{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:01:29Z","timestamp":1790748089572,"version":"4.1.0"},"reference-count":34,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100022542","name":"Breakthrough T1D","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001067","name":"JDRF","doi-asserted-by":"publisher","award":["2-SRA-2022-1212-S-B"],"award-info":[{"award-number":["2-SRA-2022-1212-S-B"]}],"id":[{"id":"10.13039\/501100001067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000938","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX002728"],"award-info":[{"award-number":["BX002728"]}],"id":[{"id":"10.13039\/501100000938","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK073716"],"award-info":[{"award-number":["R01-DK073716"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK132103"],"award-info":[{"award-number":["DK132103"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK133183"],"award-info":[{"award-number":["DK133183"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK138471"],"award-info":[{"award-number":["R01-DK138471"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Type 1 diabetes (T1D) is characterized by progressive loss of pancreatic \u03b2 cell mass driven by inflammatory cytokine\u2013induced apoptosis. Although glucagon-like peptide-1 receptor (GLP-1R) agonists improve \u03b2 cell function and survival, their efficacy may be limited under hyperglycemic conditions. Growth hormone\u2013releasing hormone receptor (GHRH-R) agonists have emerged as potential \u03b2 cell\u2013protective agents through activation of cAMP-dependent signaling pathways. Here, we investigated the effects of the GHRH-R agonist MR-409, alone or in combination with the GLP-1R agonist exendin-4 (Ex-4), on \u03b2 cell survival and glucose homeostasis. In human islets, combined MR-409 and Ex-4 treatment enhanced glucose-stimulated insulin secretion and increased CREB phosphorylation. The combination also reduced cytokine-induced apoptosis, with decreased caspase 3\/7 activity compared with MR-409 alone and reduced BAX protein levels compared with either individual treatment. MR-409 alone increased IRS2 protein levels, consistent with activation of pro-survival signaling pathways. In a multiple low-dose streptozotocin (STZ) mouse model, MR-409, Ex-4, and their combination improved glucose homeostasis and increased \u03b2 cell mass compared with vehicle-treated mice. However, the combination did not confer additional metabolic benefit over single treatments. Notably, MR-409 treatment was associated with greater improvements in glucose tolerance and insulin levels. These findings support further investigation of GHRH receptor agonism as a strategy to preserve \u03b2-cell survival under diabetogenic stress.<\/jats:p>","DOI":"10.1210\/endocr\/bqag104","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:24:41Z","timestamp":1790594681000},"source":"Crossref","is-referenced-by-count":0,"title":["GHRH and GLP-1 receptor agonism promote human \u03b2-cell survival and improve glucose homeostasis in diabetic mice"],"prefix":"10.1210","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4234","authenticated-orcid":false,"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, USA"},{"name":"Diabetes Research Institute, University of Miami Miller School of Medicine , Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-9280","authenticated-orcid":false,"given":"Marel","family":"Gonzalez Medina","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine , Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-2017","authenticated-orcid":false,"given":"Valentina","family":"Pita-Grisanti","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine , Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-8233","authenticated-orcid":false,"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, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam A","family":"Crowley","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine , Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-1785","authenticated-orcid":false,"given":"Tengjiao","family":"Cui","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami , Miami, FL 33136, USA"},{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center , Miami, FL 33125, USA"},{"name":"South Florida Veterans Affairs Foundation for Research and Education , Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sha","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami , Miami, FL 33136, USA"},{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center , Miami, FL 33125, USA"},{"name":"Department of Pathology, Miller School of Medicine, University of Miami , Miami, FL 33136, USA"},{"name":"Sylvester Comprehensive Cancer Center , University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"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, USA"},{"name":"South Florida Veterans Affairs Foundation for Research and Education , Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7338-2041","authenticated-orcid":false,"given":"Medhi","family":"Wangpaichitr","sequence":"additional","affiliation":[{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center , Miami, FL 33125, USA"},{"name":"Sylvester Comprehensive Cancer Center , University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Division of Thoracic Surgery, Department of Surgery, University of Miami Miller School of Medicine , Miami, FL 33136, USA"},{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center , Miami, FL 33125 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9997-3301","authenticated-orcid":false,"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, USA"},{"name":"Diabetes Research Institute, University of Miami Miller School of Medicine , Miami, FL 33136, USA"},{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center , Miami, FL 33125 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"6","key":"2026093001534642200_bqag104-B1","doi-asserted-by":"crossref","first-page":"979","DOI":"10.2337\/dc15-0144","article-title":"Current concepts on the pathogenesis of type 1 diabetes\u2013considerations for attempts to prevent and reverse the disease","volume":"38","author":"Atkinson","year":"2015","journal-title":"Diabetes Care"},{"issue":"4","key":"2026093001534642200_bqag104-B2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrendo.2009.21","article-title":"The role of inflammation in insulitis and beta-cell loss in type 1 diabetes","volume":"5","author":"Eizirik","year":"2009","journal-title":"Nat Rev Endocrinol"},{"issue":"3","key":"2026093001534642200_bqag104-B3","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1210\/en.2011-1895","article-title":"Antiapoptotic actions of exendin-4 against hypoxia and cytokines are augmented by CREB","volume":"153","author":"Velmurugan","year":"2012","journal-title":"Endocrinology"},{"issue":"1","key":"2026093001534642200_bqag104-B4","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1074\/jbc.M209423200","article-title":"Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis","volume":"278","author":"Li","year":"2003","journal-title":"J Biol Chem"},{"issue":"2","key":"2026093001534642200_bqag104-B5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/gt.2009.143","article-title":"DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes","volume":"17","author":"Riedel","year":"2010","journal-title":"Gene Ther"},{"issue":"10","key":"2026093001534642200_bqag104-B6","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1056\/NEJMc2302677","article-title":"Semaglutide in early type 1 diabetes","volume":"389","author":"Dandona","year":"2023","journal-title":"N Engl J Med"},{"issue":"6","key":"2026093001534642200_bqag104-B7","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2337\/db06-1033","article-title":"Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes","volume":"56","author":"Xu","year":"2007","journal-title":"Diabetes"},{"issue":"18","key":"2026093001534642200_bqag104-B8","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adf7737","article-title":"Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific beta-arrestin 2 knockout mice","volume":"9","author":"Bitsi","year":"2023","journal-title":"Sci Adv"},{"issue":"12","key":"2026093001534642200_bqag104-B9","doi-asserted-by":"crossref","first-page":"6639","DOI":"10.1172\/JCI140046","article-title":"Gs\/Gq signaling switch in beta cells defines incretin effectiveness in diabetes","volume":"130","author":"Oduori","year":"2020","journal-title":"J Clin Invest"},{"issue":"530","key":"2026093001534642200_bqag104-B10","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaw9996","article-title":"GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human beta cell regeneration","volume":"12","author":"Ackeifi","year":"2020","journal-title":"Sci Transl Med"},{"key":"2026093001534642200_bqag104-B11","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.peptides.2013.12.010","article-title":"Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities","volume":"52","author":"Cai","year":"2014","journal-title":"Peptides"},{"key":"2026093001534642200_bqag104-B12","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fendo.2016.00129","article-title":"Growth hormone-releasing hormone in diabetes","volume":"7","author":"Fridlyand","year":"2016","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"3","key":"2026093001534642200_bqag104-B13","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s11154-024-09929-2","article-title":"The development of growth hormone-releasing hormone analogs: therapeutic advances in cancer, regenerative medicine, and metabolic disorders","volume":"26","author":"Schally","year":"2025","journal-title":"Rev Endocr Metab Disord"},{"issue":"28","key":"2026093001534642200_bqag104-B14","doi-asserted-by":"crossref","first-page":"12623","DOI":"10.1073\/pnas.1005098107","article-title":"Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets","volume":"107","author":"Ludwig","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"2026093001534642200_bqag104-B15","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1073\/pnas.1221505110","article-title":"Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone","volume":"110","author":"Schubert","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"issue":"44","key":"2026093001534642200_bqag104-B16","doi-asserted-by":"crossref","first-page":"13651","DOI":"10.1073\/pnas.1518540112","article-title":"Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD\/SCID mice","volume":"112","author":"Zhang","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026093001534642200_bqag104-B17","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2021.111379","article-title":"Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress","volume":"535","author":"Rodrigues-Dos-Santos","year":"2021","journal-title":"Mol Cell