The Pharmacology of Intra-islet GLP-1 in Pancreatic Islets

Abstract

Paracrine signaling within the pancreatic islets is important for the normal secretion of insulin and glucagon. As the secretion of insulin and glucagon are central to whole body glucose homeostasis, paracrine signaling in the islet has a role in glucose control. Genetic animal models have shown that alpha cell secretion of proglucagon peptides, including GLP-1, are important for normal insulin secretion and glucose homeostasis. I hypothesized that human islets express GLP-1 and that paracrine GLP-1 secretion contributes to insulin secretion in nondiabetic and type 2 diabetic islets. I also tested the effect of increasing GLP-1 levels in the islet on insulin secretion and islet survival.To investigate my hypotheses, I used several methods known to islet biology and a population-based study. Immunohistochemistry and flow cytometry were used to examine GLP- 1 expression. GLP-1 secretion was examined using static incubations and perifusions, while islet cell survival was determined using a dead cell assay. Active GLP-1 levels were increased with the DPP4 inhibitor sitagliptin or adenoviral vectors. Finally, I designed an observational study to investigate outcomes associated with starting sitagliptin early in the therapy of type 2 diabetes.From my results, I was able to conclude that human islets do express GLP-1 and that GLP-1 expression increases in type 2 diabetic islets. I also show that the dependence of glucose-stimulated insulin secretion on GLP-1 receptor signaling is associated with the amount of GLP-1 expression in nondiabetic and type 2 diabetic islets. These results allow us to consider a GLP-1 signaling axis in human islets. Sitagliptin treatment of human islets does not increase glucose-stimulated insulin secretion, but may increase islet cell survival. Neonatal porcine islets can be engineered to increase GLP-1 secretion, but the functional consequences of this are still unknown. Finally, the results of our observational study suggest that adding sitagliptin to metformin early in therapy may slow diabetes progression and preserve beta cell function.