Etiology

DN is a complex consequence of hyperglycemia-induced alterations in multiple biochemical pathways, associated with other metabolic and vascular factors.

Hyperglycemia

  • The contribution of hyperglycemia to the pathogenesis of microvascular complications (including DN) in type 1 and type 2 diabetes is firmly established.[9][30]

  • The Diabetes Control and Complications Trial (DCCT) provided strong evidence for the importance of hyperglycemia, insulin deficiency, or both in the pathogenesis of DN in type 1 diabetes.[9]

  • The Epidemiology of Diabetes Interventions and Complications (EDIC) study, the prospective observational study of the DCCT cohort, has shown persistent beneficial effects of past glucose control on both DN and cardiovascular autonomic neuropathy in patients with type 1 diabetes.[10][11] This finding supports the impact of "metabolic memory" as previously observed for retinopathy and nephropathy.[31]

  • The results of the EDIC study also supported a close association between the severity and/or duration of hyperglycemia and the development and progression of DN.[32]

  • Patients who had received intensive insulin therapy in the DCCT were protected from the development of DN for at least 8 years following completion of the DCCT.[10][11][32]

  • The ACCORD trial reported that an intensive glucose-lowering strategy, targeting an HbA1c <6% delayed the progression of neuropathy in patients with type 2 diabetes at high risk of CVD events.[33] However, in this trial the intensive therapy was stopped before study end because of higher mortality in that group.

  • One meta-analysis that included 17 randomized studies of patients with type 1 or type 2 diabetes found high-quality evidence that tight glucose control could prevent the development of DN and reduce the incidence of clinical neuropathy in people with type 1 diabetes.[34] In type 2 diabetes, enhanced glucose control had no impact on vibration perception threshold and failed to significantly reduce the incidence of clinical neuropathy.[34]

  • However, in type 2 diabetes, the type of glucose lowering approach may have different effects on DN. Among patients with type 2 diabetes followed for up to 4 years during the BARI 2D study, a glycemic control therapy with insulin sensitizers significantly reduced the incidence of diabetic peripheral neuropathy compared with insulin provider therapy, especially in men.[19]

Other metabolic and vascular factors

  • Data from the United Kingdom Prospective Diabetes Study (UKPDS) suggest that hypertension, obesity, and smoking contribute to the development of DN in type 2 diabetes.[30]

  • Cardiovascular risk factors such as hypertension and elevated serum triglycerides are each independently associated with development of DN.[35][36][37] The EURODIAB trial found that both hypertension and hyperlipidemia accelerated the effects of hyperglycemia on nerve dysfunction in people with type 1 diabetes.[12][35]

  • Elevated triglycerides and lower HDL have been reported to be independently associated with development of DN.[37][38]

Other general factors

  • Age

  • Duration of diabetes

  • Height

  • Body mass index.

The American Diabetes Association advises physicians to be alert for other treatable causes of neuropathies occurring in patients with diabetes, such as toxins (e.g., alcohol), neurotoxic medications (e.g., chemotherapy), vitamin B12 deficiency (particularly in patients taking metformin or a proton pump inhibitor), hypothyroidism, renal disease, malignancies, monoclonal gammopathy, infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis.[39]​​​

Pathophysiology

Research supports the concept that both metabolic and vascular factors are involved in the pathogenesis of DN. Animal and in vitro experiments implicate enzymatic and nonenzymatic pathways of glucose metabolism in the initiation and progression of DN. These include:[40][41][42]

  • Increased oxidative and nitrosative stress

  • Redox imbalance, secondary to enhanced aldose reductase activity

  • Nonenzymatic glycation of structural nerve proteins

  • Increased chronic inflammation and nuclear factor kappa B (NF-kB) signaling pathways

  • Increased protein kinase C-beta activity

  • Impaired nitric oxide synthase and endothelial dysfunction

  • Cyclooxygenase-2 activation

  • Hypoxia and ischemia of nerve trunks and ganglia

  • Deficiencies in the neurotrophic support of neurons and deficiencies in C-peptide

  • Poly (ADP-ribose) polymerase (PARP) activation

  • Alterations in mitogen-activated protein kinases

  • Mobilization of transcription factors

  • Oxidized LDL cholesterol-mediated injury.

In nerve tissue, this pattern of metabolic and vascular disturbance impairs mitochondrial function and neurotrophic support, and mediates injury of neurons and Schwann cells, culminating in progressive damage and loss of peripheral nerve fibers and impaired sensory function.[43]

Similar mechanisms may be relevant to the pathogenesis of both micro- and macrovascular disease in type 2 diabetes and include endothelial dysfunction, low-grade inflammation, and rheologic abnormalities.[44]

Different types of DN produce alternate patterns of abnormal sensation and arise from different pathophysiologic mechanisms.[45]

It is now recognized that a major effect of diabetes is on the small unmyelinated or thinly myelinated C and A delta nerve fibers that modulate autonomic function and thermal and pain perception. Small-fiber neuropathy can impact on wound healing and, therefore, foot ulceration.[46] Indeed, small-fiber loss may occur prior to the development of foot ulceration.[47]  

Classification

Classification for diabetic neuropathy[1][2][3]

A. Diffuse neuropathy

  • Distal symmetric sensorimotor polyneuropathy

    • Primarily small-fiber neuropathy

    • Primarily large-fiber neuropathy

    • Mixed small- and large-fiber neuropathy

  • Autonomic neuropathy

B. Mononeuropathy

  • Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal)

  • Mononeuritis multiplex

C. Radiculopathy or polyradiculopathy

  • Radiculoplexus neuropathy (also called lumbosacral polyradiculopathy or proximal motor amyotrophy)

  • Thoracic radiculopathy

The most common forms of DN are chronic sensorimotor polyneuropathy and autonomic neuropathy.

Toronto Expert Panel on Diabetic Neuropathy Classification[3]

While this panel endorsed the classifications previously published, it also identified two major subgroups:

  • Typical diabetic peripheral neuropathy (DPN) - a chronic, symmetrical, length-dependent (longer nerves affected first in the most distal segments) sensorimotor polyneuropathy. It is thought to be the commonest variety of DPN from cohort and population-based epidemiologic studies.

  • Atypical DPN - may develop at any time during the course of a patient’s diabetes mellitus. Onset of symptoms may be acute, subacute, or chronic, but the course is usually monophasic or fluctuating over time, tending to preferentially involve small sensory and autonomic nerve fibers.

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