Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice
Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice
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DOI：
10.1152/ajpendo.2000.279.5.e1104
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发表时间：
2000-11-01
影响因子：
5.1
通讯作者：
Severson, DL
中科院分区：
文献类型：
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作者：
Belke, DD;Larsen, TS;Severson, DL
在来自遗传性糖尿病C57 BL/KsJ-lepr（db）/lepr（db）（db/db）小鼠及其非糖尿病瘦型同窝出生仔的灌注心脏中表征收缩功能和底物代谢。通过测量左心室压力和心脏功率来评估工作心脏的收缩力。使用灌注液中的放射性标记底物（[5-H-3]葡萄糖、[U-C-14]葡萄糖和[9，10-H-3]棕榈酸酯）测定糖酵解、葡萄糖氧化和脂肪酸氧化速率。db/db心脏的收缩功能障碍明显，左心室舒张末期压升高，左心室发展压、心输出量和心功率降低。糖尿病心脏外源性葡萄糖的糖酵解率为对照组的48%，而葡萄糖氧化率仅为对照组的16%。相比之下，棕榈酸氧化在db/db心脏中增加两倍。使用过表达GLUT-4葡萄糖转运蛋白的转基因db/db小鼠的灌流心脏测试了代谢改变在糖尿病诱导的收缩功能障碍中发挥致病作用的假设。在db/db-人胰岛素可调节葡萄糖转运蛋白（hGLUT-4）心脏中，葡萄糖代谢和棕榈酸代谢均正常化，收缩功能也正常化。这些发现强烈支持db/db糖尿病心脏中观察到的心肌病中代谢受损的致病作用。
Contractile function and substrate metabolism were characterized in perfused hearts from genetically diabetic C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and their non-diabetic lean littermates. Contractility was assessed in working hearts by measuring left ventricular pressures and cardiac power. Rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured using radiolabeled substrates ([5-H-3]glucose, [U-C-14]glucose, and [9,10-H-3]palmitate) in the perfusate. Contractile dysfunction in db/db hearts was evident, with increased left ventricular end diastolic pressure and decreased left ventricular developed pressure, cardiac output, and cardiac power. The rate of glycolysis from exogenous glucose in diabetic hearts was 48% of control, whereas glucose oxidation was depressed to only 16% of control. In contrast, palmitate oxidation was increased twofold in db/db hearts. The hypothesis that altered metabolism plays a causative role in diabetes-induced contractile dysfunction was tested using perfused hearts from transgenic db/db mice that overexpress GLUT-4 glucose transporters. Both glucose metabolism and palmitate metabolism were normalized in hearts from db/db-human insulin-regulatable glucose transporter (hGLUT-4) hearts, as was contractile function. These findings strongly support a causative role of impaired metabolism in the cardiomyopathy observed in db/db diabetic hearts.