Restoring glutamate receptor signaling in pancreatic alpha cells rescues glucagon responses in type 1 diabetes

Glucagon secretion from pancreatic alpha cells is crucial to prevent hypoglycemia. People with type 1 diabetes lose this glucoregulatory mechanism and are susceptible to dangerous hypoglycemia for reasons still unclear. Here we determine that alpha cells in living pancreas slices from donors with type 1 diabetes do not mount an adequate glucagon response and cannot activate the positive autocrine feedback mediated by AMPA/kainate glutamate receptors. This feedback is required to elicit full glucagon responses in the healthy state. Reactivating residual AMPA/kainate receptor function with positive allosteric modulators restores glucagon secretion in human slices from donors with type 1 diabetes as well as glucose counterregulation in non-obese diabetic mice. Our study thus identifies a defect in autocrine signaling that contributes to alpha cell failure. The use of positive allosteric modulators of AMPA/kainate receptors overcomes this deficiency and prevents hypoglycemia, an effect that could be used to improve the management of diabetes. [Display omitted] •Alpha cells fail to respond to hypoglycemia if glutamate receptor signaling is deficient•In pancreas slices from diabetic donors, alpha cells do not respond to hypoglycemia•In type 1 diabetes, alpha cells show impaired glutamate receptor signaling•Residual glutamate receptors can be reactivated to restore glucagon responses in diabetes Glucagon secretion from pancreatic alpha cells is defective in people with type 1 diabetes, putting them at risk for dangerous hypoglycemia. Panzer et al. identify a deficiency in autocrine signaling mediated by AMPA/kainate glutamate receptors that could be rescued with positive allosteric modulators to restore adequate glucagon secretion in diabetes.