Endocrinol"},{"issue":"50","key":"2026093001534642200_bqag104-B18","doi-asserted-by":"crossref","first-page":"13248","DOI":"10.1073\/pnas.1718592114","article-title":"Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy","volume":"114","author":"Thounaojam","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2026093001534642200_bqag104-B19","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41598-019-57292-z","article-title":"Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice","volume":"10","author":"Recinella","year":"2020","journal-title":"Sci Rep"},{"issue":"25","key":"2026093001534642200_bqag104-B20","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2209810120","article-title":"GHRH agonist MR-409 protects beta-cells from streptozotocin-induced diabetes","volume":"120","author":"Louzada","year":"2023","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026093001534642200_bqag104-B21","unstructured":"Louzada R, Gonzalez Medina M, Pita-Grisanti V, et al \u00a0GHRH and GLP-1 receptor agonism promote human \u03b2-cell survival and improve glucose homeostasis in diabetic mice. Figshare. Published online 2026. 10.6084\/m9.figshare.29120561"},{"issue":"2","key":"2026093001534642200_bqag104-B22","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/s00125-018-4772-2","article-title":"Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions","volume":"62","author":"Hart","year":"2019","journal-title":"Diabetologia"},{"issue":"13","key":"2026093001534642200_bqag104-B23","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1101\/gad.1097103","article-title":"cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2","volume":"17","author":"Jhala","year":"2003","journal-title":"Genes Dev"},{"issue":"6670","key":"2026093001534642200_bqag104-B24","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/36116","article-title":"Disruption of IRS-2 causes type 2 diabetes in mice","volume":"391","author":"Withers","year":"1998","journal-title":"Nature"},{"issue":"10","key":"2026093001534642200_bqag104-B25","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.2337\/db08-1602","article-title":"Islet beta-cells deficient in Bcl-xL develop but are abnormally sensitive to apoptotic stimuli","volume":"58","author":"Carrington","year":"2009","journal-title":"Diabetes"},{"issue":"17","key":"2026093001534642200_bqag104-B26","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.13852","article-title":"GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P\/Q-type Ca(2+) channels","volume":"6","author":"Ramracheya","year":"2018","journal-title":"Physiol Rep"},{"issue":"10","key":"2026093001534642200_bqag104-B27","first-page":"2805","article-title":"SV40 T antigen abrogates p53-mediated transcriptional activity","volume":"8","author":"Jiang","year":"1993","journal-title":"Oncogene"},{"issue":"2","key":"2026093001534642200_bqag104-B28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0092-8674(95)90412-3","article-title":"Tumor suppressor p53 is a direct transcriptional activator of the human bax gene","volume":"80","author":"Miyashita","year":"1995","journal-title":"Cell"},{"issue":"Suppl_3","key":"2026093001534642200_bqag104-B29","doi-asserted-by":"crossref","first-page":"S205","DOI":"10.2337\/diabetes.53.suppl_3.S205","article-title":"Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo","volume":"53","author":"Baggio","year":"2004","journal-title":"Diabetes"},{"issue":"5","key":"2026093001534642200_bqag104-B30","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2337\/diabetes.49.5.741","article-title":"Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas","volume":"49","author":"Stoffers","year":"2000","journal-title":"Diabetes"},{"issue":"5","key":"2026093001534642200_bqag104-B31","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0126003","article-title":"Liraglutide improves pancreatic beta cell mass and function in alloxan-induced diabetic mice","volume":"10","author":"Tamura","year":"2015","journal-title":"PLoS One"},{"issue":"12","key":"2026093001534642200_bqag104-B32","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.2337\/diabetes.48.12.2270","article-title":"Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats","volume":"48","author":"Xu","year":"1999","journal-title":"Diabetes"},{"issue":"3","key":"2026093001534642200_bqag104-B33","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.cmet.2016.01.009","article-title":"Liraglutide compromises pancreatic beta cell function in a humanized mouse model","volume":"23","author":"Abdulreda","year":"2016","journal-title":"Cell Metab"},{"issue":"6","key":"2026093001534642200_bqag104-B34","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0179538","article-title":"Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: a randomized, placebo-controlled trial","volume":"12","author":"Clemmons","year":"2017","journal-title":"PLoS One"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/11\/bqag104\/71494632\/bqag104.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/11\/bqag104\/71494632\/bqag104.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:53:58Z","timestamp":1790747638000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqag104\/8850254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":34,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,9,29]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqag104","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,11]]},"published":{"date-parts":[[2026,9,29]]},"article-number":"bqag104"}}