GLP-1 IN NORMAL AND ABNORMAL GLUCOSE TOLERANCE

本提案的总体目标是确定胰岛素性GI激素胰高血糖素样肽1 （GLP-1）在糖耐量正常和2型糖尿病患者中的作用。在正常受试者中，GLP-1和其他肠道因子的作用占进食后胰岛素分泌的30- 60%。这种作用在2型糖尿病患者中严重受损，提示肠道肽的分泌或作用存在缺陷。除了对-细胞的作用外，我们最近还观察到GLP-1抑制内源性葡萄糖生成（EGP）的新作用，而不依赖于其对胰岛激素分泌的影响。当给2型糖尿病患者以药理学量时，GLP-1使空腹和餐后高血糖正常，因此有潜力作为一种治疗剂。因此，了解GLP-1降低糖尿病患者血糖水平的机制，以及该激素分泌或作用的缺陷是否与糖尿病的发病机制有关，是非常重要的。该项目的具体目的是确定：1)GLP-1使糖尿病患者空腹高血糖正常化的机制。2) GLP-1是否通过抑制糖原分解、糖异生或两者同时抑制EGP。3) 2型糖尿病患者肠促胰岛素作用不足是由于GLP-1水平降低，还是由于胰岛素分泌对GLP-1的敏感性受损。为了实现这些目标：1)在糖尿病受试者输注GLP-1之前和输注过程中测量葡萄糖周转率，以确定胰岛激素的贡献，以及GLP-1对胰岛激素的非依赖性作用。2)健康人测定EGP，用2H2O法测定GLP-1前后的糖异生率和糖原溶解率。3) GLP-1在糖尿病患者和对照组中的分泌和代谢将使用我们开发的一种新的检测方法进行比较，该方法对GLP-1的特异性大大提高。此外，GLP-1将在大剂量范围内输注，以测量糖尿病和对照组受试者胰岛素反应的敏感性。这些研究结果将扩大对葡萄糖稳态的理解，并促进2型糖尿病治疗新策略的发展。

The overall goal of this proposal is to determine the role of the insulinotropic GI hormone glucagon-like peptide 1 (GLP-1) in persons with normal glucose tolerance, and with type 2 diabetes. In normal subjects the action of GLP-1 and other gut factors accounts for 30-60 percent of the insulin secreted after eating. This effect is severely impaired in persons with type 2 diabetes suggesting defects in the secretion or action of gut peptides. In addition to its action on the -cell, we have recently observed a novel effect of GLP-1 to suppress endogenous glucose production (EGP) independent of its effects on islet hormone secretion. When given to persons with type 2 diabetes in pharmacologic amounts, GLP-1 normalizes both fasting and post-prandial hyperglycemia, and so has potential as a therapeutic agent. Therefore, it is important to understand the mechanisms by which GLP-1 lowers blood glucose levels in persons with diabetes, and whether defects in the secretion or action of the hormone contribute to the pathogenesis of diabetes. The specific aims of this project are to determine: 1) the mechanism by which GLP-1 normalizes fasting hyperglycemia in diabetic subjects. 2) whether GLP-1 suppresses EGP by inhibition of glycogenolysis, gluconeogenesis, or both. 3) whether the deficient incretin effect in persons with type 2 diabetes is due to decreased levels of GLP-1, or impaired sensitivity of insulin secretion to GLP-1. To address these aims: 1) Glucose turnover will be measured in diabetic subjects before and during GLP-1 infusions, to determine the contributions of islet hormones, and islet hormone-independent effects of GLP-1 to lower blood glucose. 2) EGP will be measured in healthy subjects, and rates of gluconeogenesis and glycogenolysis determined before and after GLP-1 using the 2H2O method. 3) Secretion, and metabolism of GLP-1 in diabetic and control subjects will be compared using a new assay we have developed with greatly increased specificity for GLP-1. In addition, GLP-1 will be infused over a wide range of doses to measure the sensitivity of the insulin response in diabetic and control subjects. The results of these studies will expand the understanding of glucose homeostasis, and promote the development of new strategies to treat type 2 diabetes.