Modulation of Hypoglycemic Counterregulatory Responses

DESCRIPTION (provided by applicant): Severe hypoglycemia limits intensive insulin treatment of type 1 diabetes (11DM). It is well-established that the physiologic response to hypoglycemia is dependent on the rapid and sustained increase in endogenous glucose production (EGP). The increase in EGP during hypoglycemia in the face of hyperinsulinemia is induced by secretion of the principal counterregulatory hormones-glucagon and epinephrine-and also by a non-hormonal autoregulatory mechanism previously demonstrated in the investigators laboratory. Patients with T1DM have defective activation of EGP during hypoglycemia due to absent glucagon and impaired epinephrine responses, and also due to a defective autoregulatory response. Hepatic glycogenolysis and gluconeogenesis (GNU) are the main sources of glucose 6-P required for EGP. Both epinephrine and glucagon induce a increase in these pathways during hypoglycemia, but these pathways have not been dissected in T1DM. Recent studies hay suggested that 11DM is associated with defective hepatic glycogenolysis and GNG may also be deficient. Since glycogenolysis is considered to be the initial source of hepatic glucose 6-P during the early phase of hypoglycemic counterregulation, followed by activation of GNG, we hypothesize that defects in these two pathways may play a central role in the abnormal hypoglycemia counterregulation seen T1DM patients. Furthermore, defective glycogenolysis ma account for the impaired EGP responses due to glucose per Se. Preliminary data from the investigator's laboratory also suggest that insulin and fructose can each physiologically modulate the EGP response to hypoglycemia in nondiabetic subjects, though the mechanisms responsible for augmentation of hypoglycemia counterregulation are unknown. We hypothesize that these modulatory effects may involve steps in glycogen metabolism. The introduction of in vivo NMR spectroscopy plus isotope analyses for the study of liver glycogen metabolism and GNG provide powerful new tools. The present application will bring to bear the high-field human research NMR facility at Einstein and the required expertise in a collaborative team to study hypoglycemia counterregulation in nondiabetic and T1DM subjects. The aims are to study-in nondiabetic and intensively-treated T1DM subjects-- 1) the specific contribution of glycogenolysis and GNU during hypoglycemia resulting, from epinephrine and adrenergic stimuli or glucagon; 2) the specific contribution of glycogenolysis and GNG during non-hormonal counterregulation; 3) the modulation by physiologic hyperinsulinemia of glycogenolysis and GNG during the counterregulatory response; and 4) the modulation by fructose of glycogenolysis and GNU during the counterregulatory response.