Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study

Lydia M Le Page, Oliver J Rider, Andrew J Lewis, Vicky Ball, Kieran Clarke, Edvin Johansson, Carolyn A Carr, Lisa C Heather, Damian J Tyler

Research output: Contribution to journalArticlepeer-review

Abstract

Although diabetic cardiomyopathy is widely recognised, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate utilisation, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type-II diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate utilisation and improve cardiac function.All animals underwent in vivo hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function respectively. Diabetic animals showed significantly higher blood glucose (10.8±0.7mM vs 8.4±0.5mM), lower PDH flux (0.005±0.001s(-1) vs 0.017±0.002s(-1)) and significantly impaired diastolic function (E/E' 12.2±0.8 vs 20±2) in keeping with early diabetic cardiomyopathy. Twenty-eight days treatment with dichloroacetate restored PDH flux to normal levels (0.018±0.002s(-1)), reversed diastolic dysfunction (E/E' 14±1) and normalized blood glucose (7.5±0.7mM).Treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction and normalised blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.

Original languageEnglish
JournalDiabetes
DOIs
Publication statusPublished - 20 Mar 2015

Fingerprint

Dive into the research topics of 'Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study'. Together they form a unique fingerprint.

Cite this