{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:40:39Z","timestamp":1790127639610,"version":"4.0.1"},"reference-count":45,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The development of type 2 diabetes mellitus is closely associated with mitochondrial dysfunction of pancreatic \u03b2-cells, but the mechanisms by which glucagon-like peptide-1 receptor activation preserves mitochondrial homeostasis under glucotoxic conditions remain incompletely understood. Herein, we investigated whether Exendin-4 protects \u03b2-cells against chronic high glucose (HG)-induced mitochondrial injury by regulating the cAMP\/PKA\/Drp1 signaling pathway. INS-1 \u03b2-cells, pancreatic tissues from db\/db mice, and isolated primary islets were used to assess oxidative stress, apoptosis, mitochondrial function and morphology, insulin secretion, and cAMP\/PKA\/Drp1 signaling. Prolonged HG exposure increased oxidative stress and apoptosis, impaired mitochondrial membrane potential, elevated mitochondrial ROS accumulation, reduced ATP content, and promoted mitochondrial fragmentation in INS-1 \u03b2-cells. These changes were accompanied by increased Drp1 expression, reduced cAMP levels and PKA activity, decreased inhibitory phosphorylation of Drp1 at Ser637, and increased Ser616 phosphorylation. Exendin-4 attenuated HG-induced oxidative stress and apoptosis, restored mitochondrial function, improved mitochondrial morphology, and partially restored Drp1 Ser637 phosphorylation, whereas it did not significantly affect HG-induced Ser616 phosphorylation. In db\/db mice, Exendin-4 improved metabolic parameters and alleviated \u03b2-cell apoptosis, with partial recovery of Drp1 Ser637 phosphorylation in pancreatic islets. Furthermore, glucose-stimulated insulin secretion assays in isolated primary islets showed that Exendin-4 improved \u03b2-cell secretory function in islets isolated from db\/db mice. Pharmacological inhibition of PKA with H89 attenuated Exendin-4-induced Drp1 Ser637 phosphorylation and mitochondrial protection. Collectively, these results suggest that Exendin-4 protects pancreatic \u03b2-cells against HG-induced mitochondrial dysfunction and \u03b2-cell injury by restoring PKA-associated inhibitory phosphorylation of Drp1 at Ser637 and improving mitochondrial dynamics.<\/jats:p>","DOI":"10.1530\/joe-26-0023","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T09:53:38Z","timestamp":1784109218000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":1,"title":["Exendin-4 improves high glucose-induced mitochondrial dysfunction of pancreatic \u03b2-cells via PKA\/Drp1 signaling"],"prefix":"10.1530","volume":"270","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9999-7901","authenticated-orcid":true,"given":"Jiahao","family":"Zhao","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Xuzhou Cancer Hospital, Affiliated Hospital of Jiangsu University 2 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Fan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Fu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Xuzhou New Health Hospital, Affiliated Hospital of Jiangsu University 3 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-6620","authenticated-orcid":true,"given":"Xia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University 1 , , ,","place":["Xuzhou, Jiangsu Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"2026072108213284600_bib1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.4239\/wjd.v14.i3.130","article-title":"2023 pancreatic \u03b2-cell dysfunction in type 2 diabetes: implications of inflammation and oxidative stress","volume":"14","author":"Dludla","year":"2023","journal-title":"World J Diabetes"},{"key":"2026072108213284600_bib2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.cmet.2012.01.009","article-title":"Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells","volume":"15","author":"Wang","year":"2012","journal-title":"Cell Metab"},{"key":"2026072108213284600_bib3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/s10020-024-01027-y","article-title":"Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology","volume":"30","author":"Wang","year":"2024","journal-title":"Mol Med"},{"key":"2026072108213284600_bib4","doi-asserted-by":"crossref","DOI":"10.1016\/j.metabol.2020.154431","article-title":"A requirement for PAK1 to support mitochondrial function and maintain cellular redox balance via electron transport chain proteins to prevent \u03b2-cell apoptosis","volume":"115","author":"Ahn","year":"2021","journal-title":"Metabolism"},{"key":"2026072108213284600_bib5","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.cell.2018.08.040","article-title":"2018 acetate production from glucose and coupling to mitochondrial metabolism in mammals","volume":"175","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"2026072108213284600_bib6","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1126\/science.1104343","article-title":"Mitochondrial dysfunction and type 2 diabetes","volume":"307","author":"Lowell","year":"2005","journal-title":"Science"},{"key":"2026072108213284600_bib7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1042\/EBC20170104","article-title":"Mitochondrial dynamics: overview of molecular mechanisms","volume":"62","author":"Tilokani","year":"2018","journal-title":"Essays Biochem"},{"key":"2026072108213284600_bib8","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.1002\/ptr.8004","article-title":"Resveratrol prevents Drp1-mediated mitochondrial fission in the diabetic kidney through the PDE4D\/PKA pathway","volume":"37","author":"Zhu","year":"2023","journal-title":"Phytother Res"},{"key":"2026072108213284600_bib9","doi-asserted-by":"crossref","DOI":"10.1016\/j.exer.2022.109095","article-title":"2022 inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis","volume":"220","author":"Zhang","year":"2022","journal-title":"Exp Eye Res"},{"key":"2026072108213284600_bib10","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.biocel.2008.08.031","article-title":"Dynamin-related protein 1 mediates high glucose induced pancreatic beta cell apoptosis","volume":"41","author":"Men","year":"2009","journal-title":"Int J Biochem Cell Biol"},{"key":"2026072108213284600_bib11","article-title":"Epigallocatechin gallate attenuated high glucose-induced pancreatic beta cell dysfunction by modulating DRP1-mediated mitochondrial apoptosis pathways","volume":"14","author":"Jia","year":"2024","journal-title":"Sci Rep"},{"key":"2026072108213284600_bib12","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2020.107594","article-title":"New perspectives on the role of Drp1 isoforms in regulating mitochondrial pathophysiology","volume":"213","author":"Rosdah","year":"2020","journal-title":"Pharmacol Ther"},{"key":"2026072108213284600_bib13","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.2337\/db18-1112","article-title":"Differential effect of glucose on ER-mitochondria Ca2+ exchange participates in insulin secretion and glucotoxicity-mediated dysfunction of \u03b2-cells","volume":"68","author":"Dingreville","year":"2019","journal-title":"Diabetes"},{"key":"2026072108213284600_bib14","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41574-018-0016-2","article-title":"Glucagon-like peptide 1 in health and disease","volume":"14","author":"Andersen","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"2026072108213284600_bib15","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.2337\/diacare.28.5.1083","article-title":"Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea","volume":"28","author":"Kendall","year":"2005","journal-title":"Diabetes Care"},{"key":"2026072108213284600_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2023.175896","article-title":"Exendin-4 protects against high glucose-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y neuroblastoma cells through GLP-1 receptor\/Epac\/Akt signaling","volume":"954","author":"Pandey","year":"2023","journal-title":"Eur J Pharmacol"},{"key":"2026072108213284600_bib17","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1080\/15548627.2021.1956123","article-title":"Exendin-4 stimulates autophagy in pancreatic beta-cells via the RAPGEF\/EPAC-Ca2+-PPP3\/calcineurin-TFEB axis","volume":"18","author":"Zummo","year":"2022","journal-title":"Autophagy"},{"key":"2026072108213284600_bib18","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1210\/me.2014-1346","article-title":"Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes","volume":"29","author":"Mangmool","year":"2015","journal-title":"Mol Endocrinol"},{"key":"2026072108213284600_bib19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pharmthera.2014.03.008","article-title":"cAMP signaling in subcellular compartments","volume":"143","author":"Lefkimmiatis","year":"2014","journal-title":"Pharmacol Ther"},{"key":"2026072108213284600_bib20","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1016\/j.bbamcr.2015.04.013","article-title":"GSKIP- and GSK3-mediated anchoring strengthens cAMP\/PKA\/Drp1 axis signaling in the regulation of mitochondrial elongation","volume":"1853","author":"Loh","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"2026072108213284600_bib21","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3109\/08977194.2015.1125349","article-title":"Exendin-4 attenuates renal tubular injury by decreasing oxidative stress and inflammation in streptozotocin-induced diabetic mice","volume":"33","author":"Sancar-Bas","year":"2015","journal-title":"Growth Factors"},{"key":"2026072108213284600_bib22","first-page":"1029","article-title":"Exendin-4 protects INS-1 cells against palmitate-induced apoptosis through the IRE1\u03b1-Xbp1 signaling pathway","volume":"16","author":"Jiang","year":"2018","journal-title":"Exp Ther Med"},{"key":"2026072108213284600_bib23","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.bbrc.2006.06.027","article-title":"Exenatide inhibits \u03b2-cell apoptosis by decreasing thioredoxin-interacting protein","volume":"346","author":"Chen","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2026072108213284600_bib24","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2005.02.001","article-title":"Mitochondria, oxidants, and aging","volume":"120","author":"Balaban","year":"2005","journal-title":"Cell"},{"key":"2026072108213284600_bib25","doi-asserted-by":"crossref","first-page":"21583","DOI":"10.1074\/jbc.C700083200","article-title":"Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology","volume":"282","author":"Chang","year":"2007","journal-title":"J Biol Chem"},{"key":"2026072108213284600_bib26","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.bcp.2016.01.013","article-title":"Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation","volume":"104","author":"Torres","year":"2016","journal-title":"Biochem Pharmacol"},{"key":"2026072108213284600_bib27","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s12967-022-03327-5","article-title":"\u03b2-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic \u03b2-cells?","volume":"20","author":"Diane","year":"2022","journal-title":"J Transl Med"},{"key":"2026072108213284600_bib28","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/81649","article-title":"2000 impaired insulin secretion and \u03b2-cell loss in tissue-specific knockout mice with mitochondrial diabetes","volume":"26","author":"Silva","year":"2000","journal-title":"Nat Genet"},{"key":"2026072108213284600_bib29","doi-asserted-by":"crossref","first-page":"805","DOI":"10.3389\/fphar.2020.00805","article-title":"Stimulation