The colon is an extra-pancreatic source of glucagon: demonstration in a mouse model of pancreatectomy

Abstract

Glucagon is considered as a pancreas-specific hormone. However, an extra-pancreatic source of glucagon, which secretion is inappropriately induced by oral glucose, has been suspected for years in patients with diabetes. In a mouse model of subtotal pancreatectomy, we recapitulated the abnormal secretion of glucagon in response to oral glucose observed in pancreatectomised patients and excluded the remaining pancreas as the source of glucagon. We showed that the colon can produce and secrete glucagon. Subtotal pancreatectomy resulted in an increased expression of PCSK2 protease in the colon that favors the maturation of proglucagon into glucagon over other glucagon-related peptides normally produced by enteroendocrine cells. These results identify a mechanism that could contribute to abnormal glucagon production and poor glycemic control in pancreatectomized diabetic subjects. Moreover, our findings may pave the road to new therapeutic strategies to counteract poor glucose control for patients with diabetes.