The long-term objectives of this project are to provide greater understanding of carbohydrate metabolism and generate information applicable to the treatment of diabetes. The studies outlined herein will focus on the actions of the hormone Glucagon-like peptide 1 [7-36 amide] (GLP-1), which has broad antidiabetogenic actions, and by better defining its physiology extend the knowledge of carbohydrate metabolism. GLP-1 is an intestinal product released after stimuli from ingested nutrients. GLP- 1 augments glucose-stimulated insulin release, thus serving a physiologic role as an incretin. GLP-1 also inhibits glucagon release. Recently it has been demonstrated that GLP-1 promotes glucose disposal in diabetic subjects independent of its stimulatory effect on the pancreatic beta- cells. In addition, it has been demonstrated that in healthy subjects GLP- 1 improved IV glucose tolerance both by stimulating insulin secretion and by increasing glucose effectiveness (the action of glucose to promote its own disposal independent of insulin). This constellation of effects of GLP-1 suggest that it is an important regulator of normal carbohydrate metabolism, and that it has potential as a treatment modality in diabetes. Furthermore, the specific action of GLP-1 to increase glucose effectiveness raises the possibility that this hormone can be used to better understand the mechanisms through which this important component of glucose tolerance is mediated. The studies described here will pursue the overall hypothesis that the insulinotropic hormone GLP-1 also influences glucose disposition by directly regulating the discrete processes which comprise glucose effectiveness.
The specific aims of this study are addressed in the following questions: 1) Does GLP-1 promote glucose disposition, ie suppression of hepatic glucose output (HGO) and stimulation of glucose uptake, as part of its physiologic role? 2) Is the extrapancreatic effect of GLP-1 on glucose disposition mediated primarily at the liver, with suppression of HGO, or at peripheral sites such as skeletal muscle, by increasing glucose uptake? 3) Is the effect of GLP-1 on glucose disposition altered in persons with type I and type II diabetes mellitus (DM)? These questions will be addressed by both studies of healthy and diabetic humans, and in vitro experiments. The physiologic effects of GLP-1 will be examined by comparing infusions of synthetic GLP- 1 with meal stimulated endogenous secretion for effects on glucose disposition as quantitated by modeling of glucose kinetics during IVGTTs. The sites of action of GLP-1 will be studied in humans using hyperglycemic clamps during infusions of GLP-1, as well as isolated rat muscle preparations and cultured rat hepatocytes. The effects of GLP-1 on persons with diabetes will be studied using a modified IVGTT with modeling of glucose and insulin kinetics to obtain parameters of glucose effectiveness and insulin sensitivity. It is expected that this project will provide new information on the mechanisms by which glucose promotes its own disposition, the interplay of factors involved in glucose metabolism in the healthy and diabetic states, and the physiology of the gastrointestinal hormone GLP-1.
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