of GLP-1 receptor inhibits methylglyoxal-induced mitochondrial dysfunctions in H9c2 cardiomyoblasts: potential role of Epac\/PI3K\/Akt pathway","volume":"11","author":"Nuamnaichati","year":"2020","journal-title":"Front Pharmacol"},{"key":"2026072108213284600_bib30","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1039\/C5MB00022J","article-title":"Glucagon-like peptide 1 protects INS-1E mitochondria against palmitate-mediated beta-cell dysfunction: a proteomic study","volume":"11","author":"Ciregia","year":"2015","journal-title":"Mol Biosyst"},{"key":"2026072108213284600_bib31","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1097\/TA.0000000000003490","article-title":"Mitochondria play a key role in oxidative stress-induced pancreatic islet dysfunction after severe burns","volume":"92","author":"Liu","year":"2022","journal-title":"J Trauma Acute Care Surg"},{"key":"2026072108213284600_bib32","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s125-002-8248-z","article-title":"2002 reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients","volume":"45","author":"Sakuraba","year":"2002","journal-title":"Diabetologia"},{"key":"2026072108213284600_bib33","doi-asserted-by":"crossref","first-page":"927","DOI":"10.2337\/diabetes.48.4.927","article-title":"Hyperglycemia causes oxidative stress in pancreatic \u03b2-cells of GK rats, a model of type 2 diabetes","volume":"48","author":"Ihara","year":"1999","journal-title":"Diabetes"},{"key":"2026072108213284600_bib34","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.2337\/db13-0272","article-title":"Sweet and sour \u03b2-cells: ROS and Hif1\u03b1 induce warburg-like lactate production during type 2 diabetes","volume":"62","author":"Cantley","year":"2013","journal-title":"Diabetes"},{"key":"2026072108213284600_bib35","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1089\/ars.2016.6755","article-title":"The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus","volume":"26","author":"Gerber","year":"2017","journal-title":"Antioxid Redox Signaling"},{"key":"2026072108213284600_bib36","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/15216540152845957","article-title":"The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology","volume":"52","author":"Lenaz","year":"2001","journal-title":"IUBMB Life"},{"key":"2026072108213284600_bib37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cmet.2006.01.004","article-title":"The biology of incretin hormones","volume":"3","author":"Drucker","year":"2006","journal-title":"Cell Metab"},{"key":"2026072108213284600_bib38","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1152\/physrev.00034.2006","article-title":"The physiology of glucagon-like peptide 1","volume":"87","author":"Holst","year":"2007","journal-title":"Physiol Rev"},{"key":"2026072108213284600_bib39","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.2337\/diabetes.50.2007.S58","article-title":"2001 \u03b2-cell apoptosis: stimuli and signaling","volume":"50","author":"Mandrup-Poulsen","year":"2001","journal-title":"Diabetes"},{"key":"2026072108213284600_bib40","doi-asserted-by":"crossref","first-page":"19997","DOI":"10.1074\/jbc.M110.122127","article-title":"Effective blockage of both the extrinsic and intrinsic pathways of apoptosis in mice by TAT-crmA","volume":"285","author":"Krautwald","year":"2010","journal-title":"J Biol Chem"},{"key":"2026072108213284600_bib41","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1089\/ars.2012.4905","article-title":"Regulation of the intrinsic apoptosis pathway by reactive oxygen species","volume":"19","author":"Wu","year":"2013","journal-title":"Antioxid Redox Signaling"},{"key":"2026072108213284600_bib42","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1126\/science.1115035","article-title":"2006 caspases 3 and 7: key mediators of mitochondrial events of apoptosis","volume":"311","author":"Lakhani","year":"2006","journal-title":"Science"},{"key":"2026072108213284600_bib43","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.2337\/db13-0251","article-title":"Rhein protects pancreatic \u03b2-cells from dynamin-related protein-1-mediated mitochondrial fission and cell apoptosis under hyperglycemia","volume":"62","author":"Liu","year":"2013","journal-title":"Diabetes"},{"key":"2026072108213284600_bib44","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3390\/biom11030424","article-title":"The phosphorylation status of Drp1-Ser637 by PKA in mitochondrial fission modulates mitophagy via PINK1\/Parkin to exert multipolar spindles assembly during mitosis","volume":"11","author":"Ko","year":"2021","journal-title":"Biomolecules"},{"key":"2026072108213284600_bib45","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.2337\/db12-0009","article-title":"NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP\/PKA in the regulation of insulin secretion","volume":"61","author":"Li","year":"2012","journal-title":"Diabetes"}],"container-title":["Journal of Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article-pdf\/doi\/10.1530\/JOE-26-0023\/521948\/joe-26-0023.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article-pdf\/doi\/10.1530\/JOE-26-0023\/521948\/joe-26-0023.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T12:21:44Z","timestamp":1784636504000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/joe\/article\/270\/1\/e260023\/77804\/Exendin-4-improves-high-glucose-induced"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1530\/joe-26-0023","relation":{},"ISSN":["0022-0795","1479-6805"],"issn-type":[{"value":"0022-0795","type":"print"},{"value":"1479-6805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"article-number":"e260023"}}