We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined <sup>13</sup>C Hyperpolarized Magnetic Resonance and Echocardiography Study.
- Authors
Le Page, Lydia M.; Rider, Oliver J.; Lewis, Andrew J.; Ball, Vicky; Clarke, Kieran; Johansson, Edvin; Carr, Carolyn A.; Heather, Lisa C.; Tyler, Damian J.
- Abstract
Although diabetic cardiomyopathy is widely recognized, 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 use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1-13C]pyruvate magnetic resonance specroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s-1), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s-1), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.
- Subjects
PYRUVATE dehydrogenase kinase; DIABETIC cardiomyopathy; DEHYDROGENASES; DIABETES complications; CARDIOMYOPATHIES
- Publication
Diabetes, 2015, Vol 64, Issue 8, p2735
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db14-1560