic nerve
dysfunction may also be present. Early quantifiable features of
distal symmetrical polyneuropathy (from herein termed “diabetic 2.1.1. Initiating lesion
neuropathy,” unless stated otherwise) include slowing of large The bilateral presentation of diabetic neuropathy implies a systemic
sensory and motor fiber conduction velocity (SNCV and MNCV)32 primary lesion, although people with diabetes are also more
and depletion of small sensory nerves in the skin and cornea.274 vulnerable to focal neuropathies.330 The occurrence of neuropathy
Peripheral nerves also exhibit resistance to ischemic conduction in both insulin-deficient (type 1) and insulin-insensitive (type 2)
blockade/failure, which patients may become aware of as an diabetes has driven an overwhelming experimental focus on
ability to squat or kneel for lengthy periods of time without hyperglycemia as the initiating lesion. This was encouraged by
developing paresthesias and that can be confirmed using routine results from the Diabetic Control and Complications Trial (DCCT)
electrophysiology and a blood pressure cuff.136,314 Microvascular study, which showed that improved glycemic control beyond the
accepted standard of care slowed the onset and progression of
Sponsorships or competing interests that may be relevant to content are disclosed diabetic complications, including peripheral neuropathy, in a large
at the end of this article. cohort of type 1 diabetic patients.226 The association between
Department of Pathology, University of California, San Diego, La Jolla, CA, United hyperglycemia and complications, including neuropathy, is less
States convincing in patients with type 2 diabetes, and alternative primary
Corresponding author. Address: Department of Pathology, University of California pathogenic mechanisms have been proposed (see below). Data
San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States. Tel.: 1 858 534 from the DCCT, its follow-up, and preclinical studies also prompted
5331; fax: 1 858 534 1886. E-mail address: [email protected] (N.A. Calcutt). the concept of “metabolic memory” in which initial exposure to
PAIN 161 (2020) S65–S86 glucose makes indelible epigenetic modifications to cells that are
© 2020 International Association for the Study of Pain not amenable to acute restoration of normoglycemia.370 To date,
http://dx.doi.org/10.1097/j.pain.0000000000001922 this has proven to be more applicable to other complications of

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diabetes than to peripheral neuropathy,234 although there is 2.1.5. Pain generator site
supportive evidence associated with autonomic neuropathy.119
It is tempting to assume that if pain is perceived in the feet, then the
primary lesion site is to sensory nerves that innervate the feet.
2.1.2. Cellular targets Recent studies suggesting that pain correlates with nerve re-
generation markers in the skin30,58 have revived the old ideas that
As epineurial, perineurial, and endoneurial blood vessels are painful diabetic neuropathy may arise from the instability of
compromised in nerves of diabetic patients with early neurop- degenerating peripheral sensory neurons, ephaptic activation of
athy,222,269 a view of diabetic neuropathy emerged as repre- adjacent intact peripheral fibers, and/or activity of regenerating
senting a secondary manifestation of microvascular disease peripheral fibers.34 Hyperactive nociceptors and recruitment of
arising from hyperglycemia-induced damage to vascular endo- otherwise silent nociceptors have been recorded in subjects with
thelial cells.217 This aligns diabetic neuropathy with other painful diabetic neuropathy by microneurography257 and used to
complications of diabetes,261 and there is an association preselect subjects for clinical trial.315 However, the “irritable
between development of neuropathy and concurrent nephrop- nociceptor” phenotype (preserved small fiber function with hyper-
athy and retinopathy. The presence of resistance to ischemic algesia) formed only a small subset (6%) of a cohort comprising 191
conduction blockade also implies an early presence of ischemic subjects with painful diabetic neuropathy,348 and peripheral
hypoxia,217 although it also suggests that nerve metabolism hyperactivity may not be the only genesis of pain. A report that
adapts within acceptable tolerance limits. Whether vascular the onset of type 2 diabetes triggered symmetrical pain in both feet
insufficiency initiates peripheral neuropathy in diabetic patients of a patient who had 1 leg amputated some 44 years earlier
or impedes the capacity of cells within the nerve to withstand prompted the suggestion that the initiating lesion for diabetes-
direct glucotoxic or other insults remains an area of lively induced pain need not be at the site where pain is perceived.279 In
debate. Similarly, whether there is initial damage to Schwann support of this, there is a growing body of data emerging from
cells (primary schwannopathy)174 and to axons (primary imaging studies of diabetic subjects with painful neuropathy,
axonopathy)97 or independent and/or interdependent mecha- indicating that there is CNS dysfunction and pathology in regions
nisms of damage to each cell type122 has also been an area of associated with pain processing,310,312 whereas preclinical and
continuous investigation.349 clinical studies also suggest spinal involvement.225 In addition, there is
a growing appreciation that the genesis of neuropathic pain states
evolves over time, progressing from peripheral to central sites. Painful
2.1.3. Degenerative neuropathy diabetic neuropathy may therefore incorporate multiple generator
That numbness is usually first perceived in the toes, along with the sites whose relative dominance waxes and wanes as concurrent
early loss of epidermal fibers in the lower extremities, suggests degenerative pathology progresses. This complexity has implications
a length-dependent neuropathy associated with an inability to for selecting clinical trial populations that may be more heterogenous
maintain the regions of the axon that are most distant from the cell than previously recognized20 and result in the infrequent (number
body—not unlike the travails of Napoleon when invading Russia needed to treat: NNT . 5) and unpredictable efficacy of current pain
in the winter of 1812.197 However, reports that depletion of medications used to treat painful diabetic neuropathy.112
sensory nerves in the subbasal plexus of the cornea is an equally
sensitive marker for early neuropathy in diabetic patients indicate
that distal regions of the axon are most vulnerable, irrespective of 2.2. Glucotoxic mechanisms
the length.8,274 Longer axons may be particularly vulnerable to The occurrence of neuropathy in both forms of diabetes and the
accumulation of focal lesions due to size alone, but systemic success of intensive glycemic control regimens to slow pro-
insults do not appear to discriminate based on the absolute gression of diabetic neuropathy in type 1 diabetes267 naturally
axonal length. focused attention on hyperglycemia as the initiating event of
diabetic neuropathy. Glucose enters the peripheral nerve and
2.1.4. Painful vs painless neuropathy brain through insulin-independent glucose transporters (GLUTs).
GLUT-1 is the major glucose transporter of the microvascular and
Why approximately only a third of diabetic patients with perineurial components of the blood:brain and blood:nerve
degenerative neuropathy develop pain2 remains enigmatic. barriers,335 with GLUT-3 localized to peripheral neurons.338
Studies have sought clinical, structural, functional, or meta- Insulin-dependent GLUT-4 is restricted to select neuronal
bolic biomarkers that segregate subjects otherwise well populations of the brain.19 The search for detrimental con-
matched in presentation of diabetes and neuropathy into sequences of hyperglycemia has focused on modifications to the
those with or without pain.319,332 Recent examples are shown protein structure and function by direct glycation or enzyme-
in Table 1.30,34,58,59,76,90,98,113,114,139,176,177,195,215,223, mediated glycosylation along with excess flux through glucose
225,241,271–274,283,310,312,313,318,327,333,341,348,357,360,384,414
However, metabolism pathways (Fig. 1).
interpretation of such studies is complicated by the heteroge-
neity of the pain state caused by diabetes, and there have been
few attempts to identify biomarkers that identify specific pain 2.2.1. Models of diabetic neuropathy
subcategories identified among diabetic patients.20,348 Per- In vitro studies allow direct environmental manipulation of
haps the best examples to date are associations of burning individual cell types and are valuable for identifying plausible
pain with gain-of-function mutations in subunits of the Nav1.7 pathogenic mechanisms, with the recognized caveats that these
ion channel,11,29 although this represents a rare subgroup are traumatically excised tissues in artificial environments—
within those with painful diabetic neuropathy. Identification of neurons enter an axonal injury and regeneration phenotype while
features unique to subjects with pain could reveal potential Schwann cells return to their nonmyelinating form.117 Perhaps
pathogenic mechanisms specific for pain, with the usual the most sophisticated studies use cells derived from adult
caveat that any implied causality must be proven. control and diabetic animals maintained under conditions that

