Editors' ChoiceMetabolism

Pancreatic crosstalk among beta and delta cells

Sci. Signal.  28 Jul 2015:
Vol. 8, Issue 387, pp. ec203
DOI: 10.1126/scisignal.aad0908

Somatostatin is a peptide hormone that is released from delta cells in the pancreas (D cells); one of its actions is to attenuate the release of insulin from β cells in the pancreas. The peptide hormone urocortin3 (Ucn3) is coreleased with insulin and has been proposed to promote insulin secretion, but van der Meulen et al. showed that Ucn3 limits insulin secretion by acting on D cells to trigger somatostatin secretion. Analysis with reporter mice indicated that D cells expressed the gene encoding the type 2 corticotropin-releasing hormone receptor (Crhr2), which is the receptor for Ucn3. Compared to islets from control mice, islets from Ucn3-null mice had fewer D cells, decreased somatostatin content, and released less somatostatin and more insulin in response to glucose stimulation. The defects in somatostatin and insulin release in Ucn3-null islets were corrected by exposure to synthetic Ucn3 peptide. Administering exogenous Ucn3 to mice before glucose challenge delayed glucose clearance and decreased plasma insulin concentrations. Islets from diabetic ob/ob or db/db mice, which are genetic models of obesity, had decreased Ucn3 content at both the mRNA and peptide levels and islets from ob/ob mice released less somatostatin in response to glucose stimulation. In ob/ob mice or mice treated with streptozotocin to induce type I diabetes, both of which were engineered to also inducibly express Ucn3, hyperglycemia was exacerbated by the induction of Ucn3 expression. Ucn3 is present only in β cells in mice, but is found in both α and β cells in primates. UCN3 abundance was decreased in β cells but not α cells in islets from patients with type 2 diabetes and from macaques fed a high-fat diet. Thus, Ucn3 coreleased with insulin from β cells acts in a paracrine fashion on D cells to trigger the release of somatostatin, which limits further insulin release from β cells.

T. van der Meulen, C. J. Donaldson, E. Cáceres, A. E. Hunter, C. Cowing-Zitron, L. D. Pound, M. W. Adams, A. Zembrzycki, K. L. Grove, M. O. Huising, Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat. Med. 21, 769–776 (2015). [PubMed]