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 intra-islet paracrine effects. Here we compared the function of isolated δ-cells of cadaveric non-diabetic and type-2 diabetic donors, by single cell TIRF-microscopy and electrophysiology. Elevated glucose stimulated exocytosis of somatostatin, which was further amplified by glucagon, exendin-4, or forskolin, independent of diabetic status. GABA enhanced exocytosis and electrical activity, while insulin had no 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 lost, together with a marked reduction in somatostatin receptor (SSTR2) surface expression. We further show that resistance to somatostatin leads to hyperactive δ-cells in type-2 diabetes, and propose that this mechanism contributes to defective blood glucose control.