Pancreatic δ-cells are resistant to auto- and paracrine inhibition in human type-2 diabetes
Omar-Hmeadi, M.; Matuseviciene, L.; Liu, L.; Lund, P. E.; Barg, S.
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Somatostatin secretion from pancreatic {delta}-cells inhibits nearby -and {beta}-cells, and tunes the bodys glycemic set-point. The role of {delta}-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 {delta}-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 {delta}-cell activity, leading to autocrine feedback inhibition of somatostatin exocytosis. In type-2 diabetes, {delta}-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 {delta}-cells in type-2 diabetes, and propose that this mechanism contributes to defective blood glucose control.
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