Diabetic peripheral neuropathy

Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity.  Over time, at least 50% of individuals with diabetes develop diabetic neuropathy.  Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus.  These findings have led to new efforts to understand the etiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes.  In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued.  Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remain unknown. 

The International Diabetes Federation estimates that 425 million people worldwide have diabetes, making it the largest global epidemic of the 21st century. 115 million people in China, 73 million in India, and 30 million in the United States have diabetes.  These numbers are dwarfed by the number of individuals with prediabetes, which is estimated to be 388 million in China, 133 million in India, and 85 million in the United States.  12% of global health expenditure, or $727 billion, is directed towards diabetes and its complications, and similar to the number of individuals with diabetes, this number continues to increase at an unsustainable rate.   Without successful intervention, it is estimated that of the expected 9.7 billion individuals living in 2050, one-third will have diabetes, and half of those will have neuropathy.

The incidence of neuropathy is higher in individuals with T2DM (6,100 per 100,000 person-years) than in those with T1DM (2,800 per 100,000 personyears).  By contrast, the prevalence of neuropathy is similar in those with T2DM (8–51%) to those with T1DM (11–50%).  Importantly, the prevalence is even higher when asymptomatic neuropathy is included, with 45% of patients with T2DM and 54% of those with T1DM developing neuropathy. The higher incidence of neuropathy in patients with T2DM, with a similar prevalence in those with T2DM or T1DM, is probably secondary to multiple factors, including differences in age of onset of diabetes and differences in the underlying pathophysiology.

The prevalence of diabetic neuropathy also changes with disease duration.  Indeed, the prevalence of diabetic neuropathy increased from 8% to 42% in patients with T2DM when patients were monitored for 10 years.   Approximately 25% of patients with diabetic neuropathy will have neuropathic pain and its presence may be the impetus for referral to a neurologist. 

Definition of diabetes:

Definition of IGT and IFS:

Risk factors of diabetic neuropathy:

Mechanism and pathophysiology:

Diabetic neuropathy is a unique neurodegenerative disorder of the peripheral nervous system that preferentially targets sensory axons, autonomic axons and later, to a lesser extent, motor axons.  How diabetes mellitus targets sensory neurons remains debated.  Progressive diabetic neuropathy involves retraction and "dying back" of terminal sensory axons in the periphery, with relative preservation of the perikarya (cell bodies).  Its "stocking and glove" pattern of involvement reflects damage to the longest sensory axons first with, for example, loss of distal leg epidermal axons preceding loss in more proximal limbs; for this reason, diabetic neuropathy is considered a length-dependent neuropathy.   Substantial experimental evidence supports the notion that the entire neuron, from the perikaryon to the terminal, is targeted by diabetes.  However, whether damage first targets peripheral axons and their associated Schwann cells or the neuron perikarya that reside in the dorsal root ganglia (DRG) and act to support the axons are debated.

Although diabetic neuropathy is not considered primarily a demyelinating neuropathy, Schwann cells are targeted by chronic hyperglycaemia, and more severe cases of diabetic neuropathy in patients include features of demyelination.  Given the close and intimate mutual support between axons and Schwann cells, Schwann cell damage might lead to several alterations in the axon.  For example, Schwann cells have a fundamental role in regulating the cytoskeletal properties of axons, including the position of proteins at the nodes of Ranvier and axon trafficking parameters.  Failure by Schwann cells to support axons might involve inadequate provision of cytoskeletal support, trophic factors or failure of Schwann cell–axon ribosome transfer that supports intra-axonal mRNA translation within distal axons.  In mice, Schwann cells contain ribosome-filled vesicles that, when transferred to desomatized axons, can control axonal protein synthesis.  In settings of axonal damage and stress, this transfer of ribosomes may place increased importance on axon–Schwann cell interactions.  

Whether diabetes promotes intrinsic programmes within axons that facilitate axonal degeneration is unclear.  Studies of Wallerian degeneration have identified intracellular signaling pathways that actively induce axonal degeneration, and mononucleotide adenylyltransferase (NMNAT; also known as NMN/NaMN adenylyltransferase) seems to be a key regulator of this pathway.  However, whether these pathways are activated in diabetes is not yet clear.  

