Mechanisms of Insulin Resistance in Man

描述(由申请人提供)：在美国，大约有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正在呈指数级增长。了解这些疾病的发病机制，并根据这些疾病的致病因素开发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仍然知之甚少。在T2D中观察到的较高的空腹血糖浓度是由于不适当的反调节激素分泌(即，胰高血糖素和皮质醇)导致整个夜间的普遍血糖浓度，还是仅仅在清晨导致胰岛素抵抗和随之而来的更高的葡萄糖产生；或者可能是由于隔夜禁食状态下的生物钟被扰乱。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，T2D患者的空腹和餐后血糖浓度较高。目前的应用旨在系统地研究在特定目标1中T2D中葡萄糖产生的过夜调节的病理生理学，在特定目标2中皮质醇和胰升糖素对夜间血糖稳态的相对贡献，以及这些影响与人体测量匹配的非糖尿病受试者的不同程度。最后，在特定的目标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肝脏对T2D中胰高血糖素的反应的影响。特定目标1将确定T2D受试者和非糖尿病受试者在凌晨1点、4点和7点的内源性葡萄糖生成率为了最大限度地减少睡眠的混杂影响，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)停留2晚1天，以便在第一晚熟悉CRU的环境，并在第二晚的学习期间采取措施将睡眠干扰降至最低。糖异生的速度将用2H2O来测量。特定目标2A将测试夜间皮质醇浓度对T2D和非糖尿病受试者葡萄糖产生的影响。在随机顺序的夜间皮质醇输注中，内源性皮质醇的产生将被甲替拉酮阻断。内源性葡萄糖的产生率将在隔夜和上午7点进行估计我们还将评估在生长抑素钳夹下，在门静脉胰岛素和胰升糖素浓度匹配的情况下，在皮质醇浓度恒定和升高的情况下，每组患者胰岛素诱导的内源性葡萄糖产生的抑制情况。具体目标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率的影响。生长抑素会以随机顺序在持续或升高的夜间输注中阻断内源性胰升糖素的分泌。我们将测试在胰升糖素浓度升高期间，T2D患者胰岛素对内源性葡萄糖产生的抑制程度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，T2D组的糖原分解率是否更高。为了探索在特定目标3中，二甲双胍治疗在多大程度上改变了T2D患者肝脏对胰高血糖素的反应，T2D受试者将接受正常血糖钳制研究，血糖素剂量分别为0.65、1.5和3.0 ng/kg/min(在生长抑素存在的情况下)，以估计随机接受二甲双胍或甘精胰岛素治疗两周之前和之后的内源性葡萄糖生成率。更好地了解影响夜间糖代谢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.