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Table 1
Potential biomarkers for painful vs painless diabetic neuropathy.
Type Tissue Biomarker for painful neuropathy Representative publications
Structural (PNS) Nerve biopsy Small fiber damage and regeneration 34,215,220
Skin biopsy Increased regeneration and/or axonal swellings 30,58,59,113
Cornea Increased corneal nerve loss 176,177,225,274
Increased corneal nerve branching 272
Structural (CNS) Cortex Atrophy of the somatosensory cortex 312
Functional (PNS) Nerve Increased epineurial blood flow 98
Skin Impaired stimulus-evoked blood flow 273
Skin Increased laser Doppler image (LDI) flare (small fiber function) 195
Sensory systems Severe hypoalgesia 283,348
Functional (CNS) Spinal cord Impaired rate-dependent depression of the H wave 225
Periaqueductal gray Dysfunction of descending inhibitory systems 310
Thalamus Hyperperfusion 313
Anterior cingulate cortex Hyperperfusion 384
Limbic/striatal structures Increased responses to stimuli 360
Others Blood Increased C-reactive protein (CRP) and soluble Intercellular 90
Adhesion Molecule 1 (slCAM-1)
Increased TNFa 241,271
Increased iNOS 271
Reduced vitamin D 318
Reduced Glo-1 327
Physiology Sex (female) 139,357
Increased body mass index 414
Autonomic dysfunction 76,114,333,341
Studies in which no change was detected are shown in italics.

reflect the in vivo insulin and glycemic environment from which provide most data that underpin current hypotheses regarding the
they were derived133 and coculture neurons and Schwann cells pathogenesis of diabetic neuropathy and neuropathic pain. Both
to facilitate myelination.342,364 species can be used to model prediabetes and type 1 or type 2
Of the animal models, diabetic cats exhibit nerve pathology that diabetes using dietary, chemical, or genetic initiating events. There
most closely reflects the human condition, with prominent de- are variations in the neuropathy phenotype and rate of progression
myelination and axonal degeneration.238 Rats and mice are the between specific models, species, strains, laboratories, and
most commonly used animal models of diabetic neuropathy and assays.26 The provenance of new disorders identified in

Figure 1. Mechanisms of glucotoxicity in diabetic neuropathy: Hyperglycemia has been considered central to the pathogenesis of diabetic neuropathy, and
multiple mechanisms have been proposed from both preclinical studies and clinical observations (see text for details). AGE, advanced glycation end product; PDK,
pyruvate dehydrogenase kinase; PKC, protein kinase C; RAGE, receptor for AGE; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.

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Figure 2. Rat plantar skin stained with antibody to PGP9.5 and viewed by bright field (panel A) or fluorescence (panel B) microscopy reveals dermal nerves (yellow arrows)
projecting across the dermal:epidermal junction and into the epidermis (purple/blue counterstained nuclei) where they form profiles of intra-epidermal nerve fibers (red arrows).
Note that PGP9.5 also stains epidermal Langerhans cells (red circles). Diabetic rodents and humans (panel C) show early reductions in IENF density that are associated with
both sensory loss and pain.23,274 Confocal images of the corneal sub-basal nerve plexus of a live mouse (panel D, showing inferior whorl) and human (panel E). Reduced
corneal nerve morphometric parameters are detected within weeks of onset of diabetes in rodents52 and in early stages of clinical diabetic neuropathy.274 A cross section of
sciatic nerve from a STZ-diabetic rat (panel F), with an endoneurial blood vessel at the centre of field (black circle), lacks overt evidence of the axonal degeneration or
demyelination common in nerve biopsies from diabetic patients. Apparently misshapen axons (black arrows) represent normal paranodal regions of the nerve fiber while
multiple myelin profiles illustrate normal Schmidt-Lanterman incisures (red arrows). Mild axonal fixation artifact is illustrated by the black star. Morphometric analysis identifies
reduced mean axonal diameter in the absence of significant fiber loss, indicative of axonal atrophy or impaired maturation. Technical details of procedures used to generate
these images and representative data showing the effects of diabetes are published.167 Images provided by Ms. Katie Frizzi, Ms. Lucie Guernsey and Ms. Alex Marquez.

streptozotocin (STZ)-diabetic rodents, the most commonly used hyperglycemia-driven flux through the polyol pathway results in
model of type 1 diabetes, should be established to address accumulation of the intermediates (sorbitol and fructose) along with
concerns about acute STZ neurotoxicity.15,259,294 This can be done shifts in the redox balance of the associated cofactors nicotinamide
using concurrent 3-O-methylglucose injection,80,225 using insulin to adenine dinucleotide phosphate and nicotinamide adenine dinucle-
reverse established disorders,225 and by validating disorders using otide (NADPH and NADH). Downstream consequences potentially
genetic or dietary models.402 Rodents are frequently studied over 4 include local osmotic stress due to sorbitol accumulation,250 fructose-
to 12 weeks of diabetes and are best viewed as modeling early driven advanced glycation end product (AGE) formation12 and
nerve dysfunction in the absence of overt pathology,378 as structural subsequent receptor for AGE (RAGE) signaling, oxidative75 and
pathology in nerve trunks (Fig. 2) is limited to reduced axonal caliber nitrosative stress,72 and loss of neurotrophic support.236 As reviewed
with late (4 months1) myelin thinning, occasional segmental elsewhere,250 preclinical studies show impressive efficacy of aldose
demyelination, and minor fiber loss.157,158,182,268,288,396 This can reductase inhibitors (ARIs) against many indices of diabetic neurop-
be viewed as a boon, as molecular and biochemical changes in athy and neuropathic pain that culminated in a number of clinical trials.
nerves may be interpreted as preceding, perhaps precipitating, To date, ARI treatment has not shown sufficiently convincing efficacy
degenerative neuropathy. Unfortunately, it also limits any guaran- in clinical trials to support approval by most regulatory agencies,
tees of the translation of therapies developed using these models. although epalrestat is approved in Japan. Whether this reflects
Recognition that diabetic rodents develop early loss of sensory a pathogenic mechanism that is pertinent only to diabetic rodents,
nerve terminals in the epidermis of the plantar skin (frequently suboptimal drug properties for human use, or poor clinical trial design
termed intraepidermal nerve fibers [IENFs])23 and reduced sensory and inappropriate endpoints remains the subject of unresolved
nerve density in the cornea52 that accompany indices of both debate.250 Polyol pathway research is currently out of vogue, but the
sensory loss and hyperalgesia167 to mirror the human condition274 impressive preclinical efficacy of ARIs must either indicate a major
have revived hopes that rodent models can be used to study the contribution to downstream pathways that damage nerves or illustrate
early damage to small sensory neurons that is a feature of diabetic a disconcerting gulf between preclinical models and the human
neuropathy (Fig. 2). disease.