Changes in axons, especially distal terminals, are associated with changes in the neuronal perikarya.  Indeed, sensory neurons within the DRG alter their phenotype in chronic experimental diabetes, which might be critical in how they support distal axon branches.  For example, in chronic T1DM in rats, there is progressive loss of synthesis and export of neurofilament polymers, which are essential structural scaffolds of the axon.  Reduced mRNA expression encoding neurofilament has been proposed to underlie this loss of neurofilament polymers.  Preclinical studies in diabetic rodents also associate endoplasmic reticulum stress with diabetes-mediated peripheral nerve damage that would affect nerve function.  Similarly, in vitro and in vivo experiments in rodent models have demonstrated that hyperglycemia alters the function of key plasticity molecules, such as growth-associated protein 43 (GAP43; also known as neuromodulin) and β-tubulin, and the expression patterns of heat shock proteins (HSPs) and poly (ADP-ribose) polymerase (PARP) in the DRG.  Although the mechanisms of injury remain under investigation, data suggest that dysfunction in these pathways promotes abnormal protein processing, oxidative damage and mitochondrial dysfunction, leading to loss of peripheral nerve function.  In support of this theory, modulating specific molecules in these pathways can lead to improvement in nerve function.  For example, regulating HSP90 activity improved nerve conduction velocity (NCV) and responses to thermal and mechanical stimuli (both of which are clinically relevant end points), most likely by improving mitochondrial function. 

More recent array studies have also demonstrated a range of both mRNA and microRNA alterations in DRG sensory neurons exposed to chronic diabetes. Indeed, upregulation of pathways involved in inflammation, bioenergetics and lipid processing have been reported in arrays of sciatic nerves from preclinical models of T1DM and T2DM.  In addition, one study comparing gene expression patterns in peripheral nerves from mouse models of diabetic neuropathy with nerves from patients with T1DM and T2DM revealed multiple highly conserved pathways involved in adipogenesis, lipid synthesis and inflammation.  

Other specific changes in the DRG and nerve function can be linked to diabetic neuropathy, including altered spliceosome function, changes in expression of survival motor neuron protein and upregulation of GW-bodies (sites of mRNA processing).  Analysis of rodent models with longstanding diabetes has been essential to model chronic human disease.  DRG have reductions in local blood flow, but whether this contributes to neuronal damage or follows lower oxygen demand is unclear.  

How the peripheral nervous system uses substrates for energy, especially in diabetes, is necessary to understand the pathogenesis of diabetic neuropathy.  In Schwann cells, DRG neurons and axons, both glucose and fatty acids produce NADH and FADH2 via glycolysis and the tricarboxylic acid cycle (glucose) and β-oxidation (fatty acids).  When long-chain fatty acids are transported into Schwann cells to undergo β-oxidation, each β-oxidation cycle forms one molecule of acetyl-CoA, which is transported to the tricarboxylic acid cycle for NADH and FADH2 formation.  However, during substrate overload, such as in diabetes, the transport system becomes saturated, and acetyl-CoA molecules are converted to acylcarnitines.  The accumulation of acylcarnitines is toxic to both Schwann cells and DRG neurons, adding to the ongoing nervous system injury in diabetic neuropathy.  Accumulated acylcarnitines are released from Schwann cells and can induce axonal degeneration, which has been proposed to involve mitochondrial dysfunction and a maladaptive integrated stress response in Schwann cells.

Hyperlipidemia and hyperglcyemia.  NADH and FADH2 are shuttled in the mitochondria through Complexes I–IV to produce ATP through oxidative phosphorylation.  A byproduct of oxidative phosphorylation is the production of low levels of reactive oxygen species (ROS) that are easily neutralized by innate cellular antioxidants, such as superoxide dismutase, glutathione, and catalase.   However, during excess substrate load, such as in diabetes, oxidative phosphorylation fails, leading to loss of ATP production and increased ROS levels, which subsequently leads to mitochondrial failure and metabolic and oxidative damage of Schwann cells and DRG neurons.   Dysfunctional mitochondria produce insufficient energy and lose the ability to normally traffic down axons, further promoting axonal disruption and injury.  Increased glucose levels leads to glucose metabolism via the polyol and hexosamine pathways, resulting in increased ROS and inflammation, respectively, largely owing to mitochondrial injury, which contributes to ongoing nervous system dysfunction.  Increased glucose levels lead to the glycation of numerous structural and functional proteins to produce advanced glycation end-products (AGEs).  AGEs result in altered or loss of protein function and interact with AGE-specific receptor (RAGE) to modify gene expression and intracellular signaling and promote the release of pro-inflammatory molecules and free radicals.  In parallel, the excessive free fatty acids catabolized by β-oxidation in response to hyperlipidemia can injure the peripheral nervous system, particularly Schwann cells, through ROS generation and systemic and local inflammation via macrophage activation with subsequent cytokine and chemokine production.  Other lipids adversely affect the peripheral nervous system in diabetic neuropathy.  Oxidation of cholesterol to oxysterols in neurons mediates tissue injury, whereas plasma lipoproteins, particularly low-density lipoproteins (LDLs), are oxidized by ROS and bind oxidized LDL receptor 1 (LOX1),  Toll-like receptor 4 (TLR4) and RAGE.  Binding of oxidized LDLs to these receptors activates a series of signalling cascades, including activation of caspase 3 and nuclear DNA degradation, that mediate additional inflammation and ROS accumulation, with continued and progressive nerve injury.

