Cardiac dysfunction and metabolic inflexibility in a mouse model of diabetes without dyslipidemia

Maria Rohm, Dragana Savic, Vicky Ball, M. Kate Curtis, Sarah Bonham, Roman Fischer, Nathalie Legrave, James I. MacRae, Damian J. Tyler, Frances M. Ashcroft*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

Abstract

Diabetes is a well-established risk factor for heart disease, leading to impaired cardiac function and a metabolic switch toward fatty acid usage. In this study, we investigated if hyperglycemia/hypoinsulinemia in the absence of dyslipidemia is sufficient to drive these changes and if they can be reversed by restoring euglycemia. Using the bV59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within 2 weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13C]pyruvate MRS. Metabolomics showed accumulation of pyruvate, lactate, alanine, tricarboxyclic acid 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 h after diabetes induction. The observed effects were independent of dyslipidemia, as mice showed no evidence of elevated serum triglycerides or lipid accumulation in peripheral organs (including the heart). The effects of diabetes were reversible, as glibenclamide therapy restored euglycemia, cardiac metabolism and function, and PDK4/UCP3 levels.

Original languageEnglish
Pages (from-to)1057-1067
Number of pages11
JournalDiabetes
Volume67
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018
Externally publishedYes

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