INS and obesity due to melanocortin 4 receptor deficiency: It is now well documented that impaired autophagy in pancreatic beta cells contributes to the progression of both type 1 and type 2 diabetes, as studied in mouse models of obesity and diabetes,20 proinsulin misfolding and ER stress-induced diabetes,53 and in islets from NOD mice and human islets.54 Interestingly, impaired autophagy leads to the fusion of insulin secretory granules directly with lysosomes.45 In contrast, impaired autophagy may be a mechanism in the abnormal up-regulation of glucagon secretion from alpha cells in diabetes.