Diabetic neuropathy

Abstract

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. 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 aetiology 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 remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Fig. 1 |. Patterns of nerve injury in diabetic neuropathy.

Several different patterns of neuropathy can present in individuals with diabetes. Of these, the most common is distal symmetric polyneuropathy (DSP). Examples of patterns of neuropathy are DSP, small-fibre-predominant neuropathy or treatment-induced neuropathy (part a); radiculoplexopathy or radiculopathy (part b); mononeuropathy (part c); and autonomic neuropathy or treatment-induced neuropathy (part d). Small-fibre-predominant neuropathy has the same distribution as DSP, although the neurological examination and results from nerve conduction velocity studies are different. Diabetic radiculoplexopathy or radiculopathy can respond to immunotherapy and usually improves with time, unlike other types of nerve injury in individuals with diabetes. Treatment-induced neuropathy is under-recognized, is caused by overaggressive glycaemic control and can present in multiple forms (parts a and d). Adapted by permission from BMJ Publishing Group Limited. BMJ Peltier, A., Goutman, S. A. & Callaghan, B. C. 348, (2014).

Fig. 2 |. The peripheral nervous system and alterations in diabetic neuropathy.

Sensory neurons relay sensory information from their nerve terminals (which are located throughout the periphery) to the dorsal horn of the spinal cord. The cell bodies of these sensory neurons are located in the dorsal root ganglia (DRG). Conversely, the cell bodies of motor neurons reside in the spinal cord ventral horn and transmit information from here to the periphery. Thin and unmyelinated sensory axons (C fibres or small fibres) are grouped together by non-myelinating Schwann cells into Remak bundles and represent a large portion of neurons of the peripheral nervous system. By comparison, other sensory axons are myelinated by associated Schwann cells, which have an important role in preserving axonal function. The precise order of cellular injury (whether, for example, damage to Schwann cells or axons occurs before damage to neuronal cell bodies) in diabetes is currently unknown. These changes include alterations in Schwann cell–axon transport, alterations in protein expression in the DRG, demyelination and degeneration. GAP43, growth-associated protein 43; HSP, heat shock protein; PARP, poly(ADP-ribose) polymerase. Adapted with permission from REF., Elsevier.

Fig. 3 |. Diabetic neuropathy pathogenesis.

Hyperglycaemia and dyslipidaemia, together with altered insulin signalling, lead to several pathological alterations in neurons, glia and vascular cells that can lead to nerve dysfunction and ultimately, neuropathy, including DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction, neurodegeneration and loss of neurotrophic signalling, and can trigger macrophage activation. The importance of these pathways in the development of neuropathy varies with cell type, disease profile and time, as distinct cell types are more or less susceptible to injury depending on the metabolic impairments. AGE, advanced glycation end-product; FFAs, free fatty acids; Glucosamine-6-P, glucosamine 6-phosphate; LDL, low-density lipoprotein; LOX1, oxidized LDL receptor 1; RAGE, AGE-specific receptor; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.

Fig. 4 |. Central and peripheral mechanisms contributing to neuropathic pain in diabetic neuropathy.

a | Several alterations to peripheral and central neurons contribute to the pathophysiology of painful diabetic neuropathy. Ion channels at the terminals of nociceptors can undergo glycation through the addition of methylglyoxal to form advanced glycation end-products (AGEs), which can contribute to gain of function of these channels and neuronal hyperexcitability. Changes at the perikaryon include increased expression of voltage-gated sodium channels, such as Na_v1.8, which can lead to hyperexcitability. In myelinated axons, the expression of shaker-type potassium (K_v) channels is reduced, which can also contribute to hyperexcitability. Hyperexcitability of neurons leads to increased stimulus responses and ectopic neuronal activity, leading to excessive nociceptive input to the spinal cord. In the spinal cord, microglia become activated and further enhance excitability within the dorsal horn. b | Several ascending pathways are involved in pain perception and the psychological changes associated with pain, for example, the spinothalamic pathway (1), which is involved in pain perception, and the spinoreticular tract. In addition, ascending pathways that travel via the parabrachial nucleus (2) to the hypothalamus and amygdala (3) are involved in autonomic function, fear and anxiety. Descending pathways inhibit or facilitate the transmission of nociceptive information at the spinal level (4). Changes induced by peripheral neuropathy are shown in boxes. Adapted with permission from REF., Elsevier, and from American Diabetes Association, Diabetes Care, American Diabetes Association (2013). Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

Fig. 5 |. NCS and biopsy study in diabetic neuropathy.

Abnormal sural nerve recording from a patient with diabetic neuropathy showing a decreased sural sensory nerve action potential amplitude (normal >6 μV) and slow sural sensory nerve conduction velocity (normal >39 m s⁻¹; panel a). Intraepidermal nerve fibres (arrows) and branched fibres (arrowhead) in a skin biopsy sample from a healthy individual (panel b) and from a patient with small-fibre neuropathy (panel c). A sural nerve biopsy sample exhibiting evidence of axonal loss of small-diameter and large-diameter nerves in diabetic neuropathy (panel d). Image (×20 magnification) of an Epon-embedded, 0.5 μm thick section stained with toluidine blue (panel d). AMP, amplitude; CV, conduction velocity; Dist, distance; Lat, latency; NCS, nerve conduction studies; Rec, recording; Stim, stimulating. Parts b and c adapted from REF., Springer Nature Limited.

Fig. 6 |. 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.