2.2.2. Glucose metabolism by the polyol pathway 2.2.3. Nonenzymatic glycation and the advanced glycation
Early observations that tissues that contained the polyol pathway end product–receptor for advanced glycation end product
axis
enzymes, aldose reductase and sorbitol dehydrogenase, were prone
to diabetic complications prompted extensive research into their The posttranslational modification of cellular proteins caused by
potential pathogenic role.95 Within the peripheral nerve, aldose nonenzymatic attachment of glucose to amino acids, causing
reductase is localized to endothelial and Schwann cells164 and reversible progression from Schiff base to Amadori products and

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then irreversible formation of AGEs, has intermittently recurred as phosphate, and dihydroxyacetone phosphate) and cleared by the
a mechanism of potential glucotoxicity in many organs, including glyoxalase pathway. Both excess glycolysis and impaired activity of
nerves.350,373 Advanced glycation end products are present glyoxalase pathway enzymes may contribute to accumulation of
throughout the peripheral nerve,339 and the initial focus was on methylglyoxal in diabetes, which reacts with proteins to form AGEs
the modification of components of the axonal cytoskeleton that (see above). Mice overexpressing glyoxalase 1 do not develop
could interrupt axonal transport and axial and radial growth229 indices of degenerative diabetic neuropathy.155 A gain-of-function
along with the modification of the basement membrane and property has also been proposed from studies showing that binding
extracellular matrix proteins that could impede neuronal re- of methylglyoxal to the Nav1.8 voltage-gated sodium channel in
generation after injury.94,188 More recently, glycosylation of ion sensory neurons increases excitability,25 whereas the potential for
channels has been implicated in painful diabetic neuropa- methylglyoxal to produce pain in diabetes may also be mediated
thy,25,256,388 as discussed below. through agonism of the transient receptor potential A1 (TRPA1)
Identification of a RAGE on the surface of neurons, Schwann channel in the peripheral nerve190 and spinal cord125 and induction
cells, and vascular endothelial cells375 aligned nerves with other of the integrated stress response.21 Recent studies have confirmed
organs prone to damage during chronic diabetes.299 In other the pronociceptive properties of methylglyoxal in humans,92 and
tissues, AGE binding to RAGE activates NADPH oxidase with elevated plasma methylglyoxal has been identified as a risk factor for
subsequent release of reactive oxygen species, whereas RAGE neuropathy in patients with type 2 diabetes.13 Approaches in
signaling through NF-kB modifies gene expression, promoting reducing methylglyoxal levels or blocking downstream consequen-
inflammation and dysregulation of the survival/apoptosis equilib- ces are in development.
rium. There is evidence that similar toxic events occur in nerves,356
with recent in vitro studies demonstrating that RAGE signaling
2.2.5. Mitochondrial overdrive or idling?
potentiates transient receptor potential V1 (TRPV1)-mediated
calcium signals and contributes to painful neuropathy.24,198 It has been argued that increased substrate-driven glycolysis with
Preclinical studies of agents with anti-AGE/RAGE properties such subsequent Krebs’ cycle activity and oxidative phosphorylation
as aminoguanidine and B vitamins show some efficacy in rodent (OXPHOS) in mitochondria will result in the formation of free radicals
models of diabetic neuropathy395 and neuropathic pain,169 that may not be adequately buffered so that there is oxidative
whereas a small-scale clinical trial of the vitamin B1 derivative damage to local structures. This hypothesis was developed in
benfotiamine suggested improvement in pain.337 However, these endothelial cells exposed to short periods of hyperglycemia in
agents have other potential mechanisms of action, and it should vitro.245 There is little evidence that substrate-driven “overdrive” of
also be noted that RAGE signaling is reported to have beneficial mitochondrial OXPHOS persists and is toxic to nerves. Exposing
effects in nerves such as promoting neurite outgrowth304 and that Schwann cells to acute hyperglycemia causes an increase in free
RAGE deletion attenuated indices of neuropathy in diabetic mice.84 radical buffering capacity and does not increase reactive oxygen
species production.372 In neurons from diabetic rodents, basal
respiration is unchanged and maximal mitochondrial respiratory
2.2.4. Glycolysis
capacity reduced, not increased.60,408 This is accompanied by
Hyperglycemia-driven increases in intermediates of glycolysis have reduced expression and activity of the mitochondrial proteome7,61
been linked to diabetic complications, including neuropathy. For and dysregulation of mitochondrial biogenesis,49 with aberrant
example, metabolism of fructose 6-phosphate by the hexosamine fission/fusion dynamics.301 It has therefore been proposed that
(glucosamine) pathway produces UDP-N-acetylglucosamine, nutrient excess promotes the downregulation of mitochondrial
which is highly reactive with proteins, most notably transcription function and increasing reliance on glycolysis.105 This metabolic shift
factors, in a process called O-GlcNAcylation. This pathway has supports normal neuronal function during hyperglycemia but may
been particularly linked with cardiovascular complications of limit energy-intensive processes such as dynamic plasticity of
diabetes,263 and a recent study indicates that O-GlcNAcylation peripheral terminals in the epidermis and the capacity to respond to
regulates remyelination of peripheral neurons after injury so that other insults. Efficacy of diverse activators of the adenosine
hyperglycemia-driven abnormal O-GlcNAcylation has the potential monophosphate activated protein kinase/peroxisome proliferator-
to impact nerve structure and function in diabetes.187 activated receptor gamma coactivator 1 alpha (AMPK/PGC1a)
In vascular tissue, glucose-derived diacylglycerol (through pathway, a nutrient sensor system that regulates mitochondrial
glyceraldehyde 3-phosphate and phosphatidic acid) is a substrate activity and dynamics, in restoring mitochondrial respiration and
for protein kinase C b (PKC b), and excess glucose drives elevated preventing or reversing multiple indices of neuropathy and
PKC b activity, which in turn promotes increased vascular neuropathic pain in diabetic rodents4,43,298,400 supports this
permeability and dysfunction.120 The association of diabetic concept.
neuropathy with microvascular disease led to interest in the There is an emerging appreciation that not all cells within the
therapeutic potential of PKC b inhibitors. After supportive pre- nervous system use glucose for adenosine triphosphate (ATP)
clinical studies,45 a clinical trial of ruboxistaurin in diabetic patients production in a similar manner. For example, neurons of the CNS
with neuropathy showed some improvement in skin blood flow, the express high levels of pyruvate dehydrogenase (PDH), which
NTSS-6 questionnaire, which quantified frequency and intensity of controls entry of pyruvate into the Krebs cycle and drives
aching, burning, prickling, lancinating pain, numbness, and OXPHOS, whereas astrocytes have high levels of lactate
allodynia, and in quality of life.48 However, there was no significant dehydrogenase, which converts pyruvate to lactate.201 Utilization
effect on other measures of large and small fiber neuropathy, of glycolysis-derived pyruvate in astrocytes is also limited by the
diminishing enthusiasm in this therapeutic approach. suppression of PDH complex activity through phosphorylation by
There is an increasing focus on the role of the intermediate pyruvate dehydrogenase kinase (PDK). Consequently, these
glycation product methylglyoxal in diabetic complications, including relatively quiescent glial cells rely primarily on glycolysis-derived
neuropathy and neuropathic pain. Methylglyoxal is formed by ATP and indeed may provide lactate to neurons as energy
nonenzymatic dephosphorylation of triose phosphate intermediates substrate.172 By contrast, electrically active neurons keep the
of glycolysis (fructose 1,6-bisphosphate, glyceraldehyde 3- PDH gateway open and use the more efficient generation of ATP

