Popp D A, Shah S D, Cryer P E
J Clin Invest. 1982 Feb;69(2):315-26. doi: 10.1172/jci110455.
Initially euglycemic (overnight insulin-infused) patients with insulin-dependent diabetes mellitus (IDDM), compared with nondiabetic controls, exhibit similar, but somewhat delayed plasma glucose nadirs, delayed glucose recovery from hypoglycemia, and posthypoglycemic hyperglycemia after the rapid intravenous injection of 0.075 U/kg of regular insulin. These abnormalities are associated with and potentially attributable to markedly diminished glucagon secretory responses, partially reduced epinephrine secretory responses and delayed clearance of injected insulin in the diabetic patients. Because glucagon normally plays a primary role in hypoglycemic glucose counterregulation and enhanced epinephrine secretion largely compensates for glucagon deficiency, we hypothesized that patients with IDDM, who exhibit diminished glucagon secretory responses to hypoglycemia, would be more dependent upon epinephrine to promote glucose recovery from hypoglycemia than are nondiabetic persons. To test this hypothesis, glucose counterregulation during beta-adrenergic blockade with propranolol was compared with that during saline infusion in both nondiabetic controls and in patients with IDDM. Glucose counterregulation was unaffected by beta-adrenergic blockade in controls. In contrast, glucose recovery from hypoglycemia was significantly impaired during beta-adrenergic blockade in diabetic patients. This finding confirms the hypothesis that such patients are more dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and indicates that the measured deficiency of glucagon secretion is functionally important in patients with IDDM. Further, in the time frame of these studies, posthypoglycemic hyperglycemia was prevented by beta-adrenergic blockade in these patients. There was considerable heterogeneity among the diabetic patients with respect to the degree to which beta-adrenergic blockade limited the posthypoglycemic rise in plasma glucose. This rise was directly related to the degree of residual glucagon secretion and inversely related to plasma-free insulin concentrations.THUS, WE CONCLUDE: (a) that patients with IDDM are, to varying degrees, dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and that the degree of this dependence upon epinephrine is an inverse function of the residual capacity to secrete glucagon in response to hypoglycemia in individual patients; (b) that sympathoadrenal activation, coupled with the inability to secrete insulin, plays an important role in the pathogenesis of posthypoglycemic hyperglycemia in patients with IDDM.
与非糖尿病对照组相比，最初血糖正常（夜间输注胰岛素）的胰岛素依赖型糖尿病（IDDM）患者，在快速静脉注射0.075U/kg正规胰岛素后，表现出相似但稍有延迟的血浆葡萄糖最低点、低血糖后葡萄糖恢复延迟以及低血糖后高血糖。这些异常与糖尿病患者胰高血糖素分泌反应明显减弱、肾上腺素分泌反应部分降低以及注射胰岛素清除延迟有关，并且可能归因于此。由于胰高血糖素通常在低血糖的葡萄糖反向调节中起主要作用，而增强的肾上腺素分泌在很大程度上可补偿胰高血糖素缺乏，我们推测，对低血糖的胰高血糖素分泌反应减弱的IDDM患者，与非糖尿病患者相比，在促进低血糖后葡萄糖恢复方面会更依赖肾上腺素。为验证这一假设，在非糖尿病对照组和IDDM患者中，比较了用普萘洛尔进行β-肾上腺素能阻滞期间与输注生理盐水期间的葡萄糖反向调节情况。在对照组中，葡萄糖反向调节不受β-肾上腺素能阻滞的影响。相反，在糖尿病患者中，β-肾上腺素能阻滞期间低血糖后葡萄糖恢复明显受损。这一发现证实了这样的假设，即此类患者在促进低血糖后葡萄糖恢复方面更依赖肾上腺素介导的β-肾上腺素能机制，并且表明测得的胰高血糖素分泌不足在IDDM患者中具有功能重要性。此外，在这些研究的时间范围内，β-肾上腺素能阻滞可预防这些患者的低血糖后高血糖。糖尿病患者中，β-肾上腺素能阻滞限制低血糖后血浆葡萄糖升高的程度存在相当大的异质性。这种升高与残余胰高血糖素分泌程度直接相关，与游离胰岛素浓度呈负相关。因此，我们得出结论：（a）IDDM患者在不同程度上依赖肾上腺素介导的β-肾上腺素能机制来促进低血糖后葡萄糖恢复，并且这种对肾上腺素的依赖程度是个体患者中对低血糖反应分泌胰高血糖素残余能力的反函数；（b）交感肾上腺激活，加上无法分泌胰岛素，在IDDM患者低血糖后高血糖的发病机制中起重要作用。
