title: Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats.
abstract: Untreated diabetic rats show impaired counterregulation against hypoglycemia. The blunted epinephrine responses are associated with reduced adrenomedullary tyrosine hydroxylase (TH) mRNA levels. Recurrent hypoglycemia further impairs epinephrine counterregulation and is also associated with reduced phenylethanolamine N-methyltransferase mRNA. This study investigated the adaptations underlying impaired counterregulation in insulin-treated diabetic rats, a more clinically relevant model. We studied the effects of insulin treatment on counterregulatory hormones and adrenal catecholamine-synthesizing enzymes and adaptations after recurrent hypoglycemia. Groups included: normal; diabetic, insulin-treated for 3 wk (DI); and insulin-treated diabetic exposed to seven episodes (over 4 d) of hyperinsulinemic-hypoglycemia (DI-hypo) or hyperinsulinemic-hyperglycemia (DI-hyper). DI-hyper rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. On d 5, rats from all groups were assessed for adrenal catecholamine-synthesizing enzyme levels or underwent hypoglycemic clamps to examine counterregulatory responses. Despite insulin treatment, fasting corticosterone levels remained increased, and corticosterone responses to hypoglycemia were impaired in DI rats. However, glucagon, epinephrine, norepinephrine, and ACTH counterregulatory defects were prevented. Recurrent hypoglycemia in DI-hypo rats blunted corticosterone but, surprisingly, not epinephrine responses. Norepinephrine and ACTH responses also were not impaired, whereas glucagon counterregulation was reduced due to repeated hyperinsulinemia. Insulin treatment prevented decreases in basal TH protein and increased PNMT and dopamine beta-hydroxylase protein. DI-hypo rats showed increases in TH, PNMT, and dopamine beta-hydroxylase. We conclude that insulin treatment of diabetic rats protects against most counterregulatory defects but not elevated fasting corticosterone and decreased corticosterone counterregulation. Protection against epinephrine defects, both without and with antecedent hypoglycemia, is associated with enhancement of adrenal catecholamine-synthesizing enzyme levels.
authors.affiliation: Departments of Physiology, University of Toronto, Ontario, Canada.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Inouye
authors.forename: Jessica T Y
authors.initials: JT
authors.lastname: Yue
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.forename: Tony
authors.initials: T
authors.lastname: Kim
authors.forename: Eitan M
authors.initials: EM
authors.lastname: Akirav
authors.forename: Edward
authors.initials: E
authors.lastname: Park
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
authors.forename: Elena
authors.initials: E
authors.lastname: Burdett
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
authors.forename: Mladen
authors.initials: M
authors.lastname: Vranic
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002395:Catecholamines / Q000096:biosynthesis*; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D015309:Glucose Clamp Technique; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013311:Streptozocin; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D001786:Blood Glucose; D002395:Catecholamines; D007328:Insulin; D013311:Streptozocin; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; C494489:PEMT protein, human; D050918:Phosphatidylethanolamine N-Methyltransferase; D003345:Corticosterone