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by OXPHOS.135 The metabolic dependence of neurons on glia is notable are studies in which trace insulin was injected into the
highlighted by the report that selective damage to Schwann cell footpad,130 infused into the spinal intrathecal space,355 or applied
mitochondria results in a neuropathy with damage to both myelin topically to the eye52 of STZ-diabetic rodents. In each case,
and axons.368 Diabetes has been reported to increase PDK treatment prevented functional and structural indices of neurop-
expression and activity in peripheral neurons and glia, supporting athy without impacting hyperglycemia, indicating that provided
the idea that during persistent hyperglycemia, neurons suppress there is adequate insulin-derived trophic support, hyperglycemia is
entry to OXPHOS and rely on glycolysis for ATP production.276 not sufficient to induce neuropathy.
Conversely, PDK deficiency attenuated multiple indices of A mechanism of direct insulin action on neurons may involve
neuropathy in diabetic mice including overexpression of TRPV1 mitochondria. Insulin increases mitochondrial inner membrane
and neuropathic pain. How hyperglycemia impacts the distinct potential when applied directly to sensory neurons derived from
metabolic profiles of neurons and Schwann cells has yet to be normal rats in vitro.149 Moreover, the reduced inner membrane
widely explored, but such studies may provide insight into cell- potential, protein expression, and bioenergetics profile of
specific mechanisms of glucotoxicity. mitochondria from sensory neurons of STZ-diabetic rodents are
restored when animals received trace insulin supplementation
that also impacted functional and structural indices of diabetic
2.3. Impaired insulin signaling
neuropathy without impacting hyperglycemia.3,61,149 This ability
The correlation between glycemic control and neuropathy reported to protect against both mitochondrial dysfunction and the
in the DCCT study is not overwhelming, although a follow-up study neuropathy phenotype also extends to IGF-1,4 with the apparent
failed to show reversal of established neuropathy upon instigation redundancy perhaps reflecting the importance of the system to
of improved glycemic control.226,267 Similar studies of glycemic cells with consistently elevated energy demands.
control in type 2 diabetic subjects did not replicate the DCCT Insulin secretion is accompanied by equimolar release of C-
findings for neuropathy,289,417 and indices of neuropathy are peptide, the other product of proinsulin cleavage. Although
detected in patients with prediabetes (elevated fasting glucose initially considered inert, there is evidence that C-peptide has
levels and/or impaired glucose tolerance) and metabolic syndrome biological actions in a variety of tissues, including peripheral
(representing a combination of risk factors for progression to overt nerves,322 possibly through an insulin-sensitizing action. As C-
diabetes—central obesity, high triacylglycerides and low-density peptide prevents and reverses multiple indices of neuropathy409
lipoprotein (LDL)-cholesterol, low high-density lipoprotein (HDL)- and neuropathic pain179 in animal models of type 1 diabetes170
cholesterol, hypertension, and hyperglycemia).264 A recent study and showed efficacy against some manifestations of diabetic
that subdivided a cohort of 1105 recently diagnosed diabetics into neuropathy in a clinical trial,377 it should perhaps be aligned in
5 groups based on multiple metabolic parameters found that tandem with insulin when considering primary pathogenic
peripheral neuropathy was most prevalent in those with severe mechanisms of diabetic neuropathy and neuropathic pain.
insulin-deficient diabetes.405 Taken together, these observations
have driven interest in nonglucotoxic insults that may act either
2.4. Dyslipidemia
alone or in concert with hyperglycemia.126
Diabetes can be viewed as a disease of impaired insulin Major risk factors for developing diabetic neuropathy reflect
signaling because of insulinopenia and/or insulin resistance. exposure to impaired insulin signaling/hyperglycemia (age, duration
Insulin is structurally similar to the liver-derived peptides, insulin- of diabetes, and long-term glycemic control), followed by vascular
like growth factors 1 and 2 (IGF-1 and IGF-2), and shares their dysfunction (hypertension and smoking) and dyslipidemia (obesity,
growth factor–like properties. Insulin receptors are found on elevated plasma cholesterol, and triacylglycerols).31 Clinical evi-
peripheral neurons,35 signal through Akt,128 and activation dence linking changes in specific plasma lipids to neuropathy is
promotes growth of normal sensory111 and motor394 neurons. mixed, with studies that both demonstrated, and failed to
Conversely, sequestration of local insulin causes peripheral demonstrate, associations between elevated triacylglycerols, ele-
neuropathy in normal rats.35 Schwann cells also express insulin vated LDL-cholesterol or reduced HDL-cholesterol, and neuropa-
and IGF-1 receptors, and their depletion results in a peripheral thy. Clinical efficacy of lipid-lowering agents such as statins and
neuropathy phenotype with injury to both Schwann cells and fibrates against neuropathy is promising but limited.82,244,278,369
axons.134 Loss of insulin-mediated trophic support represents Nevertheless, there is growing interest in how dyslipidemia may
a primary pathogenic mechanism of diabetic neuropathy that is damage peripheral nerves to produce degenerative and painful
independent of hyperglycemia. This applies to both type 1 and neuropathy that is driven by recent preclinical studies.
type 2 diabetes, as studies in type 2 diabetic rodents indicate that Indices of neuropathy and neuropathic pain are detected in
insulin signaling is impaired in the peripheral nerve,127 so that the rodents fed high fat diet to induce insulin resistance and
nervous system can be considered insulin resistant. dyslipidemia but not overt hyperglycemia,80,81,252,371 although
A number of preclinical studies have demonstrated a role for the neuropathy phenotype may be species and strain specific.14
insulin deficiency in diabetic neuropathy and neuropathic pain. Many of these disorders are prevented or reversed by treating
Animals injected with STZ at doses that significantly reduce insulin prediabetic, type 1 or type 2 diabetic rodents with diets high in n-3
production but do not cause hyperglycemia go on to develop polyunsaturated fatty acids to adjust the plasma ratio of n-3:n-6
hyperalgesia in the paw pressure test.292–294 Insulin-resistant but polyunsaturated fatty acid.68–70,199,316 Adjusting high fat diets to
normoglycemic models of prediabetes also develop neuropathy,80 increase the proportion of monounsaturated fatty acids shows
and the onset of allodynia to von Frey filaments parallels the onset similar efficacy,300 and there is a growing suspicion that long-
of insulin resistance but precedes the onset of hyperglycemia in chain saturated fatty acids may therefore be a proneuropathic
a model of type 2 diabetes.295 Conversely, insulin-deficient diabetic entity in dyslipidemia.247 Downstream pathogenic mechanisms
rodents treated with trace amounts of systemic insulin for more may include disruption of mitochondrial function and transport in
than 1 year to maintain body weight without impacting systemic sensory neurons.301 Dyslipidemia thus joins glucotoxicity and
hyperglycemia showed attenuation of large fiber conduction impaired insulin signaling as a potential driver of mitochondrial
slowing and did not progress to paw heat hypoalgesia.37 Most dysfunction to cause peripheral neuropathy (Fig. 3).

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driven the growing suspicion that neuropathy in type 1 and type 2

