Impaired glucose disposal following mild hypoglycemia in nondiabetic and type I diabetic humans

Abstract

Insulin-mediated glucose disposal was studied immediately prior to and following moderate hypoglycemia in nondiabetic subjects and subjects with insulin-dependent (type I) diabetes mellitus (IDDM), the latter having varying epinephrine secretory capacities. Plasma insulin concentration was fixed throughout the study at ∼300 to 400 pmol/L to avoid effects of waning insulin action and plasma glucose was clamped at either 5 mmol/L (euglycemic control) or at 3.1 mmol/L (hypoglycemic) periods of 120 minutes. Baseline (clamp 1) and postexperiment (clamp 2) periods were assessed for net glucose disposal (as a function of the exogenous glucose infusion rate) and glucose kinetics using 3H-glucose. In normal subjects, glucose disposal increased progressively by 132% during control studies but only by 57% with intervening hypoglycemia ( P < .005). Similarly, subjects with IDDM displayed marked reduction in glucose disposal following hypoglycemia (152% increment during control v 33% during hypoglycemia, P < .025). These changes were mediated by reduction of whole-body glucose uptake (rate of glucose disappearance [Rd], [ 3H]-3-glucose) and metabolic clearance rates with comparable suppression of hepatic glucose production in both groups. The increase in plasma free-fatty acids (FFA) following hypoglycemia was modest but greater in subjects with IDDM ( P < .01), whereas IDDM had reduced concentrations of epinephrine ( P < .01) and glucagon ( P < .005) during hypoglycemia. In subjects with IDDM but not in normal subjects, the change in posthypoglycemia glucose disposal was inversely correlated with the increase in plasma norepinephrine ( R 2 = .54, P < .004) and epinephrine ( R 2 = .32, P < .04). Glucose disposal did not correlate with other counterregulatory hormones, plasma FFA, or antecedent glycemic control. The data suggest that posthypoglycemic insulin resistance develops immediately following mild hypoglycemia in humans. Impaired glucose disposal occurs in IDDM despite reduced epinephrine secretory responses and correlates with parameters of neuroadrenergic function.