Microvascular alterations.  Although many studies show no change in blood flow associated with the development of diabetic neuropathy, deficiencies in the blood supply to peripheral nerves is considered a possible additional pathological mechanism of diabetic neuropathy.  Microcirculatory dysfunction is strongly associated with peripheral nerve dysfunction, and a cycle of poor microcirculation leading to additional nerve damage has been proposed.  Increases in endoneurial capillary density are present in patients with diabetes compared with healthy individuals, suggesting that capillary density may respond to diabetes-induced nerve ischemia.  Blood vessels develop thickening of their basement membrane that correlates with nerve damage in patients.  Moreover, poor vasodilation of epineurial arterioles has been reported in diabetic rats, and this change appears before decreases in NCV.  In preclinical models, reduced endoneurial blood flow could be improved by treatment with vasodilators.  Finally, diabetes has been reported to decrease mediators of blood vessel formation, including insulin growth factors, vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and angiopoietins.  This view is supported by preclinical studies in which administration of VEGF in diabetic rats increased NCV and vasa nervora (small arteries that supply peripheral nerves) density.  Together, these findings suggest that addressing microvascular problems in diabetes should be considered as an adjunct therapy.

Impaired insulin signaling.  As structural similarities between NGF and insulin were first recognized, evidence of direct neuronal actions of insulin have emerged. Initial work demonstrated that insulin acts as a growth factor for cultured adult sensory neurons, leading to increasing neurite outgrowth.  Subsequent studies demonstrated the expression of insulin receptors by sensory neurons in DRGs and axons, particularly at nodes of Ranvier, and the reversal of features of experimental diabetic neuropathy with intrathecally or intranasally delivered insulin independent of glucose levels.  Insulin administered near the nerve, or in the plantar skin where it accesses dermal axons, also repairs abnormalities of diabetes in experimental animal models.  Despite these findings, correcting hyperglycaemia with insulin has little effect on diabetic neuropathy in patients with T2DM, in whom the disorder correlates more strongly with components of the metabolic syndrome.  By contrast, normoglycaemia achieved with insulin treatment provides a substantial therapeutic benefit for those with T1DM and diabetic neuropathy.  This conundrum might be, in part, due to the development of insulin resistance in neurons in those with T2DM, which is not unlike the resistance developed in fat, muscle and adipose tissue.  Indeed, mice with T2DM have systemic resistance to insulin therapy, and controlling glucose with insulin has little effect on diabetic neuropathy.  Altered phosphorylation of insulin-receptor substrate 2, part of the downstream insulin transduction pathway, seems important for the development of insulin resistance. 

In summary, diabetic sensory polyneuropathy is an acquired, chronic, slowly progressive, length-dependent, sensory-predominant, mixed large and small fiber, primarily axonal polyneuropathy with common concomitant dysautonomia associated with a history of diabetes. 

Mechanisms of Neuropathic pain 

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system.  Approximately 30–50% of patients with diabetic neuropathy develop neuropathic pain, which most commonly takes the form of spontaneous (that is, stimulus-independent) burning pain of the feet.  Patients can also report other positive sensory symptoms, such as brush-evoked allodynia (when a normally non-noxious stimulus evokes pain) and paresthesias.  These positive sensory symptoms are often accompanied by sensory loss, and patients will comment on the paradox that their feet are continuously painful yet insensate to touch.  Why only some patients with diabetic neuropathy develop neuropathic pain whereas others do not remains unclear, although this likely reflects a complex interplay of vulnerabilities, including genetic factors, the somatosensory circuitry and psychological factors in the face of stressors, such as the metabolic dysfunction of diabetes and neuropathy severity. 

Patterns of nerve injury in diabetic neuropathy

Central and peripheral mechanisms contributing to neuropathic pain in diabetic neuropathy. 