diabetes has many molecular dissimilarities and the recent
heightened interest in dyslipidemia as a primary pathogenic
mechanism of diabetic neuropathy.100
Both the production and degradation of mRNA and its
subsequent translation are modified by interactions between
the mRNA and the RNA-induced silencing complex that consists
of assorted proteins (the RNAse dicer, argonaute family proteins,
etc.) and single-stranded noncoding microRNAs (miRNAs). This
mechanism of gene silencing adds additional layers of control
and complexity, particularly as each gene can be silenced by
many miRNAs and each miRNA can target multiple genes.
Polymorphisms of specific miRNAs are associated
with susceptibility to peripheral and autonomic
neuropathy in patients with type 2 diabetes,63,64 and miRNA
has attracted recent interest both as potential contributors to
the pathogenesis of diabetic neuropathy and as sites of
therapeutic intervention.324 Examples are shown in
Table 2.5,53,56,104,131,147,148,163,184,214,317,379,382,392,403,410 Al-
though changes in miRNA are frequently linked with such
downstream pathogenic mechanisms of diabetic neuropathy as
Figure 3. A convergence of pathogenic mechanisms? There is accumulating
inflammation, oxidative stress, and impaired neuronal growth and
evidence that the primary initiators of pathogenic cascades, leading to diabetic
neuropathy, impaired insulin signaling, hyperglycemia, and dyslipidemia, regeneration, the primary events that trigger disruption of miRNA
share a common pathway through disruption of mitochondrial bioenergetics. expression have yet to be defined. Manipulation of miRNA is an
emerging therapeutic approach in which identifying nerve-
specific targets or delivery systems will be critical for ensuring
appropriate safety profiles that will allow translation to clinical use.
2.5. Molecular pathology
The preclinical literature on mechanisms of diabetic neuropathy
2.5.2. Structural proteins
and neuropathic pain is replete with studies describing increased/
decreased activity, expression, or mRNA of proteins in nerves Early interest in dysfunctional axonal transport as a cause of distal
from diabetic rodents frequently accompanied by data, showing degenerative neuropathy promoted interest in proteins of the
that preventing or reversing specific change can impact one or axonal cytoarchitecture, with tubulin, neurofilament subunits, and
multiple indices of neuropathy and/or neuropathic pain. Studies associated proteins variously reported as being overexpressed or
relating such changes to the primary pathogenic mechanisms underexpressed, glycated, glycosylated, polymerized, and/or
discussed previously are less frequent. The advent of what are phosphorylated.110,229,309 Proteins of the extracellular matrix also
now politely termed unbiased studies has allowed a somewhat show posttranslational modifications.10,94 Potential structural
less fragmented approach, with technical and bioinformatics consequences include reduced axonal caliber and associated
advances supporting the analysis of large data sets and large fiber conduction slowing237 and delayed axonal regrowth
identification of clusters of differentially regulated genes for following focal lesions as reported in diabetic rodents171 and
pathway analysis. humans,185 although fast axonal transport velocities are un-
changed.1 Altered expression or posttranslational modification of
myelin structural proteins such as myelin basic protein, myelin-
2.5.1. Gene expression and regulation
associated glycoprotein, myelin protein 0 (P0 or MPZ), and
Initial approaches used oligonucleotide microarrays and target peripheral myelin protein 22 (PMP22) are also reported.101,275,297
amplification to identify differentially regulated genes in autonomic Unfortunately, appropriately fixed nerve of diabetic rodents does
and sensory ganglia of type 1 diabetic rats47,270 and emphasized not display overt myelin pathology similar to that reported in
changes that preceded the onset of functional and structural animals in whom these proteins are selectively ablated.
damage. Studies followed characterizing expression profiles of
mouse models of type 156 and type 2 diabetes141,249,260 and
2.5.3. Trophic factors
prediabetes,247 contrasting profiles of type 1 vs type 2 diabetic
mice129,151 or diabetic rodents with or without an intervention that The growing repertoire of trophic factors and their receptors that
corrected indices of neuropathy78,83,220,399,407 or specifically modulate nerve phenotype and function has been frequently
painful neuropathy.399 Expression profiles of nerve biopsies from accompanied by the discovery of reduced mRNA, protein,
humans with diabetes have also been reported.152,209,228 receptor, and/or signaling in peripheral neurons, Schwann cells,
Common themes emerging from these studies largely echo the or target organs of diabetic rodents and thereafter by reports that
suspected pathogenic mechanisms described previously such delivery of the trophic factor gene or protein, mimetics, inducers,
as glucose and lipid metabolism, oxidative stress, and mitochon- or agonists corrects indices of neuropathy in the same. Examples
drial dysfunction. Additional abnormal gene expression clusters include nerve growth factor (NGF),108,140 ciliary neurotrophic
implicate impaired cytoskeletal organization, nerve growth and factor (CNTF),40,42,239 neurotrophin-3 (NT-3),109,237 IGF-
regeneration, inflammatory/immune system activity, and signal- 1,4,153,412 glial cell-derived neurotrophic factor (GDNF),62,211
ing through mitogen-activated protein kinase (MAPK), janus basic fibroblast growth factor (bFGF),243 hepatocyte growth
kinase/signal transducer and activator of transcription proteins factor (HGF),180 granulocyte colony stimulating factor (G-
(JAK/STAT), and AMPK pathways. These studies have also CSF),186 matrix metalloproteinase-2 (MMP2),10 and hedgehog

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Table 2
miRNA implicated in the pathogenesis of diabetic neuropathy.
miRNA species Impact of diabetes Model (tissue) Effective therapeutic manipulations Representative publications
Multiple Multiple upregulated STZ-mouse (DRG) Mimics/knock-out impact multiple indices of 57
Multiple downregulated degenerative and painful neuropathy
Multiple Multiple upregulated STZ-rat (DRG) Not done 131
Multiple downregulated
Multiple Multiple upregulated STZ-rat (nerve) Some expression changes normalized by taurine 317
Multiple downregulated
miR-25 Downregulated db/db-mouse (nerve) Precursor reduced inflammation markers 410
miR-29c Upregulated db/db-mouse (DRG, nerve) knock-out improved neurite growth in vitro 163
miR-34c Upregulated STZ-mouse (trigeminal) Antagomir improved corneal nerve growth 147
miR-96 Downregulated high fat diet/STZ-rat (nerve) Exercise increased miR, and reduced Nav1.3 and 5
thermal pain
miR-106a Downregulated STZ-mouse (DRG) Not done 392
miR-146a Upregulated STZ-rat (nerve) Not done 403
Downregulated db/db-mouse (nerve) Mimics improved neuropathy/pain 214
STZ-rat (nerve) Not done 104
db/db-mouse (nerve) Inducer improved neuropathy/pain 379
miR-155 Downregulated STZ-rat (nerve) Not done 184
Upregulated STZ-rat (nerve) Antagomir improved neuropathy 53
miR-181a Upregulated STZ-mouse (trigeminal) Antagomir improved corneal nerve growth 148
miR-182 Downregulated STZ-mouse (trigeminal) Agomir increased corneal nerve density 382

