Ketone ester D-Beta-hydroxybutyrate-(R)-1,3 butanediol prevents decline in cardiac function in type 2 diabetic mice
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Citation
Abstract
RATIONALE: Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes (T2D). However, existing therapeutics for T2D have limited success on the prevention of diabetic cardiomyopathy.
OBJECTIVE: To determine whether moderate elevation in D-Beta-hydroxybutyrate (Beta-OHB) improves cardiac function in T2D animals.
METHODS AND RESULTS: Type 2 diabetic (db/db) and their corresponding wild-type (WT) mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D-Beta-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester, [KE]). After 4 weeks, echocardiography demonstrated that KE diet improved systolic and diastolic function in db/db mice. KE diet increased expression of mitochondrial succinyl-CoA:3-oxoacid-CoA transferase (SCOT) and restored decreased expression of mitochondrial β-hydroxybutyrate dehydrogenase (BDH1), key enzymes in cardiac ketone metabolism. KE diet significantly enhanced both basal and ADP-mediated oxygen consumption in cardiac mitochondria from both WT and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin (TRX) and glutathione peroxidase 4 (GPX4) 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 KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 (Mfn2) expression, which contributed to improved coupling between Parkin translocation into mitochondria and LC3-mediated autophagosome formation.
CONCLUSIONS: Moderate elevation in circulating D-Beta-hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control and oxygen consumption, increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in T2D animals.
Translational perspective
Patients with type-2 diabetes mellitus (T2D) have an increased risk of developing heartfailure (HF) despite the success of anti-hyperglycemic therapies in treating elevated serum glucose. Therefore, new therapies are urgently needed to prevent progression toward HF in T2D patients. Here, we show that a moderate elevation in circulating levels of D-β-hydroxybutyrate via ketone ester supplementation prevented progression toward diabetic cardiomyopathy in db/db mice by limiting oxidative stress and enhancing mitochondrial quality control via mitophagy. These data demonstrate that ketone ester supplementation to induce mild ketosis in T2D patients could be beneficial in limiting the
progression toward HF.