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Open Access 01-12-2009 | Original investigation

Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography

Authors: Charissa E van den Brom, Marc C Huisman, Ronald Vlasblom, Nicky M Boontje, Suzanne Duijst, Mark Lubberink, Carla FM Molthoff, Adriaan A Lammertsma, Jolanda van der Velden, Christa Boer, D Margriet Ouwens, Michaela Diamant

Published in: Cardiovascular Diabetology | Issue 1/2009

Abstract

Background

In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.

Methods

Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [¹¹C]palmitate positron emission tomography (PET) under fasting, and [¹⁸F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.

Results

PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase α1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).

Conclusion

Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

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Title: Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography
Authors: Charissa E van den Brom
Marc C Huisman
Ronald Vlasblom
Nicky M Boontje
Suzanne Duijst
Mark Lubberink
Carla FM Molthoff
Adriaan A Lammertsma
Jolanda van der Velden
Christa Boer
D Margriet Ouwens
Michaela Diamant
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2009
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/1475-2840-8-39

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