proteins.38 There are also reports of diabetes-induced increased nerve macrophages67,246 and spinal microglia.361 The absence
expression of trophic factors, as occurs with brain-derived of large increases in inflammatory cell numbers is not surprising
neurotrophic factor (BDNF)107 and both hypoxia-inducible because of the physical constraints on tissue expansion imposed
factor 1 (HIF-1) and its target gene product, vascular endothelial by the epineurium and spinal column. Glial cells of the peripheral
growth factor (VEGF),50,305 that are attributed to responses to nervous system (PNS) and CNS play many roles associated with
injury or compensation for loss of other trophic support systems. peripheral inflammatory cells after nerve injury, including the
VEGF delivery improves indices of neuropathy in diabetic release of cytokines and chemokines91 and clearance of myelin
rodents,150,290,308 although the role of BDNF is more complex. debris.161 As recently reviewed in detail elsewhere,287 this
Acute spinal delivery of BDNF causes tactile allodynia in normal neuroinflammatory system is increasingly recognized as being
rats, and sequestration of endogenous spinal BDNF alleviates dysregulated in diabetes.
tactile allodynia and restores H-wave rate-dependent depression There are multiple reports of changes in both proinflammatory
(RDD) (see above) in diabetic rats.205 By contrast, chronic spinal and anti-inflammatory cytokines and chemokines in the nervous
delivery of BDNF to diabetic rats alleviated hyperalgesia.206 In system of diabetic rodents. The most widely studied are
some cases, altered neurotrophic support has been linked to increases in the proinflammatory cytokines, IL-1b, IL-6, tumor
downstream consequences of hyperglycemia. For example, necrosis factor alpha (TNFa), and interferon-g,418 along with
hyperglycemia-driven increased flux through the polyol pathway changes to downstream transcription regulators such as NF-kB
leads to reduced nerve levels of the Schwann cell–derived factors and Nrf2.196 Expression of bradykinin B1 and B2 receptors by
NGF254 and CNTF,236 and ARI treatment prevents diabetes- microglia and neurons is also increased in the spinal cord of
induced elevated Trk-C receptor mRNA expression.320 However, diabetic rodents,46,343 and receptor antagonists alleviate indices
the pathogenesis of most neurotrophic factor deficits in diabetic of pain.343 Pathogenic consequences include induction of
nerves remains unknown, and clinical trials using trophic factors enzymes such as cyclooxygenase-2 (COX-2)181,282 and isoforms
have not been promising,16,102,389 with the exception of early of nitric oxide synthase415 that can drive tissue damage through
HGF trials against neuropathic pain6 and a neurotrophic eryth- ischemic hypoxia and oxidative/nitrosative stress, thereby
ropoietin analog against pain and corneal nerve loss.33 contributing to both degenerative neuropathy and initiation or
amplification of neuropathic pain.115 For example, induction of
COX-2 and subsequent release of prostaglandins from spinal
2.5.4. Cytokines and inflammatory pathways
oligodendrocytes282 and release of proinflammatory cytokines343
There is little evidence from human studies that diabetic and BDNF240 from activated microglia have been linked to
neuropathy represents a typical inflammatory neuropathy. spinally mediated pain in diabetic rodents. Increased chemokine/
Chronic inflammatory demyelinating polyneuropathy occurs in receptor signaling, including CCL1/CCR8,420 CXCL12/
diabetic patients but is readily distinguished from diabetic CXCR4,159 CXCL13/CXCR5,213 and others,419 is also linked to
symmetrical polyneuropathy.277 Animal models of diabetes also neuropathic pain in diabetic rodents. The primary pathogenesis of
lack marked inflammatory infiltrates, although there are reports of many of the reported changes to the neuroinflammatory system
transient increases in the number and activation of peripheral remains to be determined, although hyperglycemia-driven flux

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through the polyol pathway may be involved in some sensory neurons from diabetic animals, whereas knockdown of
aspects.156,282,334 Therapeutic approaches around manipulation PTEN improved the otherwise impaired nerve regeneration after
of the neuroinflammatory system tested in diabetic rodents range crush injury in STZ-diabetic mice.325
from microglial inactivators,240,418 COX inhibitors,266,282 TNFa
inactivators397 or inhibitors,89 overexpression of anti-
2.5.6. Membrane pumps
inflammatory cytokines,347 antagonists to proinflammatory cyto-
kines,138 chemokine-neutralizing antibodies,291 and chemokine NCV slowing in short-term diabetic rodents that lack overt damage
receptor antagonists.175,231 Efficacy of stem cells137,385 and to axons or myelin led to interest in changes to nodal ion pumps
natural products78,166,253 against aspects of diabetic neuropathy that facilitate saltatory conduction in myelinated fibers. Chief of
may also be at least partly due to their anti-inflammatory these was the Na1/K1 ATPase, given its role in maintaining and
properties. To date, clinical trials have not been successful.175 restoring resting membrane potential. Reduced maximal pump
activity in membrane fragments associated with reduced protein
expression was widely studied as a potential cause of NCV slowing
2.5.5. Death and survival pathways
and is downstream of hyperglycemia-driven polyol pathway
Dysregulation of cytoplasmic calcium has been implicated in activity.124 However, Na1/K1 ATPase pump activity is not impaired
many neurodegenerative diseases, given its role in triggering in intact endoneurial preparations from diabetic rodents,216 so the
autophagic, necrotic, and apoptotic pathways.51,123 Steady- physiological relevance is unclear. Increased expression and
state cytoplasmic calcium concentrations are regulated by activity of the Na1/H1 pump has also been reported in the nerve
pumps located in mitochondria and the endoplasmic reticulum, of diabetic rodents, and inhibition of the pump reversed functional
and these organelles serve as calcium stores. Steady-state and structural indices of neuropathy and neuropathic pain.219
cytoplasmic calcium concentrations are increased in sensory Overactivity of this pump increases cytoplasmic pH, glucose
neurons from diabetic rodents,367 and this is associated with uptake, and glycolysis, thereby having the potential to trigger
impaired calcium reuptake into the endoplasmic reticulum by the multiple pathogenic mechanisms.
sarcoendoplasmic reticulum Ca21 ATPase (SERCA) pump.411 In the spinal cord, reduced expression of the potassium
Subsequent depletion of calcium in the sarcoplasmic reticulum chloride cotransporter 2 (KCC2) pump, which maintains the
produces endoplasmic reticulum (ER) stress, which can pre- chloride gradient across neuronal membranes, has been linked
cipitate cell death,306 and this mechanism has been integrated with loss of GABAergic inhibitory function and neuropathic pain in
into the schema of potential pathogenic mechanisms of diabetic diabetic rats.204 KCC2 expression is suppressed by the neuro-
neuropathy.248 It is not yet known whether mitochondrial calcium trophic factor BDNF, and increased BDNF levels in central
pumps, such as the mitochondrial calcium uniporter complex and projections of primary afferents in diabetic rats suggest that the
voltage-dependent anion channel, are dysfunctional in diabetes. primary lesion may be of peripheral origin,204 although it has also
Reports describing the marked expression of components of been linked to activated spinal microglia.240 The electrophysio-
apoptotic death pathways in the peripheral nerve of short-term logical consequence of the disrupted spinal GABAergic inhibitory
diabetic rodents302,307 were initially difficult to reconcile with the tone in diabetic rodents is loss of RDD of the H wave,205 which is
slowly evolving loss of neurons and axons in these models and secondary to impaired insulin signaling rather than hyperglyce-
clinical descriptions of a distal degenerative neuropathy. Later mia.225 Loss of RDD may serve as a biomarker for identifying
work reported that increased caspase-3 in nerves was not a subset of diabetic humans in whom painful neuropathy includes
associated with structural features of apoptosis such as nuclear a contribution from spinal disinhibition.225
fragmentation and that DNA-repair mechanisms were activated,
suggesting that the peripheral nerve uses endogenous defence
2.5.7. Transient receptor potential channels
mechanisms to block progression from caspase-3 activation to
apoptosis.57 Overactivity of the DNA-repair enzyme poly(ADP- Transient receptor potential (TRP) channels are a family of non-
ribose) polymerase (PARP) has itself been linked to a mechanism selective cation-permeable channels that transduce diverse extra-
of nerve injury.218 Elevated PARP and other survival and repair cellular stimuli into acute and chronic neuronal responses through
markers such as heat shock protein 27 (HSP27)280,416 and influx of calcium.173 TRPA, TRPV, and TRPM family members are
growth-associated protein 43 (GAP43)130 in the nerve of diabetic modulated by endocannabinoids, which may contribute to the
rodents has encouraged the view that the peripheral nerve is analgesic properties of these substances.242 There is substantial
exposed to chronic stress arising from one or more of the preclinical evidence that dysregulation or dysfunction of TRP
mechanisms described previously but can largely tolerate and channels may contribute to neuropathic pain in diabetes.
repair metabolic injuries, paralleling to the way that it survives and The TRPV1 channel, known for transducing the burning
repairs physical injury. Therapeutic approaches that strengthen sensation of capsaicin, is activated by a range of physiological
endogenous survival and repair mechanisms include over- and pathological stimuli, including heat, low pH, proinflammatory
expression of HSP 27192 and inhibition of HSP90 to induce molecules, and endocannabinoids. TRPV1 currents are also
HSP70, a molecular chaperone protein with multiple neuro- enhanced by insulin and IGF-1366 and by the TRPM8 receptor.258
protective properties including protecting mitochondrial function An initial report144 indicated that membrane-bound TRPV1
and reducing inflammation and oxidative stress.220 HSP90 protein is increased in the dorsal root ganglia (DRG) from diabetic
inhibitors reverse multiple indices of neuropathy in diabetic rats, along with the channel phosphorylation state and both
rodents and are currently in clinical development.103 Conversely, capsaicin and proton-activated currents, whereas TRPV1 protein
the emerging appreciation that there are endogenous systems expression increased in large sensory neurons and decreased in
that constrain nerve growth has provided opportunity to intervene small sensory neurons. The pattern of TRPV1 protein expression
and thereby promote nerve growth and regeneration pathways.93 and whole-cell currents in the DRG and spinal cord of diabetic
For example, the tumor suppressor molecule PTEN (phospha- rodents paralleled progression from heat hyperalgesia to
tase and tensin homolog deleted on chromosome 10) inhibits the hypoalgesia,259 and increased TRPV1 expression at peripheral
PI3K-pAkt neuronal growth pathway194 and is upregulated in and central terminals of primary afferents has been implicated in

