Mechanisms of Insulin Resistance in Man

描述（由申请人提供）：美国近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1/5。这些代谢性疾病的患病率呈指数级增长。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一个非常重要的优先事项。夜间调节人体葡萄糖产生的确切机制仍然知之甚少。关于在T2D中观察到的较高空腹葡萄糖浓度是否是由于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后的更高葡萄糖产生;或者可能导致过夜禁食状态下生物钟的破坏。在上一个资助周期中，我们已经表明，T2D患者由于葡萄糖产生和葡萄糖摄取的异常调节而具有较高的空腹和餐后葡萄糖浓度。 本申请旨在系统地研究特定目标1中T2D中葡萄糖产生的过夜调节的病理生理学，特定目标2中皮质醇和胰高血糖素对夜间葡萄糖稳态的相对贡献，以及这些作用与人体测量匹配的非糖尿病受试者不同的程度。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vs.甘精胰岛素对T2D患者肝脏对胰高血糖素反应的影响。 具体目标1将确定T2D和非糖尿病受试者在上午1点、4点和7点的内源性葡萄糖生成速率。为了尽量减少睡眠的混杂效应，将排除有睡眠障碍病史的受试者。此外，受试者将在临床研究单位（CRU）停留2晚1天，以便在第一晚熟悉CRU环境，并在第二晚采取措施尽量减少研究期间的睡眠中断。将使用2 H2O测量糖异生速率。具体目标2A将测试夜间皮质醇浓度对T2D和非糖尿病受试者葡萄糖生成的影响。内源性皮质醇的产生将被阻断甲吡酮在恒定与上升过夜皮质醇输注随机顺序。将在夜间和上午7点估计内源性葡萄糖产生速率。我们还将在匹配的门静脉胰岛素和胰高血糖素浓度期间，用生长抑素钳夹在恒定与升高的皮质醇浓度下评价各组中胰岛素诱导的内源性葡萄糖产生抑制。特定目标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速率的影响。在以随机顺序进行的恒定与升高的过夜胰高血糖素输注期间，内源性胰高血糖素分泌将被生长抑素阻断。我们将测试在胰高血糖素浓度升高期间，胰岛素诱导的内源性葡萄糖生成抑制在T2D中是否低于非糖尿病受试者。我们还将确定在胰高血糖素浓度升高的情况下，T2D的糖原分解率是否更高。为了探索二甲双胍治疗改变特定目标3中T2D患者对胰高血糖素的肝脏反应的程度，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（存在生长抑素）的正葡萄糖钳夹研究，以估计随机接受二甲双胍或甘精胰岛素治疗2周前后的内源性葡萄糖生成率。 更好地了解影响葡萄糖代谢夜间调节的因素将有助于开发合理的治疗方法来管理未来的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.