{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:03:01Z","timestamp":1791565381409,"version":"4.3.4"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,10,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D\u2010\u03b2\u2010hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Type 2 diabetic (db\/db) and their corresponding wild\u2010type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D\u2010\u03b2\u2010hydroxybutyrate\u2010(R)\u20101,3 butanediol monoester (ketone ester [KE]). After 4\u00a0weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db\/db mice. A KE diet increased expression of mitochondrial succinyl\u2010CoA:3\u2010oxoacid\u2010CoA transferase and restored decreased expression of mitochondrial \u03b2\u2010hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP\u2010mediated oxygen consumption in cardiac mitochondria from both wild\u2010type and db\/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db\/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db\/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule\u2010associated protein 1 light chain 3\u2013mediated autophagosome formation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Moderate elevation in circulating D\u2010\u03b2\u2010hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative\/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.020729","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T09:09:07Z","timestamp":1632906547000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":57,"title":["Ketone Ester D\u2010\u03b2\u2010Hydroxybutyrate\u2010(R)\u20101,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7344-150X","authenticated-orcid":false,"given":"Phung N.","family":"Thai","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Cardiovascular Medicine University of California Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles V.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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