INSULIN-ASSOCIATED MODULATION OF NEUROENDOCRINE COUNTERREGULATION, HYPOGLYCEMIA PERCEPTION, AND CEREBRAL FUNCTION IN INSULIN-DEPENDENT DIABETES-MELLITUS - EVIDENCE FOR AN INTRINSIC EFFECT OF INSULIN ON THE CENTRAL-NERVOUS-SYSTEM

Evidence for an intrinsic effect of insulin on the central nervous sys tem is accumulating. To test the hypothesis that insulin per se may mo dulate neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus, we examined 27 patients without any sign of classical autonomic neuropathy or evid ence of so-called hypoglycemia unawareness. We used the hyperinsulinem ic (0.67 vs. 2.00 mU/kg . min), stepped hypoglycemic (5.6/3.5/2.4/2.0 mmol/L) clamp technique to assess the patient's awareness of and respo nse to equivalent hypoglycemic stimuli under different degrees of phys iological hyperinsulinemia (similar to 270 vs. similar to 810 pmol/L) after an overnight euglycemic clamp (5.6 mmol/L). Simultaneously, the patient's cerebral function was assessed from his electrophysiological activity and neuropsychological skills. Higher degrees of physiologic al hyperinsulinemia caused enhanced neuroendocrine response (adrenalin e, P < 0.05; noradrenaline, P < 0.03; GH, P < 0.02; beta-endorphin, P < 0.03; ACTH, P = 0.12; cortisol, P = 0.06; PRL, P = 0.08) and symptom awareness (total symptoms, P < 0.04; autonomic symptoms, P < 0.02; ne uroglycopenic symptoms, P < 0.05; sweating, P < 0.05; heart pounding, P < 0.02; trembling, P < 0.01; lack of concentration, P < 0.02) to occ ur. Deteriorations of electrophysiological activity (middle latency au ditory-evoked potentials, P < 0.04; P-a peak latencies, P < 0.05; P-a- V interpeak latencies, P = 0.08) and neuropsychological skills (Stroop test, P < 0.05; trail making, P = 0.12) were more pronounced the high er the insulin level, but at similar blood glucose concentrations. We conclude that insulin-associated modulation of neuroendocrine counterr egulation, hypoglycemia perception, and cerebral function may occur in insulin-dependent diabetes mellitus, which indicates an intrinsic eff ect of insulin on the human brain.