Ethanol on Overnight Glucose Regulation in Diabetes

描述(由申请人提供)：低血糖是2型糖尿病患者实现目标血糖目标的主要障碍。饮酒在我们的社会中非常普遍，而且被证明是低血糖的原因。人群研究表明，需要胰岛素的老年2型糖尿病患者特别容易发生严重的低血糖，据估计，这个问题每年在美国造成5000万美元或更多的医疗费用。我们假设，低剂量乙醇显著增加了过夜低血糖的易感性，并损害了需要胰岛素治疗的2型糖尿病老年患者的血糖恢复。我们的初步研究表明，低剂量乙醇会损害2型糖尿病患者从日间胰岛素诱导的低血糖中恢复，但在年龄匹配的健康对照组中不会。这项拟议的研究将检验低剂量乙醇对需要胰岛素的老年2型糖尿病患者夜间血糖调节的影响，并将通过一系列系统评估建立这些损害的机制。具体地说，这些研究将记录乙醇对黎明现象的抑制，和/或加剧对睡眠中低血糖，特别是生长激素缺乏的反调节反应。将研究的生长激素抑制的具体机制包括：晚间乙醇(3)抑制夜间Ghrelin的分泌高峰和/或(4)降低脑下垂体对GHRH的敏感性。此外，这些研究将表征(5)乙醇对夜间血糖稳态的剂量反应特征，并将(6)仔细评估与膳食摄入有关的乙醇给药时机对夜间低血糖易感性的影响。为了达到这些目的，我们将评估中等剂量的口服乙醇或安慰剂对老年对照组和老年2型糖尿病患者的夜间生长激素释放、Ghrelin、总IGF-1、游离IGF-1、胰岛素样生长因子结合蛋白-1(IGFBP-1)浓度、葡萄糖产生和其他葡萄糖稳态参数的影响。这些重要的研究将通过对夜间低血糖原因的机械性洞察，为预防夜间低血糖(以及随之而来的成本节约)提供科学基础。

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.