{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:43:39Z","timestamp":1790790219083,"version":"4.1.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T00:00:00Z","timestamp":1686528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007496","name":"Biomedical Laboratory Research and Development, VA Office of Research and Development","doi-asserted-by":"publisher","award":["I01 BX005051"],"award-info":[{"award-number":["I01 BX005051"]}],"id":[{"id":"10.13039\/100007496","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007496","name":"Biomedical Laboratory Research and Development, VA Office of Research and Development","doi-asserted-by":"publisher","award":["IBX002728A"],"award-info":[{"award-number":["IBX002728A"]}],"id":[{"id":"10.13039\/100007496","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01-DK073716"],"award-info":[{"award-number":["R01-DK073716"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01-DK084236"],"award-info":[{"award-number":["R01-DK084236"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:p>Patients with type 1 diabetes (T1D) suffer from insufficient functional \u03b2-cell mass, which results from infiltration of inflammatory cells and cytokine-mediated \u03b2-cell death. Previous studies demonstrated the beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R), such as MR-409 on preconditioning of islets in a transplantation model. However, the therapeutic potential and protective mechanisms of GHRH-R agonists on models of T1D diabetes have not been explored. Using in vitro and in\u00a0vivo models of T1D, we assessed the protective propertie of the GHRH agonist, MR409 on \u03b2-cells. The treatment of insulinoma cell lines and rodent and human islets with MR-409 induces Akt signaling by induction of insulin receptor substrate 2 (IRS2), a master regulator of survival and growth in \u03b2-cells, in a PKA-dependent manner. The increase in cAMP\/PKA\/CREB\/IRS2 axis by MR409 was associated with decrease in \u03b2-cell death and improved insulin secretory function in mouse and human islets exposed to proinflammatory cytokines. The assessment of the effects of GHRH agonist MR-409 in a model of T1D induced by low-dose streptozotocin showed that mice treated with MR-409 exhibited better glucose homeostasis, higher insulin levels, and preservation of \u03b2-cell mass. Increased IRS2 expression in \u03b2-cells in the group treated with MR-409 corroborated the in\u00a0vitro data and provided evidence for the underlying mechanism responsible for beneficial effects of MR-409 in\u00a0vivo. Collectively, our data show that MR-409 is a novel therapeutic agent for the prevention and treatment of \u03b2-cells death in T1D.<\/jats:p>","DOI":"10.1073\/pnas.2209810120","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T15:19:12Z","timestamp":1686583152000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["GHRH agonist MR-409 protects \u03b2-cells from streptozotocin-induced diabetes"],"prefix":"10.1073","volume":"120","author":[{"given":"Ruy A.","family":"Louzada","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Blandino-Rosano","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Flores","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Lubaczeuski","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengjiao","family":"Cui","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136"},{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125"},{"name":"South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sha","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136"},{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125"},{"name":"South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzhi","family":"Cai","sequence":"additional","affiliation":[{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125"},{"name":"South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1273-6747","authenticated-orcid":false,"given":"Andrew V.","family":"Schally","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"},{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125"},{"name":"South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125"},{"name":"Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136"},{"name":"Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Bernal-Mizrachi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL 33136"},{"name":"Veterans Affairs Medical Center, Miami, FL 33136"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,12]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2209810120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T17:32:21Z","timestamp":1687455141000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2209810120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,12]]},"references-count":0,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2023,6,20]]}},"alternative-id":["10.1073\/pnas.2209810120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2209810120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,12]]},"assertion":[{"value":"2022-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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