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allodynia to von Frey filaments.74 Agents that reduce TRPV1 other indices of peripheral neuropathy were largely attributed to
expression, antagonize TRPV1, or ablate it also alleviate thermal indirect effects through improved blood flow.28
hyperalgesia and tactile allodynia in diabetic rats.17,208 Involve-
ment in diabetic neuropathy beyond indices of pain is suggested
by a report that TRPV1 agonists given to normal mice produce 2.5.9. Voltage-gated potassium channels and
hyperpolarization-activated and cyclic nucleotide–gated
multiple indices of small fiber neuropathy including IENF loss.203 channels
Upstream events that may drive TRPV1-mediated pain include
increased insulin, RAGE and PKC activity,24,366 and hypoxia.285 Given the importance of potassium channels in regulating axonal
Little is known about other TRPV family members, although excitability, there are relatively few studies implicating them in the
a recent study reported that a selective TRPV4 channel pathogenesis of diabetic neuropathy and neuropathic pain.
antagonist blocked mechanical, but not cold, allodynia in diabetic Expression of the voltage-gated Kv channel subunits Kv1.2 and
mice.86 Kv1.6, but not Kv1.1, was reduced in small neuronal cell bodies of
Early indications of a role for the irritant-sensing TRPA1 the DRG in STZ-diabetic rats coincident with reduced K1
channel in diabetes-induced hyperalgesia came from studies currents, and these changes were linked to enhanced C-fiber
with TRPA1 antagonists that alleviated allodynia to von Frey excitability and hyperalgesia.380 Most recently, voltage-gated Kv7
filaments and mechanical hyperalgesia.386,387 Cold allodynia in (KCNQ) channels, which produce a slow noninactivating outward
diabetic mice has also been attributed to TRPA1 activity.142 K1 current also called the M current due to its modulation by
Diabetes enhances channel activity without inducing TRPA1 muscarinic antagonists,390 have been examined. There was
protein expression in the DRG of diabetic animals.286 As decreased mRNA and protein for the Kv7.2, Kv7.3, and Kv7.5
discussed previously, a pathogenic mechanism linking hypergly- channels in the DRG of STZ-diabetic rats accompanied by
cemia with TRPA1 channel activation through methylglyoxal reduced M current density and increased neuronal excitability.404
binding to the channel has been proposed,99,191 and there is also A Kv7 channel activator reduced neuronal excitability and
a recent report linking TRPA1-mediated hyperalgesia in diabetic alleviated allodynia to von Frey filaments and thermal
rodents to local hydrogen sulfide.286 hyperalgesia.
Protein for the cold/menthol-sensing TRPM8 channel is elevated Hyperpolarization-activated and cyclic nucleotide–gated
in the DRG of STZ-diabetic rats with concurrent cold allodynia.401 channels (HCN1-4) are a distinct category of voltage-gated ion
Conversely, agonist-activated TRPM8 currents are decreased in channels whose threshold potentials are regulated by cyclic
the DRG of STZ-diabetic mice258 and in normal DRG cells after nucleotides and that have been implicated in neuropathic pain
exposure to methylglyoxal.66 Although this does not appear to be states.359 Inhibition of HCNs1-4 or ablation of HCN2 alleviated
consistent with a role for methylglyoxal in diabetes-evoked pain allodynia to von Frey filaments but not thermal hypoalgesia in
(see above), it has been argued that loss of TRPM8 activity diabetic mice.358 Expression of HCN1-4 protein was not altered
enhances other TRP channel activities associated with neuropathic in the peripheral nerve of diabetic mice, and it was speculated that
pain.258 There is clearly room for additional studies in this area. a measured increase in intracellular cAMP might activate HCN2
and thus increase primary afferent firing.

2.5.8. Voltage-gated calcium channels

2.5.10. Voltage-gated sodium channels
Gabapentin and pregabalin, widely used to treat painful neuropathy
in diabetic patients,9 target the a2d 2 1 subunit of voltage-gated Ca2 Voltage-gated sodium channels (VGSCs: Nav1.1-1.9) are critical
channels.22 This subunit regulates the trafficking and activation regulators of neuronal excitability, and the discovery of gain-of-
kinetics of pore-forming a1 subunits and thus surface expression function mutations to Nav1.7, NAv1.8, and Nav1.9 in human small
and activity of voltage-gated Ca2 channels.262 The plasmalemma of fiber “channelopathy” pain states331 has focused interest on the
sensory neurons contains multiple voltage-gated Ca21 channels, potential role of VGSC in painful diabetic neuropathy. Diabetes
including L type (Cav1.2 and Cav 1.3), N type (Cav 2.2), R type (Cav alters currents and protein expression of a variety of VGSCs:
2.3), and T type (Cav 3.2 and Cav 3.3). Of these, the most extensively Nav1.8 protein expression is consistently reported as being
studied in the context of diabetic neuropathy is the T-type (Cav 3.2) decreased73,145,255 with a parallel increased phosphorylation or
calcium channel.352 This channel shows altered kinetics because of posttranslational modification by methylglyoxal (see above)
posttranslational modification by glycosylation under hyperglycemic considered indicative of activation.25,146 Others, such as Navs
conditions accompanied by enhanced gene expression and 1.1, 1.2, 1.3, 1.7, and 1.9, show increased protein expres-
glucose-regulated trafficking.202,388 A role in neuropathic pain is sion,73,145,146,326 whereas there is disagreement over the fate of
suggested by reports that diverse interventions that target the Cav Nav1.6.73,145,284 Interestingly, around 10% of a cohort of patients
3.2 channel reverse allodynia to von Frey filaments and thermal with painful diabetic neuropathy expressed rare Nav1.7 variants,
hyperalgesia in diabetic rodents.116,200,232,251 Clinical trials of T-type some of which were gain-of-function variants.29 These patients
calcium channel antagonists, including one that used the innovative tended to report more severe burning pain and increased
design of using microneurography to preselect diabetic subjects pressure sensitivity. A gain-of-function variant to the b subunit
with both pain and spontaneously active C fibers,315 have yet to of VGSCs has also been identified in a patient with painful diabetic
show efficacy.183,413 neuropathy,11 although a recent genome-wide association study
Increased mRNA for subunits of the P/Q-type, but not N-type, of type 2 diabetics with or without pain has drawn attention to
calcium channels has been reported in the DRG of STZ-diabetic Nav1.2.345
mice,363 and a P/Q-type and R-type channel antagonist There have been a number of studies that have manipulated
alleviated allodynia to von Frey filaments in STZ-diabetic rats VGSC activity. Antagonists of overexpressed VGSC have been
and mice.77 Reports of increased L-type currents in both primary studied for their ability to block indices of neuropathic pain in both
afferent and dorsal horn neurons of STZ-diabetic rats193,374 have preclinical and clinical studies.351 In diabetic rodents, indices of
promoted studies of the efficacy of the L-type channel neuropathic pain have been reduced by the nonselective VGSC
antagonists against hyperalgesia,321 although efficacy against blockers, lidocaine41 and mexiletine,398 by selective knockdown

