Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.
Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.
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DOI：
10.2337/db13-1130
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发表时间：
2014-08
期刊：
影响因子：
7.7
通讯作者：
DeFronzo RA
中科院分区：
文献类型：
--
作者：
Daniele G;Eldor R;Merovci A;Clarke GD;Xiong J;Tripathy D;Taranova A;Abdul-Ghani M;DeFronzo RA
胰岛素抵抗和游离脂肪酸(FFA)代谢紊乱是2型糖尿病(T2 DM)和肥胖正常糖耐量(NGT)患者的核心缺陷。肌肉线粒体功能受损(ATP合成减少)也被描述为胰岛素抵抗的T2 DM和肥胖者。我们研究了阿昔莫司降低血浆FFA浓度是否提高了ATP合成速率和改变了活性氧(ROS)的产生。11例NGT肥胖者和11例T2 DM患者接受1)OGTT，2)正常血糖胰岛素钳夹加肌肉活检，3)阿昔莫司治疗前后的胫前肌核磁共振波谱检查(250 mg，每6h一次，共12天)。分别用化学发光法和荧光法测定体外分离的肌肉组织线粒体的ATP合成速率和ROS生成。Acipimox1)显著降低肥胖NGT和T2 DM患者的空腹血浆FFA浓度，并在口服糖耐量试验和胰岛素钳夹试验中增强对血浆FFA的抑制作用；2)增强胰岛素介导的肌肉葡萄糖代谢和抑制肝脏葡萄糖的产生。肥胖的NGT(r=0.81)和T2 DM(r=0.76)(P<；0.001)患者胰岛素敏感性的改善与血浆游离脂肪酸的降低密切相关。在肥胖的NGT和T2 DM受试者中，线粒体三磷酸腺苷合成率都增加了50%，并且与血浆游离脂肪酸的下降和胰岛素介导的葡萄糖处置的增加密切相关(r>；0.70P<；0.001)。阿昔莫司治疗后ROS的产生无明显变化。肥胖的NGT和T2 DM患者血浆FFA的减少提高了线粒体的ATP合成速率，表明胰岛素抵抗患者的线粒体缺陷至少部分是可逆的。
Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) 1H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.
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影响因子：
8.2
作者：
Krssak, M;Petersen, KF;Roden, M
通讯作者：
Roden, M
影响因子：
--
作者：
Abdul-Ghani MA;DeFronzo RA
通讯作者：
DeFronzo RA
影响因子：
7.7
作者：
Hoeks J;van Herpen NA;Mensink M;Moonen-Kornips E;van Beurden D;Hesselink MK;Schrauwen P
通讯作者：
Schrauwen P
DOI：
10.1007/s10334-003-0029-1
发表时间：
2004-03-01
影响因子：
2.3
作者：
Krssak, M;Mlynárik, V;Roden, M
通讯作者：
Roden, M
影响因子：
5.8
作者：
Bajaj, M;Suraamornkul, S;DeFronzo, RA
通讯作者：
DeFronzo, RA