Mechanisms of Insulin Resistance in Man

描述（由申请人提供）：美国约有1亿人患有2型糖尿病（T2D）或糖尿病前期，占医疗保健费用的五分之一。这些代谢紊乱的患病率呈指数增长。了解这些疾病的发病机制，并根据致病因素制定合理的治疗方法是非常重要的。人类夜间调节葡萄糖产生的确切机制尚不清楚。关于T2D中观察到的较高的空腹血糖浓度是否由于夜间或清晨单独的葡萄糖浓度不适当的反调节激素分泌（即胰高血糖素和皮质醇）导致胰岛素抵抗和随之而来的更高的葡萄糖生成，存在争议；或者可能是夜间禁食状态下生物钟的紊乱。在之前的资助周期中，我们已经表明，由于葡萄糖产生和葡萄糖摄取的异常调节，t2dm患者的空腹和餐后葡萄糖浓度较高。当前的应用程序旨在系统地研究特定目的1中T2D中夜间葡萄糖产生调节的病理生理学，特定目的2中皮质醇和胰高血糖素对夜间葡萄糖稳态的相对贡献，以及这些影响与人体测量匹配的非糖尿病受试者的差异程度。最后，在具体目标3中，我们将进行一项临床试验，以确定二甲双胍与甘精胰岛素对T2D中胰高血糖素肝脏反应的影响。特异性目的1将测定T2D和非糖尿病受试者在上午1、4和7时的内源性葡萄糖生成率。为尽量减少睡眠的混杂效应，有睡眠障碍史的受试者将被排除在外。此外，受试者将在临床研究单元（CRU）居住2晚1天，以便在第一天晚上熟悉CRU的环境，并在第二天晚上采取措施尽量减少研究期间的睡眠中断。用2H2O测定糖异生速率。特异性Aim 2A将测试T2D和非糖尿病受试者夜间皮质醇浓度对葡萄糖生成的影响。内源性皮质醇的产生将被甲屈酮阻断，在恒定和上升的夜间皮质醇输注随机顺序。内源性葡萄糖生成率将在夜间和早上7点进行评估。我们还将评估在匹配门静脉胰岛素和胰高血糖素浓度的生长抑素钳夹下，在皮质醇浓度不变和升高的情况下，每组胰岛素诱导的内源性葡萄糖产生的抑制。特异性Aim 2B将确定夜间胰高血糖素浓度对T2D和非糖尿病受试者内源性葡萄糖生成率的影响。内源性胰高血糖素的分泌将被生长抑素阻断，在持续和上升的夜间胰高血糖素输注随机顺序。我们将测试在胰高血糖素浓度升高时，t2dm患者胰岛素诱导的内源性葡萄糖生成抑制是否低于非糖尿病患者。我们还将确定在胰高血糖素浓度升高的情况下，t2dm的糖原溶解率是否更高。在Specific Aim 3中，为了探索二甲双胍治疗在多大程度上改变了T2D患者对胰高血糖素的肝脏反应，T2D受试者将接受胰高血糖素剂量为0.65、1.5和3.0 ng/kg/min（在生长抑素存在的情况下）的正血糖钳夹研究，以估计随机分配到两周二甲双胍或甘精胰岛素治疗前后的内源性葡萄糖生成率。更好地了解影响夜间葡萄糖代谢调节的因素将有助于在未来开发合理的治疗方法来管理T2D患者。

DESCRIPTION (provided by applicant): Almost ~ 100 million people in the US have type 2 diabetes (T2D) or pre-diabetes that accounts for 1 in 5 health care dollars. The prevalence of these metabolic disorders is increasing exponentially. Understanding the pathogenesis of, and developing rational therapies based on the pathogenic factors for these conditions is a very high priority. The exact mechanism of nocturnal regulation of glucose production in humans remains poorly understood. There is controversy regarding whether the higher fasting glucose concentration observed in T2D is due to inappropriate counter-regulatory hormone secretion (i.e., glucagon and cortisol) for the prevailing glucose concentrations throughout the night or during early morning hours alone resulting in insulin resistance and consequent higher glucose production; or perhaps to a disruption of the biological clock in the overnight fasted state. In th previous grant cycle we have shown that people with T2D have higher fasting and post prandial glucose concentrations as a result of abnormal regulation of glucose production and glucose uptake. The current application is designed to systematically investigate the pathophysiology of overnight regulation of glucose production in T2D in specific aim 1, the relative contributions of cortisol and glucagon to nocturnal glucose homeostasis in specific aim 2, and the extent to which these effects differ from anthropometrically matched nondiabetic subjects. Finally, in specific aim 3, we will conduct a clinical trial to determine the effect of metformin vs. insulin glargine on hepatic response to glucagon in T2D. Specific Aim 1 will determine the rates of endogenous glucose production in T2D and nondiabetic subjects at 1, 4 and 7 AM. To minimize confounding effects of sleep, subjects with a history of sleep disorders will be excluded. Moreover, subjects will stay at clinical research unit (CRU) for 2 nights and 1 day so as to be familiarized to the CRU environment on the first night and measures in place to minimize sleep disruption during study period on the second night. Rates of gluconeogenesis will be measured using 2H2O. Specific Aim 2A will test the effects of nocturnal cortisol concentrations on glucose production in T2D and nondiabetic subjects. Endogenous cortisol production will be blocked by metyrapone during constant vs. rising overnight cortisol infusions in random order. Rates of endogenous glucose production will be estimated overnight and at 7 AM. We will also evaluate insulin induced suppression of endogenous glucose production in each group at constant vs. rising cortisol concentrations during matched portal insulin and glucagon concentrations with a somatostatin clamp. Specific Aim 2B will determine the effects of nocturnal glucagon concentrations on rates of endogenous glucose production in T2D and nondiabetic subjects. Endogenous glucagon secretion will be blocked by somatostatin during constant vs. rising overnight glucagon infusions in random order. We will test whether insulin induced suppression of endogenous glucose production is lower in T2D than nondiabetic subjects during rising glucagon concentrations. We will also determine whether glycogenolysis rates are higher in T2D in the presence of rising glucagon concentrations. To explore the extent to which metformin therapy alters the hepatic response to glucagon in people with T2D in Specific Aim 3, T2D subjects will undergo euglycemic clamp studies with glucagon doses at 0.65, 1.5 and 3.0 ng/kg/min (in the presence of somatostatin) to estimate rates of endogenous glucose production before and following randomization to either two weeks of metformin or insulin glargine therapy. A better understanding of factors that impact the nocturnal regulation of glucose metabolism will help to develop rational therapeutic approaches to manage individuals with T2D in the future.