Impaired Glucose Tolerance Causes Neuropathy

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DESCRIPTION (provided by the applicant): Sensory neuropathy, often with pain, is a common neurologic patient. In developed countries, type-2 diabetes is the most frequently-defined cause of sensory neuropathy. We have found that 36 of 72 prospectively evaluated patients with otherwise idiopathic peripheral neuropathy have Impaired Glucose Tolerance (IGT). This is a significantly greater frequency of IGT (50%) than reported in large epidemiological studies of the age-matched general population (14%). IGT, defined as a 2-hour Oral Glucose Tolerance Test (OGTT) between 140 and 200 mg/dl, represents an intermediate defect in glucose metabolism, which correlates with insulin resistance syndrome, and has been shown to carry an independent risk for cardiovascular morbidity. Patients with IGT almost uniformly have a painful sensory neuropathy, linking them to the phenotype of early diabetic neuropathy. The recently completed Diabetes Prevention Program (DPP) shows that intensive diet and exercise modification can slow progression from IGT to diabetes. The Diabetes Control and Complications Trial (DCCT) clearly shows that neuropathy onset and severity correlates with glycemic control in diabetes. In the DCCT, aggressive treatment of hyperglycemia prevented or slowed the progression of neuropathy. We hypothesize that the post-prandial hyperglycemia, identified by IGT, causes or contributes to a painful, small fiber neuropathy, which is indistinguishable from that observed in early frank diabetes, and that aggressive treatment to normalize hyperglycemia will slow or prevent progression of neuropathy. The purpose of this Clinical Pilot Study is to lay the groundwork for a prospective clinical trial in patients with IGT, and neuropathy, to determine if intensive exercise and diet counseling alone, or with a glucose-lowering agent, can stabilize or reverse neuropathy. We have three specific aims:1. Confirm the statistical association between IGT and neuropathy using control subjects with chronic pain, matched for age and body mass index.2. Characterize the clinical, electrodiagnostic, and histologic phenotype of neuropathy associated with IGT.Define the progression of neuropathy associated with IGT using two validated measures of neuropathy severity (cold detectiort threshold and nerve conduction velocity), and validate the use of intraepidermal nerve fiber countin as a measure of small fiber neuropath progression.