Kinsley B T, Simonson D C
Joslin Diabetes Center, New England Deaconess Hospital, Boston, Massachusetts 02115, USA.
J Clin Endocrinol Metab. 1996 Feb;81(2):684-91. doi: 10.1210/jcem.81.2.8636289.
The epinephrine and cortisol responses to hypoglycemia are reduced in insulin-dependent diabetes mellitus (IDDM) patients in strict glycemic control. However, it is not known whether these abnormalities are mediated at a central (hypothalamic-pituitary) or peripheral (adrenal) level. To examine this question, we measured counterregulatory hormone secretion during a 3-h hypoglycemic hyperinsulinemic clamp (12 pmol/kg.min) that lowered glucose from 5.0 to 2.2 mmol/L in steps of 0.55 mmol/L every 30 min in 13 well controlled IDDM subjects (hemoglobin A1, 7.8 +/- 0.2%), 14 poorly controlled IDDM subjects (hemoglobin A1, 12.3 +/- 1.5%), and 20 healthy volunteers. Basal levels of ACTH, cortisol, and epinephrine were similar in all 3 groups before hypoglycemia. At the nadir glucose level (2.2 mmol/L), ACTH, cortisol, and epinephrine levels were significantly lower in well controlled IDDM compared to healthy controls, and the glucose levels required for significant secretion of ACTH, cortisol, and epinephrine also were lower in well controlled IDDM compared to those in both poorly controlled IDDM and healthy volunteers (P < 0.05). During hypoglycemia, ACTH levels were significantly correlated with cortisol levels (r = 0.43; P < 0.05). Because adrenomedullary epinephrine synthesis is partially dependent on adequate adrenocortical function, we also determined whether the blunted epinephrine response might result from the reduced cortisol secretion. Eleven of the control subjects underwent a second identical insulin clamp study during which metyrapone was administered to produce adrenal cortical blockade. Despite higher basal ACTH levels after metyrapone and sustained elevations in ACTH during hypoglycemia, the cortisol response was abolished during metyrapone treatment, indicating effective blockade. However, epinephrine responses did not differ during hypoglycemia with or without metyrapone treatment. We conclude that 1) ACTH, cortisol, and epinephrine responses during hypoglycemia are reduced in IDDM patients in strict glycemic control; 2) the lower cortisol response is correlated with reduced ACTH levels; and 3) in healthy subjects, the cortisol response to hypoglycemia is abolished by adrenocortical blockade with metyrapone, whereas the epinephrine response to hypoglycemia remains intact. These data suggest that central adaptations in hypothalamic-pituitary responses to hypoglycemia rather than alterations in adrenal gland function per se underlie the reduced counterregulatory responses seen in IDDM subjects in strict glycemic control.
在严格血糖控制的胰岛素依赖型糖尿病（IDDM）患者中，对低血糖的肾上腺素和皮质醇反应降低。然而，尚不清楚这些异常是在中枢（下丘脑 - 垂体）还是外周（肾上腺）水平介导的。为了研究这个问题，我们在13名血糖控制良好的IDDM受试者（糖化血红蛋白A1，7.8±0.2%）、14名血糖控制不佳的IDDM受试者（糖化血红蛋白A1，12.3±1.5%）和20名健康志愿者中，进行了一项为期3小时的低血糖高胰岛素钳夹试验（12 pmol/kg·min），每30分钟将血糖从5.0 mmol/L逐步降至2.2 mmol/L，每次降低0.55 mmol/L，并测量了对抗调节激素的分泌。低血糖发作前，所有3组的促肾上腺皮质激素（ACTH）、皮质醇和肾上腺素基础水平相似。在血糖最低点（2.2 mmol/L）时，与健康对照组相比，血糖控制良好的IDDM患者的ACTH、皮质醇和肾上腺素水平显著降低，且血糖控制良好的IDDM患者中，ACTH、皮质醇和肾上腺素显著分泌所需的血糖水平也低于血糖控制不佳的IDDM患者和健康志愿者（P<0.05）。在低血糖期间，ACTH水平与皮质醇水平显著相关（r = 0.43；P<0.05）。由于肾上腺髓质肾上腺素的合成部分依赖于足够的肾上腺皮质功能，我们还确定了肾上腺素反应减弱是否可能是由于皮质醇分泌减少所致。11名对照受试者进行了第二次相同的胰岛素钳夹研究，在此期间给予甲吡酮以产生肾上腺皮质阻滞。尽管甲吡酮给药后基础ACTH水平较高，且低血糖期间ACTH持续升高，但在甲吡酮治疗期间皮质醇反应被消除，表明阻滞有效。然而，有无甲吡酮治疗时，低血糖期间的肾上腺素反应并无差异。我们得出结论：1）严格血糖控制的IDDM患者在低血糖期间的ACTH、皮质醇和肾上腺素反应降低；2）较低的皮质醇反应与ACTH水平降低相关；3）在健康受试者中，用甲吡酮进行肾上腺皮质阻滞可消除对低血糖的皮质醇反应，而对低血糖的肾上腺素反应保持不变。这些数据表明，在严格血糖控制的IDDM受试者中，下丘脑 - 垂体对低血糖反应的中枢适应性改变而非肾上腺功能本身的改变是对抗调节反应降低的基础。
