Dual Role of VAMP8 in Regulating Insulin Exocytosis and Islet β Cell Growth

Optimal insulin secretion required to maintain glucose homeostasis is the summation of total pancreatic islet beta cell mass and intrinsic secretory capacity of individual beta cells, which are regulated by distinct mechanisms that could be amplified by glucagon-like-peptide-1 (GLP-1). Because of these actions of GLP-1 on islet beta cells, GLP-1 has been deployed to treat diabetes. We employed SNARE protein VAMP8-null mice to demonstrate that VAMP8 mediates insulin granule recruitment to the plasma membrane, which partly accounts for GLP-1 potentiation of glucose-stimulated insulin secretion. VAMP8-null mice also exhibited increased islet beta cell mass from increased beta cell mitosis, with beta cell proliferative activity greatly amplified by GLP-1. Thus, despite the beta cell exocytotic defect, VAMP8-null mice have an increased total insulin secretory capacity, which improved glucose homeostasis. We conclude that these VAMP8-mediated events partly underlie the therapeutic actions of GLP-1 on insulin secretion and beta cell growth.