Affiliation:
1. Department of Internal Medicine Cardiovascular Medicine University of California Davis CA
2. Department of Pharmacology University of California Davis CA
3. Laboratory of Metabolic Control National Institute on Alcohol Abuse and AlcoholismNational Institutes of Health Rockville MD
4. Department of Veterans Affairs Northern California Health Care System Mather CA
5. Department of Molecular Biosciences University of California Davis CA
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
15 articles.
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