somatostatin-28 and Hypoglycemia

To understand the mechanisms whereby recurrent hypoglycemia increases the risk of subsequent hypoglycemia, it was necessary to differentiate the effects of recurrent hyperinsulinemia from those of hyperinsulinemic hypoglycemia. We examined basal and hypoglycemic endocrine function in normal rats, streptozotocin-diabetic controls, and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (DH) or hyperinsulinemic hyperglycemia (DI). DH and DI rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. In diabetic controls, basal plasma ACTH tended to be increased, and plasma corticosterone, plasma somatostatin, and pancreatic prosomatostatin and proglucagon mRNA were increased (P < 0.05) vs. normal rats. These parameters were normalized in DH and DI rats. In diabetic controls, glucagon, epinephrine, norepinephrine, corticosterone, and peak glucose production responses to hypoglycemia were reduced (P < 0.05) vs. normal rats. In DI rats, epinephrine responses were normalized. Conversely, DH rats displayed marked further impairment of epinephrine and glucose production responses and increased peripheral insulin sensitivity (P < 0.05 vs. diabetic controls). Both insulin regimens partially normalized glucagon and fully normalized norepinephrine and corticosterone responses. In summary, recurrent hyperinsulinemia in diabetic rats normalized most pituitary-adrenal, sympathoadrenal, and pancreatic parameters. However, concurrent hypoglycemia further impaired epinephrine and glucose production responses and increased insulin sensitivity. We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia.

Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Corticosterone; Diabetes Mellitus, Experimental; Epinephrine; Glucagon; Glucose; Glucose Clamp Technique; Homeostasis; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Insulin; Male; Norepinephrine; Pancreas; Proglucagon; Protein Precursors; Rats; Rats, Sprague-Dawley; Recurrence; RNA, Messenger; Somatostatin

Insulin-induced hypoglycemia stimulates a rise of somatostatin-like immunoreactivity (SLI) in the venous circulation of man. Plasma SLI is comprised of a heterogenous group of peptides including somatostatin-28 (SS-28) somatostatin-28-(15-28), somatostatin-28-(16-28), and prosomatostatin (Pro-SS). To determine which of these Pro-SS related peptides is released after hypoglycemia, we developed an immunoadsorption method that rapidly and accurately separates SS-28 from the other somatostatins. This method involves the selective retention of SS-28 on a conjugate of agarose with immunoglobulins that recognize an epitope in the NH2-terminal region of SS-28. Pro-SS, SS-28-(15-28), SS-28-(16-28), henceforth referred to collectively as SS-28-(15-28), and SS-28, once separated, were then analyzed by RIA with a COOH-terminal antibody. Ten normal men were studied after an overnight fast. Pork insulin (0.05 U/kg) was injected iv, and blood was collected before and after the onset of hypoglycemia. The mean basal SS-28-(15-28) level was 13 +/- 1 (+/- SEM) pg/mL, and the mean basal SS-28 levels were 19 +/- 3 (+/- SEM) pg/mL. Plasma SS-28-(15-28) did not increase after insulin administration, but the mean SS-28 level increased by 76% (P less than 0.01). We propose that the release of SS-28, presumably from the gastrointestinal tract, during hypoglycemia occurs as a result of activation of the autonomic nervous system and speculate that SS-28, because of its ability to inhibit insulin secretion, may be important in counterregulation during glucopenia.

Topics: Adult; Humans; Hypoglycemia; Insulin; Male; Peptides; Protein Precursors; Somatostatin; Somatostatin-28