Interest in tight glycemic control in the insulin-dependent diabetic has intensified over the past decade. This was prompted by observations that such regimens may decrease the long term sequelae of diabetes. Such regimens, however, are usually associated with frequent episodes of hypoglycemia. Several studies in the literature have suggested that insulin-induced hypoglycemia is associated with enhanced glucose production, ketogenesis and lipolysis. Recent observations in the investigators laboratory have also indicated that hypoglycemia, secondary to insulin use, is also associated with enhanced total body proteolysis. The studies further showed that most of this response was secondary to enhanced proteolysis by the extra-hepatic splanchnic tissues (the gut). The mechanism of such changes in total body and regional proteolytic rates remains obscure and will be the subject of the investigator's revised proposal. Additional studies from the investigator's laboratory have also shown that the maintenance of relative """"""""central glycemia"""""""", using selective infusions of glucose into both carotid and vertebral arteries, while peripheral hypoglycemia was maintained (= 43 mg/dl) completely) completely abolished this excessive proteolytic response. Relative """"""""central glycemia"""""""" blunted but did not abolish the response in plasma catecholamines. In attempt to establish whether the observed rises in plasma glucagon, cortisol, and catecholamines played a role in the proteolytic response, the investigators infused these hormones intravenously, either singly or in combination, with and without insulin, at rates intended to achieve plasma levels comparable to those seen with insulin induced hypoglycemia. Changes in amino acid fluxes were estimated using established isotopic methods in combination with regional balance techniques. The investigator's data indicate that in none of these studies, however, did the investigators observe any increase in the rates of proteolysis. Only central (intracerebroventricular) administration of beta-endorphin resulted in marked stimulation of the proteolytic responses. These data suggest that the majority of the proteolytic responses with insulin-induced hypoglycemia are most likely centrally mediated, and are triggered by """"""""central glucopenia"""""""" which in turn activates the central endorphinergic system. The present proposal will examine these mechanisms in more detail and will attempt to determine the role that the central endorphinergic system plays in eliciting this proteolytic response.
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