Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts
Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts
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DOI：
10.2337/diabetes.53.9.2366
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发表时间：
2004-09-01
期刊：
影响因子：
7.7
通讯作者：
Abel, ED
中科院分区：
文献类型：
--
作者：
Mazumder, PK;O'Neill, BT;Abel, ED
糖尿病改变心脏底物代谢。胰岛素抵抗状态下的心脏表型尚未得到全面表征。这些研究的目的是确定瘦素缺乏的8周龄ob/ob小鼠的心脏是否能够调节心脏底物利用，以响应胰岛素或脂肪酸输送的变化。Ob/ Ob小鼠胰岛素抵抗和葡萄糖不耐受。胰岛素信号转导和胰岛素刺激的葡萄糖摄取在ob/ob心肌细胞中明显受损。胰岛素刺激的糖酵解率和葡萄糖氧化率分别是野生型心脏的1.5倍和1.8倍，而野生型心脏的糖代谢对胰岛素没有反应。棕榈酸浓度从0.4 mmol/l（低）增加到1.2 mmol/l（高）导致野生型心脏中葡萄糖氧化下降，而在ob/ob小鼠心脏中葡萄糖氧化保持抑制且没有变化。相比之下，在没有或存在1 nmol/l胰岛素的情况下，ob/ob心脏的脂肪酸利用率高出1.5至2倍，并随着棕榈酸盐浓度的增加而增加。此外，胰岛素降低棕榈酸酯氧化速率的能力在ob/ob小鼠的心脏中被钝化。在低棕榈酸盐和无胰岛素的条件下，野生型心脏的心脏性能显著提高。然而，在高棕榈酸盐和1 nmol/l胰岛素的存在下，ob/ob小鼠心脏的功能相对保留，而野生型小鼠心脏的功能则大幅下降。在所有灌注条件下，ob/ob心脏的心肌耗氧量较高，从低棕榈酸盐条件下的30%到高棕榈酸盐条件下的两倍以上。这些数据表明，尽管葡萄糖不耐受ob/ob小鼠的心脏在脂肪酸供应增加和高胰岛素血症的情况下能够维持其功能，但它们是胰岛素抵抗的，代谢效率低下，并且无法调节底物利用以响应胰岛素和脂肪酸供应的变化。
Diabetes alters cardiac substrate metabolism. The cardiac phenotype in insulin-resistant states has not been comprehensively characterized. The goal of these studies was to determine whether the hearts of leptin-deficient 8-week-old ob/ob mice were able to modulate cardiac substrate utilization in response to insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant and glucose intolerant. Insulin signal transduction and insulin-stimulated glucose uptake were markedly impaired in ob/ob cardiomyocytes. Insulin-stimulated rates of glycolysis and glucose oxidation were 1.5- and 1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose metabolism in ob/ob hearts was unresponsive to insulin. Increasing concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a decline in glucose oxidation in wild-type hearts, whereas glucose oxidation remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty acid utilization in ob/ob hearts was 1.5- to 2-fold greater in the absence or presence of 1 nmol/l insulin and rose with increasing palmitate concentrations. Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions, cardiac performance was significantly greater in wildtype hearts. However, in the presence of high palmitate and 1 nmol/l insulin, cardiac performance in ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse hearts declined substantially. Under all perfusion conditions, myocardial oxygen consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate conditions to greater than twofold higher under high-palmitate conditions. These data indicate that although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply.