Neuropathy, womens' health, and socioeconomic aspects of diabetes.

NEUROPATHY At a symposium on neuropathy sponsored by the University of Texas Southwestern at the American Diabetes Association meeting in San Antonio, Texas, Soroku Yagihashi (Hirosaki, Japan) discussed aspects of the pathogenesis of distal symmetric polyneuropathy. In a recent survey in Tohoku, Japan, of 32,955 individuals with diabetes, history or symptoms of neuropathy made it the most common complication, occurring in 27% of patients. There are two major histologic findings in nerve biopsy from patients with distal symmetric polyneuropathy. Myelinated fiber density decreases, falling by approximately one-third with mild neuropathy and by two-thirds with severe neuropathy, reflecting loss of nerve fibers with degeneration of remaining fibers. There is also evidence of microangiopathy in the vasa nervosum. Nerve capillary density again decreases in proportion to the severity of the neuropathy, with capillary basement membrane area nearly doubled with mild neuropathy and tripled with severe neuropathy. The susceptibility of peripheral nerve to ischemia may be partly related to its great axon length with sparse blood supply. As with retinopathy and nephropathy, poor glycemic control is a major cause of neuropathy, with nerves not showing insulin-mediated glucose uptake, but rather allowing direct glucose entry, which increases with hyperglycemia. In the Tohoku survey, the likelihood of neuropathy increased 2.7-, 1.7-, and 1.2-fold in individuals whose HbA1c was 10, 7.5–9.9, and 6.5–7.49%, in comparison to those with HbA1c 6.5%. In the nerve, glucose is metabolized through the polyol pathway to sorbitol via the enzyme aldose reductase (AR). Sorbitol can cause osmotic stress and can lower nerve myoinositol and taurine levels, with decreases in Na /K -ATPase, which is involved in intracellular energy homeostasis. In addition, conversion of NADPH to NADP as glucose is metabolized to sorbitol decreases availability of this substrate for the action of nitric oxide (NO) synthase in forming citrulline and NO from arginine, with potentiation of vascular dysfunction by NO deficiency. In contrast to AR, which is located within nerve fascicles, immunohistochemical staining shows that the enzyme sorbitol dehydrogenase (SDH), which metabolizes sorbitol to fructose, is present largely in epineurial arterioles and hence becomes unavailable with diabetic vasculopathy. Yagihashi reviewed the strong relationship between AR and neuropathy, with erythrocyte AR protein levels that are similar in individuals with diabetes and in the general population, but that are lower in diabetic individuals without neuropathy than in those who have neuropathy (1). In experimental models of diabetes, AR levels in both the sciatic nerve and the renal cortex are elevated, whereas SDH levels are comparable to those in nondiabetic animals. Furthermore, ARoverexpressing transgenic mice that are made diabetic show increased nerve sorbitol in association with greater reduction in motor nerve conduction velocity (NCV) and myelinated fiber size when compared with nontransgenic mice with diabetes. Na /K -ATPase is decreased with diabetes alone, and it is further decreased in the diabetic animals overexpressing AR. Furthermore, intraneural diacylglycerol (DAG) decreases, with a fall in protein kinase C(PKC), which further decreases Na /K -ATPase activity. The diabetic mice overexpressing AR show further decreases in PKC. This relationship between a lowering of neural PKCand diabetic neuropathy contrasts with vascular smooth muscle and the endothelium, where diabetic complications appear to be mediated by increases in DAG and PKC. Abnormalities of the polyol pathway may also increase production of advanced glycation end products, including the toxic intermediates 3-deoxyglucosone (3DG), methylglyoxal, and carboxymethyl lysine (CML). The AR inhibitor epalrestat has been shown to decrease blood sorbitol and also CML and 3-DG in patients with diabetes (2). A number of such compounds have been studied. Zenarestat shows a dose-related decrease in nerve sorbitol and an increase in peroneal NCV and nerve fiber density in individuals with diabetic neuropathy (3), and fidarestat improves a number of indexes of nerve function when administered to patients for a 1-year period (4). Yagihashi concluded that with coming advances in treatment “we will have a method for the treatment and prevention of diabetic neuropathy.” Joseph C. Arezzo (Bronx, NY) discussed the role of electrophysiological testing in diabetic neuropathy. These testing modalities are of great value in multicenter studies, providing objective and specific evidence of the efficacy of new therapies. In the future, however, Arezzo pointed out that with metabolic therapies, it may be important to monitor patients’ progress, particularly with “technological breakthroughs which allow measurement [of nerve conduction] at the point of care.” Electrophysiology can be used to assess abnormality of proximal and distal ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●