{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:27:07Z","timestamp":1790011627841,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Comprehensive Physiology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Type 2 diabetes mellitus (T2DM) is increasingly recognized as a disorder of inappropriate glucagon secretion in addition to \u03b2\u2010cell dysfunction and insulin resistance. Chronic hyperglucagonemia, driven by \u03b1\u2010cell dysregulation, contributes directly to the development of diabetic cardiomyopathy (DCM) through hepatic, systemic, and myocardial mechanisms. Emerging evidence shows that glucagon receptor (GCGR) signaling is active in cardiomyocytes, endothelial cells, and vascular smooth muscle, where persistent activation promotes cAMP\/PKA\u2010mediated stress, calcium dysregulation, oxidative injury, and adverse remodeling. Hyperglucagonemia further exacerbates metabolic toxicity by enhancing fatty acid flux, lipotoxic intermediate accumulation, and amino\u2010acid driven proteolysis. These changes converge on myocardial fibrosis, diastolic dysfunction, and cardiac steatosis characteristic of DCM. Therapeutic interventions that modulate glucagon biology including glucagon receptor antagonists (GRAs), GLP\u20101 receptor agonists, and multi\u2010agonist incretin therapies demonstrate cardioprotective potential by restoring glucagon\u2010insulin balance and attenuating glucagon\u2010driven metabolic stress. This mini\u2010review highlights mechanistic links and therapeutic implications.<\/jats:p>","DOI":"10.1002\/cph4.70145","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:25:57Z","timestamp":1775625957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Glucagonocentric Basis of Diabetic Cardiomyopathy: Pancreas\u2013Heart Crosstalk Linking \u03b1\u2010Cell Dysregulation to Cardiac Metabolic Stress and Fibrosis"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8329-3173","authenticated-orcid":false,"given":"Nila","family":"Ganamurali","sequence":"first","affiliation":[{"name":"Helix Research Lab, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University  Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhupriya","family":"Prabhakaran","sequence":"additional","affiliation":[{"name":"Helix Research Lab, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University  Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0792-392X","authenticated-orcid":false,"given":"Sarvesh","family":"Sabarathinam","sequence":"additional","affiliation":[{"name":"Helix Research Lab, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University  Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"e_1_2_22_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13643\u2010026\u201003117\u2010w"},{"key":"e_1_2_22_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2011.01714.x"},{"key":"e_1_2_22_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12185806"},{"key":"e_1_2_22_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018\u201000117"},{"key":"e_1_2_22_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13221914"},{"key":"e_1_2_22_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933\u2010016\u20100440\u20103"},{"key":"e_1_2_22_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2025.06.013"},{"key":"e_1_2_22_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09\u20109028"},{"key":"e_1_2_22_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaf162"},{"key":"e_1_2_22_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2018.11.001"},{"key":"e_1_2_22_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15462"},{"key":"e_1_2_22_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/db22\u20100079"},{"key":"e_1_2_22_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11883\u2010025\u201001346\u20103"},{"key":"e_1_2_22_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133314"},{"key":"e_1_2_22_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311586"},{"key":"e_1_2_22_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113259"},{"key":"e_1_2_22_18_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.32.5.387"},{"key":"e_1_2_22_19_1","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2016.233"},{"key":"e_1_2_22_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1645041"},{"key":"e_1_2_22_21_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.59965"},{"key":"e_1_2_22_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132023"},{"key":"e_1_2_22_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2025.112925"},{"key":"e_1_2_22_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241612829"},{"key":"e_1_2_22_25_1","volume-title":"Endotext","author":"Oktay A. 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