Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response
Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response
复制标题
DOI：
10.2337/diabetes.51.4.958
复制
发表时间：
2002-04-01
期刊：
影响因子：
7.7
通讯作者：
Cryer, PE
中科院分区：
文献类型：
--
作者：
Banarer, S;McGregor, VP;Cryer, PE
由于缺乏胰高血糖素对血糖浓度下降的反应在胰岛素缺乏型糖尿病患者医源性低血糖的发病机制中起着关键作用，并且这种缺陷的机制尚不清楚，并且在实验动物中给出的证据表明胰岛内胰岛素减少是胰高血糖素分泌增加的信号，我们研究了内源性胰岛素在胰高血糖素对低血糖的生理反应中的作用。我们检验了胰岛内高胰岛素血症阻止胰高血糖素对低血糖反应的假设，尽管胰岛-肾上腺髓质、交感神经和副交感神经反应完整，α-细胞葡萄糖浓度低。12名健康的年轻人在三个不同的场合进行了研究。胰岛素以相对低的剂量（1.5、3.0、4.5和6.0 pmol（.）kg（-1）（.）min（-1））。一次将血糖水平限制在正常水平（类似于5.0 mmol/l，类似于90 mg/dl），另两次从60分钟至300分钟以类似于4.7、4.2、3.6和3.0 mmol/l（类似于85、75、65和55 mg/dl）的每小时步长进行。在后一种情况下，β细胞促分泌剂甲苯磺丁脲以1.0 g/h的剂量从60分钟输注到300分钟。与单独的类似低血糖相比，甲苯磺丁脲输注的低血糖与更高的（P < 0.0001）C肽水平（最终值为1.0 +/- 0.2 vs. 0.1 +/- 0.0 nmol/1），较高（P < 0.0001）胰岛素分泌率（最终值为198 +/- 60对15 +/- 4 pmol/min），以及更高（P < 0.0001）的胰岛素水平（最终值为325 +/- 30对245 +/- 20 pmol/l），如预期的那样。输注甲苯磺丁脲可防止胰高血糖素对低血糖的反应（P < 0.0001）。在两种情况下，基线时胰高血糖素水平均为17 1 pmol/l，在初始高胰岛素血症正常期间分别为14 +/-1 pmol/l vs. 15 +/- 1 pmol/l，在低血糖伴和不伴甲苯磺丁脲输注期间分别为15 +/- 1 pmol/l vs. 22 +/- 2 pmol/l。在甲苯磺丁脲输注期间，对低血糖的自主肾上腺髓质（血浆肾上腺素）、交感神经（血浆去甲肾上腺素）和副交感神经（血浆胰多肽）反应未降低。我们的结论是，胰岛内高胰岛素血症阻止胰高血糖素对低血糖的反应，尽管有完整的自主反应和低α细胞葡萄糖浓度。
Because absence of the glucagon response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia in patients with insulin-deficient diabetes and the mechanism of this defect is unknown, and given evidence in experimental animals that a decrease in intraislet insulin is a signal to increased glucagon secretion, we examined the role of endogenous insulin in the physiological glucagon response to hypoglycemia. We tested the hypothesis that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic-adrenomedullary, sympathetic neural, and parasympathetic neural-response and a low a-cell glucose concentration. Twelve healthy young adults were studied on three separate occasions. Insulin was infused in hourly steps in relatively low doses (1.5, 3.0, 4.5, and 6.0 pmol (.) kg(-1) (.) min(-1)) from 60 through 300 min on all three occasions. Plasma glucose levels were clamped at euglycemia (similar to5.0 mmol/1, similar to90 mg/dl) on one occasion and at hourly steps of similar to4.7, 4.2, 3.6, and 3.0 mmol/1 (similar to85, 75, 65, and 55 mg/dl) from 60 through 300 min on the other two occasions. On one of the latter occasions, the beta-cell secretagogue tolbutamide was infused in a dose of 1.0 g/h from 60 through 300 min. Hypoglycemia with tolbutamide infusion, compared with similar hypoglycemia alone, was associated with higher (P < 0.0001) C-peptide levels (final values of 1.0 +/- 0.2 vs. 0.1 +/- 0.0 nmol/1), higher (P < 0.0001) rates of insulin secretion (final values of 198 +/- 60 vs. 15 +/- 4 pmol/min), and higher (P < 0.0001) insulin levels (final values of 325 +/- 30 vs. 245 +/- 20 pmol/1) as expected. The glucagon response to hypoglycemia was prevented during tolbutamide infusion (P < 0.0001). Glucagon levels were 17 1 pmoL/1 at baseline on both occasions, 14 +/- 1 vs. 15 +/- 1 pmol/1, respectively, during the initial hyperinsulinemic euglycemia, and 15 +/- 1 vs. 22 +/- 2 pmol/1, respectively, during hypoglycemia with and without tolbutamide infusion. Autonomic-adrenomedullary (plasma epinephrine), sympathetic neural (plasma norepinephrine), and parasympathetic neural (plasma pancreatic polypeptide)-responses to hypoglycemia were not reduced during tolbutamide infusion. We conclude that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response and a low alpha-cell glucose concentration.