van den Brom Charissa E, Huisman Marc C, Vlasblom Ronald, Boontje Nicky M, Duijst Suzanne, Lubberink Mark, Molthoff Carla F M, Lammertsma Adriaan A, van der Velden Jolanda, Boer Christa, Ouwens D Margriet, Diamant Michaela
Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands.
Cardiovasc Diabetol. 2009 Jul 22;8:39. doi: 10.1186/1475-2840-8-39.
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.
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.
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 alpha1/2 (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).
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.
体外数据表明，心肌底物代谢的变化可能导致糖尿病性心肌病（DCM）患者心肌功能受损。本研究的目的是在早期DCM大鼠模型中，研究心肌底物代谢的体内变化及其与心肌功能的关系。
对Zucker糖尿病肥胖（ZDF）大鼠和Zucker瘦（ZL）大鼠进行超声心动图检查，然后在禁食状态下进行[11C]棕榈酸正电子发射断层扫描（PET），并在高胰岛素正常血糖钳夹条件下进行[18F]-2-氟-2-脱氧-D-葡萄糖PET检查。使用分离的心肌细胞来测定等长力的产生。
PET数据显示，与ZL大鼠相比，ZDF大鼠胰岛素介导的心肌葡萄糖利用率降低66%，脂肪酸（FA）氧化增加41%（两者p<0.05）。超声心动图显示，与ZL大鼠相比，ZDF大鼠存在舒张和收缩功能障碍，同时单个心肌细胞的最大力（降低68%）和最大力再发展速率（降低69%）显著降低。心肌功能变化与全身胰岛素敏感性及心肌葡萄糖利用率降低显著相关。与ZL大鼠心脏相比，ZDF大鼠心脏葡萄糖转运蛋白4 mRNA表达降低68%（p<0.05），葡萄糖转运蛋白4蛋白表达降低22%（p = 0.10），丙酮酸脱氢酶激酶4蛋白表达水平无变化，AMP活化蛋白激酶α1/2磷酸化降低57%（p<0.05），FA转运蛋白CD36向肌膜的丰度增加2.4倍（p<0.01），这些变化与底物代谢改变相符。与ZL大鼠心脏相比，ZDF大鼠心脏中胰岛素介导的Akt磷酸化降低2.4倍（p<0.05）。
通过PET和超声心动图，我们发现早期DCM患者心肌FA氧化增加，同时胰岛素介导的心肌葡萄糖利用率降低。此外，后者与心肌功能受损有关。这些体内数据扩展了先前的体外研究结果，表明心肌底物代谢的早期改变会导致心肌功能障碍。
