Somatostatin receptors shape insulin and glucagon output within the pancreatic islet in mice through direct and paracrine effects.

aims/hypothesisPancreatic delta cells secrete somatostatin (SST), which can inhibit both alpha cells and beta cells of the pancreatic islet. By controlling insulin and glucagon release, delta cells play an important role in maintaining nutrient homeostasis. However, the mechanism by which a single inhibitory hormone inhibits both alpha cells and beta cells, which are often considered as functional antagonists in the counterregulatory control of blood glucose, has been a physiological riddle. Here, we solve this riddle through assessment of the contributions of alpha cell-specific and beta cell-specific SST receptors to cell-intrinsic behaviours and hormone release.

methodsIslets from mice constitutively expressing fluorescent sensors reporting on cyclic AMP and Ca

resultsOur results support and extend prior observation that SST receptor 2 (SSTR2) is the only SST receptor expressed by mouse alpha cells, while SST receptor 3 (SSTR3) is the only receptor expressed by beta cells. Interestingly, SSTR2 and SSTR3 regulate downstream cAMP and Ca CONCLUSIONS/

interpretationOur observations address the physiological riddle of the delta cell's role during the postprandial phase where we demonstrate that SST primarily inhibits alpha cell cAMP and Ca CODE AVAILABILITY: All code used for analyses and data processing are available on GitHub ( https://github.com/Huising-Lab/Hart-et-al.-Diabetologia-2026 ).