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Diabetes is a well-established risk factor for heart disease leading to impaired cardiac function and a metabolic switch towards fatty acid usage. Here, we investigated if hyperglycaemia/hypoinsulinaemia in the absence of dyslipidaemia is sufficient to drive these changes, and if they can be reversed by restoring euglycaemia. Using the βV59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within two weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy. Metabolomics showed accumulation of pyruvate, lactate, alanine, TCA cycle metabolites, and branched chain amino acids. Myristic and palmitoleic acid were decreased. Proteomics revealed proteins involved in fatty acid metabolism were increased whereas those involved in glucose metabolism decreased. Western blotting showed enhanced pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) expression. Elevated PDK4 and UCP3 and reduced pyruvate usage were present 24 hr after diabetes induction. The observed effects were independent of dyslipidaemia, as mice showed no evidence of elevated serum triglycerides or lipid accumulation in peripheral organs (including heart). The effects of diabetes were reversible, as glibenclamide therapy restored euglycaemia, cardiac metabolism and function, and PDK4/UCP3 levels.

Original publication

DOI

10.2337/db17-1195

Type

Journal article

Journal

Diabetes

Publication Date

02/04/2018

Addresses

Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Oxford OX1 3PT, UK.