Gaster Michael
KMEB, Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.
Biochim Biophys Acta. 2007 Jul;1772(7):755-65. doi: 10.1016/j.bbadis.2007.03.007. Epub 2007 Apr 1.
In order to better understand the impact of reduced mitochondrial function for the development of insulin resistance and cellular metabolism, human myotubes were established from lean, obese, and T2D subjects and exposed to mitochondrial inhibitors, either affecting the electron transport chain (Antimycin A), the ATP synthase (oligomycin) or respiratory uncoupling (2,4-dinitrophenol). Direct inhibition of the electron transport chain or the ATP synthase was followed by increased glucose uptake and lactate production, reduced glycogen synthesis, reduced lipid and glucose oxidation and unchanged lipid uptake. The metabolic phenotype during respiratory uncoupling resembled the above picture, except for an increase in glucose and palmitate oxidation. Antimycin A and oligomycin treatment induced insulin resistance at the level of glucose and palmitate uptake in all three study groups while, at the level of glycogen synthesis, insulin resistance was only seen in lean myotubes. Primary insulin resistance in diabetic myotubes was significantly worsened at the level of glucose and lipid uptake. The present study is the first convincing data linking functional mitochondrial impairment per se and insulin resistance. Taken together functional mitochondrial impairment could be part of the pathophysiology of insulin resistance in vivo.
为了更好地理解线粒体功能降低对胰岛素抵抗和细胞代谢发展的影响，从瘦人、肥胖者和2型糖尿病患者中建立人肌管，并使其暴露于线粒体抑制剂，这些抑制剂分别影响电子传递链（抗霉素A）、ATP合酶（寡霉素）或呼吸解偶联（2,4-二硝基苯酚）。直接抑制电子传递链或ATP合酶后，葡萄糖摄取和乳酸生成增加，糖原合成减少，脂质和葡萄糖氧化减少，脂质摄取不变。呼吸解偶联期间的代谢表型与上述情况相似，只是葡萄糖和棕榈酸氧化增加。抗霉素A和寡霉素处理在所有三个研究组的葡萄糖和棕榈酸摄取水平上诱导胰岛素抵抗，而在糖原合成水平上，仅在瘦人肌管中观察到胰岛素抵抗。糖尿病肌管中的原发性胰岛素抵抗在葡萄糖和脂质摄取水平上显著恶化。本研究是将功能性线粒体损伤本身与胰岛素抵抗联系起来的首个有说服力的数据。综上所述，功能性线粒体损伤可能是体内胰岛素抵抗病理生理学的一部分。
