Key result
Induction of diabetes in the βV59M mouse model reduced stroke volume and cardiac output within 2 weeks, which was independent of dyslipidemia and reversible with glibenclamide therapy.
Why the study?
Does hyperglycemia and hypoinsulinemia without dyslipidemia cause cardiac dysfunction and metabolic inflexibility, and is it reversible with glibenclamide in a mouse model?
Does hyperglycemia and hypoinsulinemia without dyslipidemia cause cardiac dysfunction and metabolic inflexibility, and is it reversible with glibenclamide in a mouse model?
Hyperglycemia and hypoinsulinemia alone, independent of dyslipidemia, are sufficient to drive cardiac dysfunction and metabolic inflexibility in mice, which can be reversed by restoring euglycemia.
Hyperglycemia may impair cardiac output rapidly in diabetes models; leaves open reversibility by euglycemia in patients.
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 βV59M 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.
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Rohm et al. (2018) studied Diabetes without dyslipidemia. Diabetes induction vs. Euglycemia was evaluated on Cardiac function and metabolic changes. Induction of diabetes in the βV59M mouse model reduced stroke volume and cardiac output within 2 weeks, which was independent of dyslipidemia and reversible with glibenclamide therapy.
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