Pancreatic α-cells integrate immune and neuronal stimuli for insulin secretion

Insulin secretion can be stimulated by immune and neuronal processes prior to a rise in blood glucose, exemplified by the cephalic phase of insulin response in the anticipation of food. Pancreatic α-cells prevent hypoglycemia by releasing glucagon. Here, we identified α-cells as critical mediators of IL-1β- and cholinergic agonist-driven insulin secretion. Cholinergic blockade prevented glucagon-stimulated insulin secretion in mice. Selective ablation of α-cells abolished cephalic phase insulin release. Islets from α-cell-deficient mice also failed to secrete insulin in response to IL-1β or muscarinic receptor activation. However, glucagon, acting on glucagon and GLP-1 receptors, rescued this insulin-stimulatory response. Mechanistically, intracellular Ca²⁺ mobilization at fasting glucose mediated cholinergic and IL-1β-stimulated insulin release. Short-term high-fat diet impaired glucagon-induced insulin secretion in vivo, while isolated islets showed increased insulin secretion after cholinergic stimulation versus chow-fed controls. These findings reveal α-cell-derived glucagon as a gatekeeper of immune and neuronal control of insulin secretion at fasting glucose.