title: Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats.
abstract: 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.
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
authors: Karen
authors: K
authors: Inouye
authors: Kathy
authors: K
authors: Shum
authors: Owen
authors: O
authors: Chan
authors: Julian
authors: J
authors: Mathoo
authors: Stephen G
authors: SG
authors: Matthews
authors: Mladen
authors: M
authors: Vranic
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D004837:Epinephrine / Q000097:blood; D005934:Glucagon / Q000097:blood / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D006706:Homeostasis; D006943:Hyperglycemia / Q000503:physiopathology; D006946:Hyperinsulinism / Q000503:physiopathology*; D007003:Hypoglycemia / Q000503:physiopathology*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000097:blood; D010179:Pancreas / Q000737:chemistry; D052336:Proglucagon; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013004:Somatostatin / Q000097:blood / Q000235:genetics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; D013004:Somatostatin; D052336:Proglucagon; C028456:prosomatostatin; D000324:Adrenocorticotropic Hormone; D005934:Glucagon; D005947:Glucose; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine