GLP-1 IN NORMAL AND ABNORMAL GLUCOSE TOLERANCE

本提案的总体目标是确定促胰岛素GI激素胰高血糖素样肽1（GLP-1）在葡萄糖耐量正常和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分泌的胰岛素的30- 60%。这种作用在2型糖尿病患者中严重受损，表明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抑制内源性葡萄糖产生（EGP）的新作用，而不依赖于其对胰岛激素分泌的作用。当以药理学量给予2型糖尿病患者时，GLP-1使空腹和餐后高血糖症正常化，因此具有作为治疗剂的潜力。因此，重要的是要了解GLP-1降低糖尿病患者血糖水平的机制，以及激素分泌或作用的缺陷是否有助于糖尿病的发病机制。 本项目的具体目的是确定：1）GLP-1使糖尿病受试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、糖原生成或两者来抑制EGP。 3)2型糖尿病患者中肠促胰岛素作用不足是否是由于GLP-1水平降低或胰岛素分泌对GLP-1的敏感性受损。为实现这些目标：1）在GLP-1输注之前和输注期间测量糖尿病受试者的葡萄糖周转，以确定胰岛激素的贡献和GLP-1对降低血糖的胰岛非依赖性作用。 2)将在健康受试者中测量EGP，并使用2 H2O方法在GLP-1之前和之后测定血管生成和糖原分解的速率。 3)将使用我们开发的对GLP-1特异性大大增加的新测定法比较糖尿病受试者和对照受试者中GLP-1的分泌和代谢。 此外，GLP-1将在广泛的剂量范围内输注，以测量糖尿病受试者和对照受试者的胰岛素反应敏感性。 这些研究的结果将扩大对葡萄糖稳态的理解，并促进治疗2型糖尿病的新策略的发展。

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.