{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:59:35Z","timestamp":1794049175823,"version":"4.8.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>Pancreatic delta cells secrete somatostatin (SST), which can inhibit both alpha cells and beta cells of the pancreatic islet. By controlling insulin and glucagon release, delta cells play an important role in maintaining nutrient homeostasis. However, the mechanism by which a single inhibitory hormone inhibits both alpha cells and beta cells, which are often considered as functional antagonists in the counterregulatory control of blood glucose, has been a physiological riddle. Here, we solve this riddle through assessment of the contributions of alpha cell-specific and beta cell-specific SST receptors to cell-intrinsic behaviours and hormone release.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Islets from mice constitutively expressing fluorescent sensors reporting on cyclic AMP and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      in both alpha and beta cells were imaged using stimuli to mimic the postprandial state of a meal consisting of glucose and amino acids. This approach was coupled with cell-specific SST receptor antagonists to identify how SST inhibits alpha and beta cell hormone output through modulation of cAMP and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      second messengers and paracrine interactions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results support and extend prior observation that SST receptor 2 (SSTR2) is the only SST receptor expressed by mouse alpha cells, while SST receptor 3 (SSTR3) is the only receptor expressed by beta cells. Interestingly, SSTR2 and SSTR3 regulate downstream cAMP and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signalling cascades differently within alpha and beta cells of intact islets. Stimulation of SST receptors robustly inhibits cyclic AMP in alpha cells and beta cells. In contrast, stimulation of SSTR2 inhibits alpha cell Ca\n                      <jats:sup>2+<\/jats:sup>\n                      with significantly greater potency compared with inhibition of beta cell Ca\n                      <jats:sup>2+<\/jats:sup>\n                      via SSTR3. Despite the absence of SSTR2 on beta cells, blocking alpha cell SSTR2 during nutrient stimulation resulted in a significant increase in insulin release downstream of local release of glucagon.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Our observations address the physiological riddle of the delta cell\u2019s role during the postprandial phase where we demonstrate that SST primarily inhibits alpha cell cAMP and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      via SSTR2, preventing glucagon release. Blocking SSTR2 results in an increase in locally released glucagon, which coupled with muted ability for SSTR3 to inhibit beta cell calcium under strong nutrient stimulation, results in potentiation of glucose-stimulated insulin secretion from the beta cell. We conclude that the role of delta cells under nutrient stimulation is to modulate the volume of insulin release by tuning the strength of intra-islet paracrine potentiation of insulin secretion by glucagon, mediated via beta cell glucagon-like peptide-1 receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Code availability<\/jats:title>\n                    <jats:p>\n                      All code used for analyses and data processing are available on GitHub (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/github.com\/Huising-Lab\/Hart-et-al.-Diabetologia-2026\" ext-link-type=\"uri\">https:\/\/github.com\/Huising-Lab\/Hart-et-al.-Diabetologia-2026<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06769-4","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T12:59:13Z","timestamp":1781960353000},"page":"2569-2584","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Somatostatin receptors shape insulin and glucagon output within the pancreatic islet in mice through direct and paracrine effects"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-6652","authenticated-orcid":false,"given":"Ryan G.","family":"Hart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3990-6495","authenticated-orcid":false,"given":"Karen","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharlene","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashita","family":"Chauhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidean","family":"Hosseini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin D.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-2205","authenticated-orcid":false,"given":"Mark O.","family":"Huising","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"issue":"7","key":"6769_CR1","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1073\/pnas.0510790103","volume":"103","author":"O Cabrera","year":"2006","unstructured":"Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. 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