Diabetic autonomic neuropathy 

It encompasses a group of disorders caused by impairment of the sympathetic and parasympathetic nervous system.  Cardiac autonomic neuropathy (CAN) can present as generalized weakness, light-headedness or frank syncope accompanied by orthostatic tachycardia or bradycardia and exercise intolerance. Symptoms of gastrointestinal autonomic dysfunction (also known as gastroparesis) include nausea, bloating, early satiety with poor appetite, postprandial vomiting and brittle diabetes (that is, hard-to-control diabetes).  Esophageal dysfunction can also occur with dysphagia (difficulty swallowing) for solid foods and heartburn secondary to acid reflux.  Urogenital autonomic neuropathy presents as bladder dysfunction (also known as diabetic cystopathy) that can range from urinary retention with hesitancy to urinary incontinence with urgency. - Sexual dysfunction is another common manifestation of urogenital autonomic neuropathy.  In men, sexual dysfunction manifests as impotence, decreased libido and abnormal ejaculation, whereas in women, sexual dysfunction presents as pain during intercourse, poor lubrication and reduced libido.  Sudomotor autonomic dysfunction presents as dry skin (anhydrosis) with gustatory sweating. Treatment of diabetic autonomic neuropathy depends on the specific subtype. Optimization of glucose control early in the course of type 1 diabetes mellitus (T1DM) is recommended to prevent or delay CAN, whereas targeting all metabolic risk factors is the recommendation for type 2 diabetes mellitus (T2DM). Volume repletion, physical activity, low-dose fludrocortisone or midodrine and compression stockings are among treatment options for CAN in patients with T1DM or T2DM. Excluding other causes of gastrointestinal autonomic dysfunction, particularly opioids or glucagon-like peptide 1 receptor agonists as well as gastric obstruction, is essential before instituting a short-term course of metoclopramide for gastroparesis.  Urogenital autonomic neuropathy is a diagnosis of exclusion, with multiple medications, low hormone levels and infections being the main three differential diagnoses to consider before attributing dysfunction to diabetes.  Pharmacological treatment of male erectile dysfunction includes phosphodiesterase type 5 inhibitors. The topical antimuscarinic drug glycopyrrolate can be used for the treatment of gustatory sweating, whereas daily moisturizing lotions provide relief for dry skin. 

DLRPN Case.

A 68-year-old man with a 3-year history of type 2 diabetes, a hemoglobin A1C of 6.4, and mild distal sensory loss developed severe pain in his back and right leg over the course of 1 week.  During the next 2 weeks he noted profound weakness of his leg with frequent buckling of his knee when ambulating.  In addition, he reported generalized weakness and had experienced an unintentional 10 kg (22 lb) weight loss.  His neurologic examination demonstrated severe weakness in his right iliopsoas, quadriceps, and hip adductors, and moderate weakness in his hip abductors, hamstrings, anterior tibialis, peronei, and posterior tibialis. In his left leg, mild, patchy weakness was present in most muscles.  Reflexes were absent diffusely, and he demonstrated moderate sensory loss distally to his knees bilaterally as well as in his right thigh.  An MRI of the lumbar spine was notable for mild diffuse degenerative changes but not for a focal compressive lesion involving the conus or the roots.  An EMG demonstrated findings of a diffuse asymmetric axonal polyradiculopathy with abnormalities most severe in the right L3-L4 root distribution.  He was treated with pain medication and physical therapy, and after 2 months his pain had decreased substantially, but he experienced moderately severe residual proximal right leg weakness. 

Comment. This case illustrates a fairly stereotypical presentation of diabetic lumbosacral radiculoplexus neuropathy (DLRPN).  Patients often present with a syndrome that most profoundly involves the lumbar plexus or upper lumbar roots but have more diffuse involvement clinically and electromyographically in multiple lumbosacral and thoracic roots.  The syndrome often occurs in a period of reasonably well-controlled diabetes.  Given the relatively acute initial presentation, imaging of the spine is justified and is often performed to assess for a structural radiculopathy.  No established treatment exists for DLRPN, and supportive management and time often leads to improvement of pain and weakness.

Diagnostic Workup for Lumbosacral Plexopathy

Treatment of painful diabetic neuropathy. 

First-line and second-line treatments for painful diabetic neuropathy include several drug classes, such as anticonvulsants (gabapentin or pregabalin), serotonin and noradrenaline reuptake inhibitors (SNRIs; duloxetine or venlafaxine) and tricyclic antidepressants (amitriptyline, nortriptyline, desipramine or imipramine). Opioids should be avoided owing to their serious adverse effects and association with addiction