Mechanisms underlying impaired hypoglycemic counterregulation following recurrent hypoglycemia in diabetes.

摘要

Antecedent hypoglycemia is a major cause of defective glucose counterregulation in type 1 diabetes. This thesis aimed to elucidate potential mechanisms underlying the effect of recurrent hypoglycemia to impair counterregulation in diabetes. In streptozotocin-diabetic rats, a model of type 1 diabetes, two studies were performed. Study 1 aimed to differentiate the effects of recurrent hyperinsulinemic-hypoglycemia from those of recurrent hyperinsulinemia per se on counterregulatory system function in untreated diabetic rats. Study 2 aimed to determine the effects of insulin treatment of diabetic rats on (1) counterregulatory responses to hypoglycemia and adrenal catecholamine-synthesizing enzyme mRNA and (2) adaptations in these parameters following recurrent hypoglycemia. In study 1, untreated diabetic rats displayed marked overall impairment of counterregulatory responses to hypoglycemia. The decreased epinephrine and norepinephrine responses were associated with reduced adrenomedullary mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis. Recurrent hyperinsulinemia, irrespective of concurrent glycemic levels, partially normalized glucagon responses to subsequent hypoglycemia, and fully normalized norepinephrine and corticosterone responses. Conversely, recurrent hypoglycemia further impaired epinephrine and glucose production responses. The further defect in epinephrine counterregulation was associated with reduced adrenomedullary mRNA for phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. In study 2, insulin treatment of diabetic rats prevented the impairment of counterregulation and the decrease in TH mRNA seen in untreated diabetic control rats. Surprisingly, recurrent hyperinsulinemic-hypoglycemia in insulin-treated diabetic rats nearly abolished corticosterone responses to hypoglycemia, but did not diminish epinephrine responses or basal PNMT mRNA. In normal and insulin-treated diabetic control rats, but not in rats exposed to recurrent hyperinsulinemic-hypoglycemia or hyperinsulinemic-hyperglycemia, PNMT mRNA decreased in response to hypoglycemia. Thus, the lack of an effect of repeated hypoglycemia to impair epinephrine counterregulation was related to an effect of insulin treatment combined with repeated exposure to hyperinsulinemia to protect against decreases in PNMT mRNA. We conclude that hypoglycemia decreases adrenal PNMT mRNA, whereas insulin treatment protects against such decreases. An understanding of the mechanisms underlying these effects of hypoglycemia and insulin on PNMT mRNA may aid in the development of treatments to improve epinephrine counterregulation in type 1 diabetic humans.