Hypoglycemia is a common and potentially serious problem for diabetic patients regardless of whether they are treated with insulin or oral agents. Conventional risk factors (wrong insulin doses, skipped or delayed meals, exercise) explain only a small percentage of episodes. However, hypoglycemia unawareness and abnormal glucose counterregulation have recently been identified as likely explanations for many cases. The overall goal of this grant is to delineate the mechanisms responsible for hypoglycemia unawareness and for abnormal glucose counterregulation in diabetic patients.
The Specific Aims of the grant application are: A) To establish the mechanisms responsible for hypoglycemia unawareness in insulin dependent Type I diabetes. The investigators will; 1) establish the normal threshold for induction of hypoglycemia unawareness by hypoglycemia and test the hypothesis that in diabetic patients the threshold is reduced; 2) test the hypothesis that hypoglycemia unawareness in diabetic individuals involves diminished beta adrenergic sensitivity; 3) test the hypothesis that hypoglycemia per se reduces beta adrenergic sensitivity; 4) test the hypothesis that there are two types of hypoglycemia unawareness - an acute reversible type due to recurrent hypoglycemia and another chronic irreversible type related to duration of diabetes, possibly representing an encephalopathic complication of diabetes. B) To assess the mechanisms responsible for impaired glucose counterregulation in noninsulin dependent diabetes mellitus. The investigator will test the hypotheses that 1) reduced glucagon responses are due to increased plasma free fatty acid levels; 2) that increased catecholamine responses are secondary (e.g. compensatory) to reduced glucagon responses; 3) that increased catecholamine responses are in part the result of poor metabolic control; 4) that subnormal increase in glucose production during hypoglycemia results from impaired glucagon responses; 5) that enhanced suppression of glucose utilization results from the effects of increased catecholamine responses on muscle; and 6) that increased muscle glycogenolysis provides gluconeogenic precursors and promotes the compensatory increase in glucose production observed during hypoglycemia. To achieve these aims the investigator will use a combination of glucose clamp, isotope and limb balance techniques in conjunction with pharmacologic interventions in normal volunteers and in research subjects having either Type I or Type II diabetes. Better understanding of the pathogenesis of hypoglycemia unawareness and abnormal glucose counterregulation should make treatment of diabetes safer and improve the chances of achieving optimal glycemic control.
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