SAT-244 - Urocortin 3 Inhibits Pancreatic Alpha Cells via Paracrine Signaling

Background: Glucagon secretion by pancreatic alpha cells must be tightly controlled to maintain normal blood glucose levels. While somatostatin from neighboring delta cells is known to suppress alpha cell activity at high blood glucose, the role of urocortin 3 (UCN3) – a peptide co-released with insulin from beta cells – as it relates to alpha cells is unclear. We hypothesized that the paracrine action of UCN3 to potentiate delta cell somatostatin release contributes to alpha cell inhibition at high glucose. Approach: To measure islet cell activity, we used transgenic mice expressing fluorescent Ca²⁺ or cAMP sensors specifically in alpha cells or delta cells. We imaged the activity of cells in intact islets as well as dispersed, isolated alpha cells in real time via confocal microscopy with a perfusion system for applying different treatments.

Results: We observed that exogenous UCN3 lowered alpha cell Ca²⁺ and cAMP levels. Furthermore, direct delta cell imaging confirmed that UCN3 activates delta cell cAMP, boosting somatostatin release. Isolated alpha cells did not respond to UCN3, confirming that the inhibition is paracrine.

Conclusion: At high glucose, UCN3 indirectly restrains alpha cell glucagon output by enhancing somatostatin release from delta cells, adding an extra layer to the local paracrine regulation within the islet.

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