{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:35:14Z","timestamp":1790836514734,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","award":["00056853"],"award-info":[{"award-number":["00056853"]}],"id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","award":["00107048"],"award-info":[{"award-number":["00107048"]}],"id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["16CVD04"],"award-info":[{"award-number":["16CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic cardiomyopathy (DCM) is a leading complication in type 2 diabetes patients. Recently, we have shown that the reticulum-mitochondria Ca2+ uncoupling is an early and reversible trigger of the cardiac dysfunction in a diet-induced mouse model of DCM. Metformin is a first-line antidiabetic drug with recognized cardioprotective effect in myocardial infarction. Whether metformin could prevent the progression of DCM remains not well understood. We therefore investigated the effect of a chronic 6-week metformin treatment on the reticulum-mitochondria Ca2+ coupling and the cardiac function in our high-fat high-sucrose diet (HFHSD) mouse model of DCM. Although metformin rescued the glycemic regulation in the HFHSD mice, it did not preserve the reticulum-mitochondria Ca2+ coupling either structurally or functionally. Metformin also did not prevent the progression towards cardiac dysfunction, i.e., cardiac hypertrophy and strain dysfunction. In summary, despite its cardioprotective role, metformin is not sufficient to delay the progression to early DCM.<\/jats:p>","DOI":"10.3390\/ijms23073569","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"3569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Metformin on T2D-Induced MAM Ca2+ Uncoupling and Contractile Dysfunction in an Early Mouse Model of Diabetic HFpEF"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6531-9176","authenticated-orcid":false,"given":"Maya","family":"Dia","sequence":"first","affiliation":[{"name":"Laboratoire CarMeN\u2014IRIS Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Leon","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014IRIS Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6930-6671","authenticated-orcid":false,"given":"Stephanie","family":"Chanon","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014MERISM Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69921 Oullins, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Bendridi","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014MERISM Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69921 Oullins, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Gomez","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014IRIS Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Rieusset","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014MERISM Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69921 Oullins, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9784-0425","authenticated-orcid":false,"given":"Helene","family":"Thibault","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014IRIS Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France"},{"name":"Hospices Civils de Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4912-4915","authenticated-orcid":false,"given":"Melanie","family":"Paillard","sequence":"additional","affiliation":[{"name":"Laboratoire CarMeN\u2014IRIS Team, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, 69500 Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0002-9149(74)90089-7","article-title":"Role of diabetes in congestive heart failure: The Framingham study","volume":"34","author":"Kannel","year":"1974","journal-title":"Am. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/HJH.0b013e3283331169","article-title":"Diabetes and incident heart failure in hypertensive and normotensive participants of the Strong Heart Study","volume":"28","author":"Devereux","year":"2010","journal-title":"J. Hypertens."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCULATIONAHA.114.014796","article-title":"Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry","volume":"132","author":"Cavender","year":"2015","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"695792","DOI":"10.3389\/fmed.2021.695792","article-title":"The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms","volume":"8","author":"Salvatore","year":"2021","journal-title":"Front. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.cardfail.2014.02.007","article-title":"The prevalence of diabetic cardiomyopathy: A population-based study in Olmsted County, Minnesota","volume":"20","author":"Dandamudi","year":"2014","journal-title":"J. Card. Fail."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.jchf.2019.12.015","article-title":"Contemporary Treatment Patterns and Clinical Outcomes of Comorbid Diabetes Mellitus and HFrEF: The CHAMP-HF Registry","volume":"8","author":"Vaduganathan","year":"2020","journal-title":"JACC Heart Fail."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dziubak, A., Wojcicka, G., Wojtak, A., and Beltowski, J. (2018). Metabolic Effects of Metformin in the Failing Heart. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102869"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fendo.2019.00294","article-title":"Role of Mitochondria in the Mechanism(s) of Action of Metformin","volume":"10","author":"Vial","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10557-012-6425-x","article-title":"Chronic metformin associated cardioprotection against infarction: Not just a glucose lowering phenomenon","volume":"27","author":"Whittington","year":"2013","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_10","first-page":"5","article-title":"Biphasic effect of metformin on human cardiac energetics","volume":"229","author":"Emelyanova","year":"2021","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: An overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Apaijai, N., Chinda, K., Palee, S., Chattipakorn, S., and Chattipakorn, N. (2014). Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102374"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s10557-013-6504-7","article-title":"Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction","volume":"28","author":"Lexis","year":"2014","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Rinaldi, L., Coviello, F., Di Martino, A., Albanese, G., Marfella, R., and Sardu, C. (2021). Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence. Biomolecules, 11.","DOI":"10.3390\/biom11121834"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Boussageon, R., Supper, I., Bejan-Angoulvant, T., Kellou, N., Cucherat, M., Boissel, J.P., Kassai, B., Moreau, A., Gueyffier, F., and Cornu, C. (2012). Reappraisal of metformin efficacy in the treatment of type 2 diabetes: A meta-analysis of randomised controlled trials. PLoS Med., 9.","DOI":"10.1371\/journal.pmed.1001204"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s00395-020-00835-7","article-title":"Reduced reticulum-mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy","volume":"115","author":"Dia","year":"2020","journal-title":"Basic Res. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1083\/jcb.200608073","article-title":"Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels","volume":"175","author":"Szabadkai","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e47928","DOI":"10.15252\/embr.201947928","article-title":"Metabolic implications of organelle-mitochondria communication","volume":"20","author":"Canto","year":"2019","journal-title":"EMBO Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1080\/15548627.2020.1749490","article-title":"The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses","volume":"17","author":"Hu","year":"2021","journal-title":"Autophagy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fonc.2015.00173","article-title":"Mitochondria-Associated Endoplasmic Reticulum Membranes Microenvironment: Targeting Autophagic and Apoptotic Pathways in Cancer Therapy","volume":"5","author":"Patergnani","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.mce.2017.09.016","article-title":"Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production","volume":"461","author":"Tubbs","year":"2018","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.2337\/db13-1751","article-title":"Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance","volume":"63","author":"Tubbs","year":"2014","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"626359","DOI":"10.3389\/fendo.2021.626359","article-title":"Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes","volume":"12","author":"Silamikele","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"704112","DOI":"10.3389\/fphar.2021.704112","article-title":"Metformin Alleviates Steatohepatitis in Diet-Induced Obese Mice in a SIRT1-Dependent Way","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bbrc.2021.11.018","article-title":"Morphological and functional characterization of diabetic cardiomyopathy in db\/db mice following exercise, metformin alone, or combination treatments","volume":"584","author":"Lu","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/sj.ijo.0803695","article-title":"Metformin and body weight","volume":"32","author":"Golay","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1172\/JCI40671","article-title":"Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1\/AMPK pathway via a decrease in hepatic energy state","volume":"120","author":"Foretz","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1124\/jpet.102.034140","article-title":"Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin","volume":"302","author":"Wang","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1124\/mol.51.6.913","article-title":"Cloning and functional expression of a human liver organic cation transporter","volume":"51","author":"Zhang","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"660698","DOI":"10.3389\/fcvm.2021.660698","article-title":"Myocardial Ischemia-Reperfusion and Diabetes: Lessons Learned From Bedside to Bench","volume":"8","author":"Dia","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1161\/CIRCULATIONAHA.113.001225","article-title":"Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury","volume":"128","author":"Paillard","year":"2013","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in Heart Failure with a Preserved Ejection Fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.amjmed.2020.01.016","article-title":"Does Metformin Interfere With the Cardiovascular Benefits of SGLT2 Inhibitors? Questions About Its Role as the Cornerstone of Diabetes Treatment","volume":"133","author":"Packer","year":"2020","journal-title":"Am. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1463-1326.2010.01349.x","article-title":"Effect of metformin on cardiovascular events and mortality: A meta-analysis of randomized clinical trials","volume":"13","author":"Lamanna","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1161\/CIRCULATIONAHA.118.034222","article-title":"Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program","volume":"138","author":"Radholm","year":"2018","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/dom.13938","article-title":"Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?","volume":"22","author":"Inzucchi","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12933-022-01480-1","article-title":"Direct cardiac effects of SGLT2 inhibitors","volume":"21","author":"Chen","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Palmiero, G., Cesaro, A., Vetrano, E., Pafundi, P.C., Galiero, R., Caturano, A., Moscarella, E., Gragnano, F., Salvatore, T., and Rinaldi, L. (2021). Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115863"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3569\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:42:57Z","timestamp":1760136177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073569"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073569","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}