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bioRxiv · 10.64898/2025.12.12.693197

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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Abstract

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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Omar-Hmeadi, M., Matuseviciene, L., Liu, L., Lund, P. E., Barg, S.. 2025-12-15. Pancreatic δ-cells are resistant to auto- and paracrine inhibition in human type-2 diabetes. https://doi.org/10.64898/2025.12.12.693197

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