Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance.
Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance.
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DOI：
10.2337/db10-0519
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发表时间：
2010-09
期刊：
影响因子：
7.7
通讯作者：
Schrauwen P
中科院分区：
文献类型：
--
作者：
Hoeks J;van Herpen NA;Mensink M;Moonen-Kornips E;van Beurden D;Hesselink MK;Schrauwen P
2 型糖尿病和胰岛素抵抗与线粒体功能障碍有关，但这是否是该疾病发病机制的主要因素尚存在争议。为了检验线粒体功能障碍继发于胰岛素抵抗的概念，我们采用了人类长期禁食的独特模型。长时间禁食是一种生理状况，在游离脂肪酸 (FFA) 水平增加、脂肪氧化增加以及葡萄糖和胰岛素水平较低的情况下，会出现肌肉胰岛素抵抗。因此，预计骨骼肌线粒体功能将得到维持，以适应增加的脂肪氧化，除非继发于胰岛素抵抗的因素对线粒体功能产生负面影响。在呼吸室中，12 名健康雄性在随机交叉设计中接受 60 小时禁食和 60 小时正常进食条件。随后，使用高胰岛素-正常血糖钳评估胰岛素敏感性，并使用高分辨率呼吸测定法对透化肌纤维中的线粒体功能进行离体定量。事实上，健康男性受试者禁食 60 小时后，FFA 水平增加了约九倍，导致肌内脂质水平升高和肌肉胰岛素敏感性降低。尽管全身脂肪氧化增加，但我们观察到透化骨骼肌纤维中耦合态 3 呼吸和最大非耦合呼吸的总体减少，这不能用线粒体密度的变化来解释。这些发现证实胰岛素抵抗状态对线粒体功能具有继发性负面影响。鉴于长时间禁食后胰岛素和葡萄糖水平较低，高血糖和胰岛素作用本身可以被排除为潜在机制，表明血浆 FFA 升高和/或肌内脂肪积累可能是观察到的线粒体能力下降的原因。
Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function. While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry. Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density. These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity.
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影响因子：
15.9
作者：
Bonnard, Charlotte;Durand, Annie;Rieusset, Jennifer
通讯作者：
Rieusset, Jennifer
影响因子：
4.8
作者：
Moreno, M;Lombardi, A;Goglia, F
通讯作者：
Goglia, F
DOI：
10.1152/ajpendo.90287.2008
发表时间：
2008-09-01
影响因子：
5.1
作者：
Abdul-Ghani, Muhammad A.;Muller, Florian L.;DeFronzo, Ralph A.
通讯作者：
DeFronzo, Ralph A.
影响因子：
8.2
作者：
Boushel, R.;Gnaiger, E.;Schjerling, P.;Skovbro, M.;Kraunsoe, R.;Dela, F.
通讯作者：
Dela, F.
影响因子：
4.8
作者：
Pagel-Langenickel, Ines;Bao, Jianjun;Sack, Michael N.
通讯作者：
Sack, Michael N.