Ketone ester d-β-hydroxybutyrate-(R)-1,3 butanediol prevents decline in cardiac function in type 2 diabetic mice

Phung N. Thai, Charles V. Miller, M. Todd King, Saul Schaefer, Richard L. Veech, Nipavan Chiamvimonvat, Donald M. Bers, Elena N. Dedkova

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: 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-β-hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. METHODS AND RESULTS: Type 2 diabetic (db/db) and their corresponding wild-type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl-CoA:3-oxoacid-CoA transferase and restored decreased expression of mitochondrial β-hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP-mediated oxygen consumption in cardiac mitochondria from both wild-type 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-associated protein 1 light chain 3–mediated autophagosome formation. CONCLUSIONS: Moderate elevation in circulating D-β-hydroxybutyrate 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.

Original languageEnglish (US)
Article numbere020729
JournalJournal of the American Heart Association
Volume10
Issue number19
DOIs
StatePublished - Oct 5 2021

Keywords

  • Cardiac function
  • Glutathione peroxidase 4
  • Ketone bodies metabolism
  • Ketone ester
  • Mitochondrial permeability transition
  • Mitofusin 2
  • roGFP2-GRX1
  • roGFP2-ORP1
  • Thioredoxin
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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