Targeting the Pancreatic a-Cell to Prevent Hypoglycemia in Type 1 Diabetes

Life-threatening hypoglycemia is a limiting factor in the management of type 1 diabetes. People with diabetes are prone to develop hypoglycemia because they lose physiological mechanisms that prevent plasma glucose levels from falling. Among these so-called counter regulatory responses, secretion of glucagon from pancreatic a-cells is preeminent. Glucagon, a hormone secreted in response to a lowering in glucose concentration, counteracts a further drop in glycemia by promoting gluconeogenesis and glycogenolysis in target tissues. In diabetes, however, a-cells do not respond appropriately to changes in glycemia and, thus, cannot mount a counter regulatory response. If the a-cell could be targeted therapeutically to restore its ability to prevent hypoglycemia, type 1 diabetes could be managed more efficiently and safely. Unfortunately, the mechanisms that allow the a-cell to respond to hypoglycemia have not been fully elucidated. We know even less about the pathophysiological mechanisms that cause a-cell dysfunction in diabetes. Based on published findings and unpublished observations, and taking into account its electrophysiological properties, we propose here a model of a-cell function that could explain its impairment in diabetes. Within this frame, we emphasize those elements that could be targeted pharmacologically with repurposed U.S. Food and Drug Administration–approved drugs to rescue a-cell function and restore glucose counter regulation in people with diabetes.