Peripheral neuropathy in prediabetes and the metabolic syndrome

Abstract

Peripheral neuropathy is a major cause of disability worldwide. Diabetes is the most common cause of neuropathy, accounting for 50% of cases. Over half of people with diabetes develop neuropathy, and diabetic peripheral neuropathy (DPN) is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. Most patients with non-diabetic neuropathy have cryptogenic sensory peripheral neuropathy (CSPN). A growing body of literature links prediabetes, obesity and metabolic syndrome to the risk of both DPN and CSPN. This association might be particularly strong in type 2 diabetes patients. There are no effective medical treatments for CSPN or DPN, and aggressive glycemic control is an effective approach to neuropathy risk reduction only in type 1 diabetes. Several studies suggest lifestyle-based treatments that integrate dietary counseling with exercise might be a promising therapeutic approach to early DPN in type 2 diabetes and CSPN associated with prediabetes, obesity and metabolic syndrome.

Keywords: Metabolic syndrome; Peripheral neuropathy; Prediabetes.

Figure 1

(a) Skin biopsy stained with PGP 9.5 shows normal intra‐epidermal nerve fiber density at the distal leg in a control participant. (b) Intra‐epidermal nerve fiber density is significantly reduced in a patient with distal symmetric polyneuropathy and type 2 diabetes mellitus. Images courtesy of the University of Utah Cutaneous Nerve Laboratory.

Figure 2

(a) Corneal confocal microscopy from a normal participant shows a normal nerve fiber density of 66.7 fibers/mm² and nerve fiber length of 37.8 mm/mm². (b) Images from a patient with distal symmetric polyneuropathy show reduced nerve fiber density (12.0 fibers/mm²) and nerve fiber length (12.0 mm/mm²). There is also proliferation of dendritic cells (Langerhans cells), similar to what is observed in skin biopsies of patients with diabetic neuropathy (arrowhead).

Figure 3

Diabetic neuropathy (DPN) and cryptogenic sensory peripheral neuropathy associated with metabolic syndrome likely share common disease mechanisms. Insulin resistance is a core metabolic feature of type 2 diabetes. Obesity and insulin resistance each lead to overlapping and self‐reinforcing mechanisms that converge on direct axonal injury, as well as endothelial injury and abnormal vascular reactivity, each of which in turn lead to axonal injury. AGEs, advanced glycosylation end‐products FA, fatty acid; FFA, free fatty acids; eNOS, endothelial nitric oxides synthase; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NO, nitric oxide; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha.

Figure 4

The capsaicin axotomy technique can be used to assess peripheral nerve regenerative capacity in vivo. (a) At baseline, a 3‐mm punch biopsy is obtained from the distal lateral thigh. The baseline intra‐epidermal nerve fiber density is 21.1 fibers/mm (×40 magnification). (b) Topical capsaicin is placed for 48 h and a biopsy is repeated from the area treated. The post‐capsaicin intra‐epidermal nerve fiber density is markedly reduced (1.0 fibers/mm²). (c) One month after capsaicin application, a skin biopsy is repeated adjacent to the prior biopsies, showing significant nerve fiber regeneration (intra‐epidermal nerve fiber density 10.4 fibers/mm).