2165-P: In Vivo Islet Imaging Reveals that GLP-1 Paradoxically Increases Insulin Content

Glucagon-like peptide-1 (GLP-1) is an incretin, secreted in response to a meal that promotes glucose-stimulated insulin secretion in animal models and diabetic and nondiabetic humans. GLP-1 analogues have been successfully used as an effective treatment for both obesity and type 2 diabetes. While the general mechanisms of actions of GLP-1 on β-cell growth and function have been extensively studied, a number of questions regarding the dynamic and heterogeneity of the response of individual islets to GLP-1 in vivo remain. Using a fluorescent reporter mouse model originally created by the Arvan Lab, we have optimized a platform allowing us to monitor the content of individual islets in live animals. In this model, a super-folded GFP is bound to the C-Peptide, allowing the fluorescent visualization and quantification of insulin content within the islets without altering their normal physiology. After an overnight fast, the pancreas is exposed by laparotomy in anesthetized mice and the reporter in individual islets can be imaged repeatedly to quantify their insulin content. Upon glucose challenge, the GFP intensity within the islets progressively decreases in control mice, correlating with the insulin secretion within the bloodstream. In order to study the effects of GLP-1 on individual islet secretion, mice were either treated either with Liraglutide, a stable GLP-1 analog, or subjected to Vertical Sleeve Gastrectomy (VSG), a surgical procedure known to increase GLP-1 levels in obese mice. Surprisingly, with both approaches, in addition to increasing insulin secretion upon a glucose challenge, we could also observe insulin content actually increasing within the islets over the course of the excursion. This finding was later confirmed by measuring total insulin content in liraglutide-treated mice. This data indicates that despite causing enhanced insulin secretion, GLP-1 can also very rapidly increase insulin content within islets.