Nerve Glucose, Fructose, Sorbitol, myo-Inositol, and Fiber Degeneration and Regeneration in Diabetic Neuropathy

We measured the alcohol sugars in sural nerves from 11 controls, 21 conventionally treated patients with diabetes and neuropathy, and 4 diabetics without neuropathy. The results were related to metabolic control and to clinical, neuropathological, and morphometric abnormalities in the nerves. The mean endoneurial glucose, fructose, and sorbitol values were higher in diabetic patients than in controls. Linear regression analysis revealed that nerve sorbitol content in the diabetics was inversely related to the number of myelinated fibers (P = 0.003). Mean nerve levels of myo-inositol were not decreased in the diabetic patients, with or without neuropathy, and were not associated with any of the neuropathological end points of diabetes. Our results indicate that myo-inositol deficiency is not part of the pathogenesis of human diabetic neuropathy, as had been hypothesized. Other accumulated alcohol sugars, however, were increased in diabetes and were associated with the severity of neuropathy. On repeat biopsy, six diabetics, treated for a year with the aldose reductase inhibitor sorbinil, had decreased endoneurial levels of sorbitol (P<0.01) and fructose (0.05<P<0.1), but unchanged levels of myo-inositol. (N Engl J Med 1988; 319:542–8.) THE mechanisms underlying the development of diabetic polyneuropathy remain unknown.^{1 2 3} Chronic hyperglycemia may be a primary event, but rigorous prospective studies await completion.⁴ Chronic hyperglycemia is associated with various metabolic alterations in lipids,^{5 6 7 8} alcohol sugars,^{3,9 10 11 12 13} and myo-inositol.^{14 15 16} A decrease in tissue levels of myo- inositol is hypothesized to cause a sequence of events leading to deficiency of sodium–potassium–ATPase activity, altered axolemmal sodium permeability, and structural alterations at the nodes of Ranvier.^{17 18 19 20 21} The role of tissue accumulation of glucose, fructose, and sorbitol in causing diabetic complications has also received considerable attention.^{3,9 10 11 12 13} Sorbitol accumulation may cause osmotic swelling of tissues.