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of NAv1.3,344 by induction of miR-96 to reduce Nav1.3 NMDA NR1 and NR2B subunits also show an increased
expression,5 and by blockers of Nav1.7383 and Nav1.8.365 Topical phosphorylation (activation)79,154 secondary to elevated protein
lidocaine has shown efficacy against painful diabetic neuropa- tyrosine phosphatase activity.340 NR2B expression is also
thy391 and is used off-label.9 A clinical trial of a Nav1.7 blocker in increased in a model of prediabetes.340 These findings are
subjects with painful diabetic neuropathy showed only minor consistent with the efficacy of spinally delivered NK-1 and NMDA
effects,227 perhaps reflecting the cohort of subjects in whom pain antagonists against allodynia and hyperalgesia in diabetic
could be due to a variety of diabetes-related mechanisms. rodents.39,71,79,296 Unfortunately, side-effect–free targeting of
Although the pathogenesis of altered expression and/or function spinal excitatory receptors as a strategy to treat painful diabetic
of VGSC is not clear, other than relatively rare gain-of-function neuropathy has been largely unsuccessful to date.
mutations and a link to hyperglycemia through increased Of the spinal inhibitory receptors, GABAA expression is
glycolysis and methylglyoxal for modification of Nav1.8 activity,25 unchanged by diabetes,168 but inhibitory function is diminished
there is an interesting suggestion that mutations in Nav1.7 may be secondary to reduced KCC2 activity (see above), whereas
a primary cause of both painful diabetic neuropathy and diabetes GABAB expression is reduced.381 Both basal and stimulus-
itself because of the location of this channel on both primary evoked spinal GABA levels are increased in diabetic rats224 and
sensory neurons and pancreatic b cells.143 may contribute to pain through dysfunctional GABAA receptors,
as GABAA antagonists alleviate allodynia and hyperalgesia,168
whereas activation of GABAB receptors shows the expected
2.5.11. Neurotransmitters and receptors
inhibitory effects.212 Multiple serotonergic receptor agonists have
Purinergic P2X receptors are ligand (ATP)-gated nonselective cation been shown to alleviate indices of pain in animal models of
channels located on neurons, Schwann cells, and microglia.36 There diabetes, including agonists or indirect activators of 5-HT1A,162
is increased P2X2R and P2X3R expression and current density in 5HT2A/C,235 and 5HT7362 receptors. Although spinal expression
the DRG of STZ-diabetic rats and mice and increased P2X4R of 5HT2A receptors is unchanged by diabetes,265 efficacy of
expression by satellite glial cells.346 Increased gene expression of duloxetine, a selective serotonin reuptake inhibitor approved for
P2X3R in diabetic rats has been linked to demethylation of the p2x3r use against pain in diabetic patients,9 is through activation of
gene.406 Involvement of P2XR in pain is suggested by reports that these receptors in the spinal cord of diabetic rats.235 Muscarinic
peripheral and intrathecal delivery of antagonists alleviated tactile M2 receptors are increased in the spinal cord of diabetic rats55
and thermal hyperalgesia in diabetic animals.233,346,393,406 Increased and facilitate the antinociceptive actions of cholinergic agonists
activity of receptors located at synapses and on adjacent microglia operating through GABAB receptors.54
has the potential to enhance primary afferent input and spinal Although increased expression and/or activity of ion channels
sensitization of sensory processing. and receptors may lead to hypersensitive or destabilized primary
The spinal cord of diabetic rodents shows increased glutamate afferents and inappropriate electrical activity, the contribution of
and substance P ligand binding178,207 and increased mRNA for peripherally drive to pain in diabetes may be offset by progression
subunits of glutamatergic NMDA and AMPA receptors.353 The to a degenerative neuropathy phenotype. No matter how

Figure 4. A plethora of potential pain precipitating pathways? Animal models of diabetic neuropathy develop molecular and functional disorders throughout the
neuraxis that have the potential to generate or amplify pain and thus serve as targets for therapeutic intervention. The majority of these disorders have yet to be
validated in the human condition. TRP, transient receptor potential.

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electrically active a primary afferent becomes, it is effectively silent 10).112 Refinement of models of neuropathic pain and of assays
if it cannot release adequate neurotransmitter at the spinal dorsal towards those that incorporate more complex cognitive functions
horn. For example, in diabetic rats, there is an early reduction in may improve the predictive value of preclinical studies87 and have
the synthesis,88 transport,354 and stimulus-evoked spinal release begun to be used in models of diabetes.376 There is also
of both neuropeptide44,118 and amino acid224 excitatory neuro- a growing appreciation that pain in diabetic patients falls into
transmitters that are concurrent with enhanced pain-associated distinct subtypes,20 potentially reflecting different dominant
behavior in the same animals. There is also a progression from pathogenic mechanisms and thus responsiveness to targeted
increased, to loss of, synaptic markers in the spinal cord of therapeutic interventions. Drugs not statistically effective against
diabetic rats.165,210 Pain generator sites may evolve over time, pain in an unrefined cohort have been shown to be effective in
with initial pain driven by a hypersensitive or hyperactive periphery a subgroup defined by pain mechanism,85 and clinical trial
but progressing to spinal and CNS generator/maintenance sites designs are beginning to incorporate patient stratification based
as the primary afferent input fades with first neurochemical, then on the likely mechanism of both pain generation and the agent
physical, degeneration. Longitudinal clinical studies in subjects under investigation.315 Together, these advances may allow the
with diabetic neuropathy, using such techniques as micro- identification and development of translatable therapies that are
neurography,315 RDD,225 and magnetic resonance imaging,312 tested against the mechanistically appropriate population and
to track activity of generator sites over time may be of value. open an encouraging gateway into the world of personalized
medicine.
2.6. Summary
A PubMed search at 7 PM Pacific Standard TIme on February 14, Conflict of interest statement
2020, using the search phrase “diabetic neuropathy treatment” N.A. Calcutt is a paid consultant for Torrey Industries Inc and has
returned 17,238 hits—a lot of words for a condition with no equity interest in WinSanTor, Inc and CerSci Inc, these being
approved therapy. It is challenging to reconcile the plethora of commercial entities that may potentially benefit from research
biochemical and molecular changes in the nervous system of and insights in this area. The terms of these arrangements have
diabetic rodents described previously with their mildly dysfunc- been reviewed and approved by the University of California, San
tional neuropathy phenotype and limited nerve pathology. It is Diego, in accordance with its conflict of interest policies.
also remarkable that so many highly selective interventions
against specific pathways are completely effective in preventing
or reversing indices of neuropathy and pain, despite presumably Acknowledgements
continued operation of multiple other documented pathways.
The sheer volume of effective interventions must raise concerns The author thanks Dr. Corinne Jolivalt for helpful discussions and
about the relevance of preclinical models and assays to the appropriately brutal editing.
clinical condition. Experimental models of diabetic neuropathy Supported by NIH award DK104512.
are perhaps best viewed as hypothesis-generating tools that offer
a veritable cornucopia of potential pathogenic events and Article history:
plausible targets for therapeutic intervention against neuro- Received 5 March 2020
degeneration and pain (Fig. 4). Relatively few of the biochemical Received in revised form 5 May 2020
and molecular changes described previously have been con- Accepted 7 May 2020
firmed in humans and, when they are, it is not easy to determine
whether altered protein expression and/or activity has physio-
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