Mechanisms of Insulin Resistance in Man

项目摘要 人类胰岛素抵抗的机制 美国近1亿人患有2型糖尿病（T2 D）或糖尿病前期，占1/5 医疗保健美元。这些代谢性疾病的患病率呈指数级增长。了解 发病机制和发展更好的和合理的治疗方法的基础上的因果因素为这些条件 是非常重要的我们以前评估了夜间血糖调节和反- 调节激素（胰高血糖素、皮质醇）对2型糖尿病患者夜间内源性葡萄糖生成（EGP）的影响。我们 观察到T2 D患者的EGP率整夜保持较高（凌晨1点vs. 4点vs. 7点）。然而，我们没有 确定较高的夜间EGP是否是由于全天较高的EGP率，即早餐后， 午餐和晚餐后。我们也没有确定EGP、胰岛素作用和胰岛素抵抗的日间时间曲线。 分泌物因此，T2 D中EGP的日间调节机制和昼夜模式仍然很差 理解，即什么时候EGP的比率增加-他们在一天中更高，因为他们在 为什么EGP更高-是由于肝糖原含量异常吗？我们如何控制 更高的EGP？我们设计了一组实验来测试与各种特定的 解决这些基本问题的目标。在具体目标1A中，我们将确定 EGP使用稳定标记三重示踪剂方法和特定目标1B同时估计胰岛素作用 和β细胞的反应性。我们将研究肝糖原在夜间EGP中的作用 在糖原负荷与非糖原负荷的T2 D中，使用NMR测量肝糖原含量， 氘标记的水，以测量作为特定目标2的一部分的再生。我们设计了一个 特异性目的3中的机制临床试验，以测试胚胎发生调节剂（二甲双胍）的作用， 糖原分解（甘精胰岛素）和葡萄糖激酶活性（新型葡萄糖激酶激活剂药物：dorzagliatin） T2 D中的EGP。我们已经组建了一个多学科的研究团队（内分泌学家，数学家）。 建模师、放射科医生、生物统计学家），以设计T2 D成人受试者的各种特定目标 最先进的成像（肝脏的NMRS以估计糖原含量）、同位素、葡萄糖钳夹技术和 葡萄糖/激素模型结合CGM数据进行创新和全面的评估， 很容易转化为临床实践。总之，我们相信我们的方法将回答一些至关重要的问题， 关于空腹和餐后白天和夜间葡萄糖产生的调节 T2 D受试者的高血糖。计划中的研究将填补监管方面的知识空白， 内源性葡萄糖生成、糖原分解和糖原生成，并提供了见解 用于未来治疗这种疾病的创新疗法。

PROJECT SUMMARY Mechanisms of Insulin Resistance in Man 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 better and rational therapies based on the causal factors for these conditions is a very high priority. We have previously evaluated nighttime regulation of glucose and effects of counter- regulatory hormones (glucagon, cortisol) on nocturnal endogenous glucose production (EGP) in T2D. We observed that rates of EGP remained high all night (at 1AM vs. 4 AM vs. 7 AM) in T2D. However, we did not determine whether the higher nighttime EGP was due to higher EGP rates all day i.e. post breakfast, post lunch and post dinner. We also did not determine the daytime temporal profiles of EGP, insulin action and secretion. Therefore, the mechanism of daytime regulation and diurnal pattern of EGP in T2D remains poorly understood i.e. when do rates of EGP increase - are they higher throughout the day as they are during the night; why is EGP higher – is it due to abnormalities in hepatic glycogen content? How can we control the higher rates of EGP? We have designed a set of experiments to test hypotheses related to various specific aims that address these fundamental questions. In Specific Aim 1A we will determine the diurnal pattern of EGP using a stable label triple tracer approach and in Specific aim 1B concurrently estimate insulin action and beta cell responsivity during the day in T2D. We will study the role of hepatic glycogen on nocturnal EGP in T2D with glycogen loading vs. non-glycogen loading using NMR to measure hepatic glycogen content and deuterium labeled water to measure gluconeogenesis as part of Specific Aim 2. We have designed a mechanistic clinical trial in Specific Aim 3 to test the effects of modulators of gluconeogenesis (metformin), glycogenolysis (insulin-glargine) and glucokinase activity (novel glucokinase activator drug: dorzagliatin) on EGP in T2D. We have assembled a multi-disciplinary team of investigators (endocrinologists, mathematical modelers, radiologist, biostatistician) to design the various specific aims in adult subjects with T2D using state of the art imaging (NMRS of liver to estimate glycogen content), isotopic, glucose clamp techniques and glucose/hormonal modeling coupled with CGM data for innovative and comprehensive assessments which will be easily translatable to clinical practice. Taken together, we believe our approach will answer vital questions regarding the regulation of daytime and nighttime glucose production on fasting and post-prandial hyperglycemia in subjects with T2D. The planned research will fill knowledge gaps in regulation of endogenous glucose production, glycogenolysis, and gluconeogenesis in people with T2D and provide insights into future innovative therapies for this condition.