Complications: Neuropathy, Pathogenetic Considerations

Abstract

The most common form of neuropathy associated with diabetes mellitus is distal symmetric sensorimotor polyneuropathy, often accompanied by autonomic neuropathy. This disorder is characterized by striking atrophy and loss of myelinated and unmyelinated fibers accompanied by Wallerian degeneration, segmental, and paranodal demyelination and blunted nerve fiber regeneration. In both humans and laboratory animals, this progressive nerve fiber damage and loss parallels the degree and/or duration of hyperglycemia. Several metabolic mechanisms have been proposed to explain the relationship between the extent and severity of hyperglycemia and the development of diabetic neuropathy. One mechanism, activation of the polyol pathway by glucose via AR, is a prominent metabolic feature of diabetic rat peripheral nerve, where it promotes sorbitol and fructose accumulation, myo-inositol depletion, and slowing of nerve conduction by alteration of neural Na(+)-K(+)-ATPase activity or perturbation of normal physiological osmoregulatory mechanisms. ARIs, which normalize nerve myo-inositol and nerve conduction slowing, are currently the focus of clinical trials. Other specific metabolic abnormalities that may play a role in the pathogenesis of diabetic neuropathy include abnormal lipid or amino acid metabolism, superoxide radical formation, protein glycation, or potential blunting of normal neurotrophic responses. Metabolic dysfunction in diabetic nerve is accompanied by vascular insufficiency and nerve hypoxia that may contribute to nerve fiber loss and damage. Although major questions about the pathogenesis of diabetic neuropathy remain unanswered and require further intense investigation, significant recent progress is pushing us into the future and likely constitutes only the first of many therapies directed against one or more elements of the complex pathogenetic process responsible for diabetic neuropathy.

Autonomic Neuropathy in Nondiabetic Offspring of Type 2 Diabetic Subjects Is Associated With Urinary Albumin Excretion Rate and 24-h Ambulatory Blood Pressure

“…Other studies found autonomic neuropathy in newly diagnosed type 2 diabetic subjects (36,37). It has generally been accepted that neuropathy is a consequence of long-term hyperglycemia (38,39), and studies have shown that dysregulation of diabetes affects the progression of autonomic neuropathy in a negative way (40,41). In our study, long-term hyperglycemia is not a plausible cause of autonomic neuropathy.…”

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

“…The polyol pathway is thought to play a major metabolic role in the development of diabetic neuropathy (Greene & Sima, 1992;Sima & Sugimoto, 1999;Zochodne, 1999;Vinik, Pittenger, McNitt, & Stansberry, 2000). Persistent hyperglycemia increases the polyol pathway activity in conjunction with accumulation of sorbitol and fructose in nerves, and this is accompanied by a reduction in myo-inositol uptake and inhibition of Na + /K + -ATPase, resulting in Na + retention, edema, myelin swelling, axoglial disjunction, and nerve degeneration (Greene, Lattimer, & Sima, 1987;Vinik, Pittenger, McNitt, & Stansberry, 2000).…”

Effect of Sorbinil and Ascorbic Acid on myo‐Inositol Transport in Cultured Rat Schwann Cells Exposed to Elevated Extracellular Glucose

“…All these observations have collectively given rise to the sorbitol theory of diabetic neuropathy, linking the changes in inositol and sorbitol content in a mostly chronic diabetic nerve to its functional alterations, e.g., altered phosphoinositide metabolism, Na+ ,K + -ATPase activity, and nerve conduction velocity. AR activation by hyperglycemia has been linked to myo-inositol (MI) depletion, defects in phosphoinositide and Na+ ,K + -ATPase regulation, slowing nerve conduction, and structural defects in diabetic neuropathy (Greene et al, 1992). Experimental diabetes also gives rise to MI depletion, reduced nerve Na + ,K + -ATPase activity, and nerve conduction slowing, which can be prevented by dietary MI supplementation (Greene et a!., 1975(Greene et a!., , 1982Palmano et al, 1977;Greene and Winegrad, 1981;Greene and Lattimer, 1983;Mayer and Tomlinson, 1983).…”