Pancreatic δ cells are resistant to auto- and paracrine inhibition in human type-2 diabetes

Somatostatin secretion from pancreatic δ cells inhibits nearby α- and β cells and tunes the body's glycemic set-point. The role of δ cells in diabetes remains unclear, in part due to the difficulty separating intrinsic regulation from intraislet paracrine effects. Here, we compared the function of isolated δ cells of cadaveric nondiabetic and type-2 diabetic donors by single cell total internal reflection microscopy, electrophysiology, and secretion measurements. Elevated glucose stimulated exocytosis of somatostatin, which was further amplified by glucagon, exendin-4, or forskolin, independent of diabetic status. gamma-aminobutyric acid (GABA) enhanced exocytosis and electrical activity, while insulin had no detectable effect. Adrenaline and somatostatin strongly inhibited δ cell activity, leading to autocrine feedback inhibition of somatostatin exocytosis. In type-2 diabetes, δ cell inhibition by somatostatin and adrenaline was impaired, together with a marked reduction in somatostatin receptor (SSTR2) surface expression. The data suggest that selective loss of inhibitory control of δ cells may dysregulate intraislet somatostatin signaling in type-2 diabetes.