Mechanisms of Insulin Resistance in Man

项目总结 人类胰岛素抵抗的机制 在美国，近1亿人患有2型糖尿病(T2D)或糖尿病前期，占五分之一 医疗保健费。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和根据病因开发更好和合理的治疗方法 是非常高的优先事项。我们之前已经评估了夜间血糖调节和反-胰岛素的影响 调节激素(高血糖素、皮质醇)对T2D夜间内源性葡萄糖产生(EGP)的影响。我们 观察到在T2D中，EGP的发生率整夜都很高(凌晨1点对4点对7点)。然而，我们没有 确定夜间较高的EGP是否是由于全天较高的EGP费率，即早餐后、 午餐和晚餐后。我们也没有确定EGP、胰岛素作用和 分泌物。因此，在T2D中，EGP的昼夜调节机制和昼夜模式仍然很差 理解，即当EGP率增加时-它们在一天中是否像在 夜间；为什么EGP较高-是由于肝糖原含量异常吗？我们如何才能控制 更高的EGP发生率？我们设计了一系列实验来检验与各种具体情况相关的假设 旨在解决这些根本问题。在具体目标1a中，我们将确定 使用稳定标记三重示踪剂的EGP和在特定目标1B中同时估计胰岛素的作用 以及T2D中白天的β细胞反应性。我们将研究肝糖原在夜间EGP中的作用 在有糖原负荷和非糖原负荷的T2D中，使用核磁共振测量肝糖原含量和 作为特定目标2的一部分，我们设计了一种用于测量糖异生作用的氚标记水 特定目标的机械性临床试验3，以测试糖异生调节剂(二甲双胍)的效果， 糖原分解(胰岛素-甘精)和葡萄糖激酶活性(新的葡糖激活剂药物：多扎格列汀) T2D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 造型师、放射科医生、生物统计学家)使用状态在成人受试者中设计各种特定目标 ART成像(肝脏NMRS以估计糖原含量)、同位素、葡萄糖钳夹技术和 葡萄糖/荷尔蒙模型结合CGM数据进行创新和全面的评估，这将 易于转化为临床实践。综上所述，我们相信我们的方法将回答关键问题 关于空腹和餐后昼夜血糖生成的调节 T2D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 T2D患者的内源性葡萄糖产生、糖原分解和糖异生，并提供了见解 未来针对这种情况的创新疗法。

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.