Endocrine Abstracts

The preproglucagon gene (Gcg), expressed in the intestine, the pancreas, and a small cluster of neurons in the hindbrain, encodes multiple peptides in a tissue-specific manner. One of these peptides, glucagon like peptide-1 (GLP-1) increases following meals, functions to stimulate insulin secretion, and is essential for normal glucose tolerance. The dogma is that intestinally-derived GLP-1 acts as a hormone binding to pancreatic GLP-1 receptors (GLP-1r) to stimulate insulin secretion. However, limited by rapid intravascular metabolism, the plasma concentrations of GLP-1 are relatively low and are only modestly elevated during meal ingestion. We have developed several mouse models that all tissue-specific gain- or loss-of-function manipulation of the GLP-1 system. We used these models to advance our understanding of the physiology and pharmacology of the GLP-1 system. An alternative to the endocrine model of GLP-1 physiology in regulation of glucose homeostasis is a paracrine model within the islet. To explore this hypothesis we administered a GLP-1r antagonist to our gain-of-function mouse targeted to Gcg. This work suggests that it is pancreatic, and not intestinal-derived GLP-1 that mediates the physiological regulation of glucose homeostasis. Thus, we hypothesize that the acute insulinotropic effects of endogenous GLP-1 are paracrine rather than endocrine, derived from islet a-cells and acting on β-cell GLP-1r to stimulate insulin secretion. Pharmacologically, while pancreatic but not central nervous system GLP-1r are necessary to regulate improvements in glucose homeostasis by long-acting GLP-1r agonists, central but not peripheral nervous system GLP-1r are necessary for these agonists to induce weight loss.