Ethanol on Overnight Glucose Regulation in Diabetes

描述（由申请人提供）：低血糖是2型糖尿病患者达到血糖目标的主要障碍。酒精消费在我们的社会中非常普遍，并且被证明是低血糖的原因。人口研究表明，老年人，需要胰岛素的2型糖尿病患者特别容易发生严重的低血糖，这一问题在美国每年的医疗费用估计为5000万美元或更多。我们假设，低剂量乙醇显著增加了老年、需要胰岛素的2型糖尿病患者夜间低血糖的易损性，并损害了血糖的恢复。我们的初步研究表明，低剂量乙醇会损害2型糖尿病患者白天胰岛素诱导的低血糖的恢复，但对年龄匹配的健康对照者没有影响。本研究将探讨低剂量乙醇对老年、需要胰岛素的2型糖尿病患者夜间血糖调节的影响，并通过一系列系统评估建立这些损伤的机制。具体来说，这些研究将记录乙醇对黎明现象的抑制，和/或对睡眠期间低血糖的有缺陷的反调节反应的加剧，特别是生长激素。抑制生长激素的具体机制有待研究，包括夜间乙醇(3)抑制夜间ghrelin分泌高峰和/或(4)降低垂体对GHRH的敏感性。此外，这些研究将表征(5)乙醇对夜间葡萄糖稳态的剂量响应特性，并将(6)仔细评估与膳食摄入有关的乙醇给药时间对夜间低血糖易损的影响。为了实现这些目标，我们将评估中等剂量口服乙醇或安慰剂对老年对照受试者与老年、需要胰岛素的2型糖尿病受试者之间夜间生长激素释放、生长素、总IGF- 1、游离IGF- 1、胰岛素样生长因子结合蛋白1 （IGFBP- 1）浓度、葡萄糖生成和其他葡萄糖稳态参数的影响。这些重要的研究将为夜间低血糖的预防提供科学依据（以及随之而来的成本节约），为夜间低血糖的发生提供机理上的见解。

DESCRIPTION (provided by applicant): Hypoglycemia is the principal barrier to the achievement of target glycemic goals in type 2 diabetes. Alcohol consumption is very prevalent in our society and a proven cause of hypoglycemia. Population studies suggest that elderly, insulin requiring type 2 diabetes patients are particularly vulnerable to severe hypoglycemia and that this problem accounts for an estimated $50 million or more in healthcare costs in the USA each year. We hypothesize that low dose ethanol significantly increases the vulnerability to overnight hypoglycemia and impairs the recovery of plasma glucose in elderly, insulin requiring patients with type 2 diabetes. Our preliminary studies suggest that low dose ethanol impairs recovery from day time insulin-induced hypoglycemia in type 2 diabetes patients but not in age matched healthy control subjects. The proposed studies will examine the effects of low dose ethanol on overnight glucose regulation in elderly, insulin requiring type 2 diabetes patients and will establish the mechanism of these impairments through a series of systematic evaluations. Specifically, these studies will document suppression of the dawn phenomenon by ethanol, and/or exacerbation of a deficient counterregulatory response to hypoglycemia during sleep, especially growth hormone. Specific mechanisms for the suppression of growth hormone to be examined include that evening ethanol (3) inhibits peak overnight ghrelin secretion and/or (4) reduces pituitary sensitivity to GHRH. Additionally, these studies will characterize (5) the dose response characteristics of ethanol on overnight glucose homeostasis and will (6) carefully evaluate the effect of the timing of ethanol administration in relation to meal ingestion on overnight hypoglycemic vulnerability. To address these aims, we will assess the effect of moderate doses of orally administered ethanol or placebo on overnight growth hormone release, ghrelin, total IGF- 1, free IGF- 1, insulin-like growth factor binding protein 1 (IGFBP- 1) concentrations, glucose production and other parameters of glucose homeostasis among elderly control subjects versus elderly, insulin requiring subjects with type 2 diabetes. These important studies will provide a scientific basis for the prevention of overnight hypoglycemia (and the attendant cost savings) by providing mechanistic insights into the causes of nocturnal hypoglycemia.