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

• Main Authors: Lammertsma Adriaan A, Molthoff Carla FM, Lubberink Mark, Duijst Suzanne, Boontje Nicky M, Vlasblom Ronald, Huisman Marc C, van den Brom Charissa E, van der Velden Jolanda, Boer Christa, Ouwens D Margriet, Diamant Michaela
• Format: Article
• Language: English
• Published: BMC 2009-07-01
• Series: Cardiovascular Diabetology
• Online Access: http://www.cardiab.com/content/8/1/39

<p>Abstract</p> <p>Background</p> <p><it>In vitro </it>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, <it>in vivo </it>changes in myocardial substrate metabolism and their association with myocardial function.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 <it>glucose transporter-4 </it>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).</p> <p>Conclusion</p> <p>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 <it>in vivo </it>data expand previous <it>in vitro </it>findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.</p>