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What are the Biochemical Mechanisms Responsible for Enhanced Fatty Acid Utilization by Perfused Hearts from Type 2 Diabetic db/db Mice?

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Abstract

Introduction

It is generally accepted that diabetic hearts have an altered metabolic phenotype, with enhanced fatty acid (FA) utilization. The over-utilization of FA by diabetic hearts can have deleterious functional consequences, contributing to a distinct diabetic cardiomyopathy. The objective of this review will be to examine which biochemical mechanisms are responsible for enhanced FA utilization by diabetic hearts.

Methodology and results

Studies were performed with db/db mice, a monogenic model of type 2 diabetes with extreme obesity and hyperglycemia. Perfused db/db hearts exhibit enhanced FA oxidation and esterification. Hypothesis 1: Cardiac FA uptake is enhanced in db/db hearts. The plasma membrane content of two FA transporters, fatty acid translocase/CD36 (FAT/CD36) and plasma membrane fatty acid binding protein (FABPpm), was increased in db/db hearts, consistent with hypothesis 1. Hypothesis 2: Cardiac FA oxidation is enhanced in db/db hearts due to mitochondrial alterations. However, the activity of carnitine palmitoyl transferase-1 (CPT-1) and sensitivity to inhibition by malonyl CoA was unchanged in mitochondria from db/db hearts. Furthermore, total malonyl CoA content was increased, not decreased as predicted for elevated FA oxidation. Finally, the content of uncoupling protein-3 was unchanged in db/db heart mitochondria.

Conclusion

Increased plasma membrane content of FA transporters (FAT/CD36 and FABPpm) will increase FA uptake into db/db cardiomyocytes and thus increase FA utilization. On the other hand, mitochondrial mechanisms do not contribute to elevated rates of FA oxidation in db/db hearts.

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Acknowledgement

Results from the Severson laboratory were enabled by financial support from the Canadian Institutes of Health Research (MT13227).

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  1. Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada

    Andrew N. Carley & David L. Severson

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  1. Andrew N. Carley
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Correspondence to David L. Severson.

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Carley, A.N., Severson, D.L. What are the Biochemical Mechanisms Responsible for Enhanced Fatty Acid Utilization by Perfused Hearts from Type 2 Diabetic db/db Mice?. Cardiovasc Drugs Ther 22, 83–89 (2008). https://doi.org/10.1007/s10557-008-6088-9

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