Inouye Karen E, Yue Jessica T Y, Chan Owen, Kim Tony, Akirav Eitan M, Park Edward, Riddell Michael C, Burdett Elena, Matthews Stephen G, Vranic Mladen
Departments of Physiology, University of Toronto, Ontario, Canada.
Endocrinology. 2006 Apr;147(4):1860-70. doi: 10.1210/en.2005-1040. Epub 2006 Jan 5.
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.
未经治疗的糖尿病大鼠对低血糖的对抗调节功能受损。肾上腺素反应减弱与肾上腺髓质酪氨酸羟化酶（TH）mRNA水平降低有关。反复低血糖会进一步损害肾上腺素的对抗调节功能，并且还与苯乙醇胺N-甲基转移酶mRNA减少有关。本研究调查了胰岛素治疗的糖尿病大鼠（一种更具临床相关性的模型）对抗调节功能受损背后的适应性变化。我们研究了胰岛素治疗对对抗调节激素和肾上腺儿茶酚胺合成酶的影响以及反复低血糖后的适应性变化。分组包括：正常组；糖尿病组，胰岛素治疗3周（DI）；以及接受胰岛素治疗的糖尿病大鼠，经历7次（在4天内）高胰岛素血症性低血糖（DI-hypo）或高胰岛素血症性高血糖（DI-hyper）发作。DI-hyper大鼠区分了高胰岛素血症和低血糖的影响。在第5天，评估所有组大鼠的肾上腺儿茶酚胺合成酶水平，或进行低血糖钳夹以检查对抗调节反应。尽管进行了胰岛素治疗，但DI大鼠的空腹皮质酮水平仍然升高，并且对低血糖的皮质酮反应受损。然而，胰高血糖素、肾上腺素、去甲肾上腺素和促肾上腺皮质激素的对抗调节缺陷得到了预防。DI-hypo大鼠的反复低血糖使皮质酮反应减弱，但令人惊讶的是，肾上腺素反应并未减弱。去甲肾上腺素和促肾上腺皮质激素反应也未受损，而由于反复高胰岛素血症，胰高血糖素的对抗调节功能降低。胰岛素治疗可防止基础TH蛋白减少，并增加PNMT和多巴胺β-羟化酶蛋白。DI-hypo大鼠的TH、PNMT和多巴胺β-羟化酶增加。我们得出结论，糖尿病大鼠的胰岛素治疗可预防大多数对抗调节缺陷，但不能预防空腹皮质酮升高和皮质酮对抗调节功能降低。无论有无先前的低血糖，对肾上腺素缺陷的保护都与肾上腺儿茶酚胺合成酶水平的提高有关。
