Skeletal muscle from sedentary obese patients is characterized by depressed electron transport activity, reduced expression of genes required for oxidative metabolism, altered mitochondrial morphology and lower overall mitochondrial content. These findings imply that obesity, or more likely the metabolic imbalance that causes obesity, leads to a progressive decline in mitochondrial function, eventually culminating in mitochondrial dissolution or mitoptosis. A decrease in the sensitivity of skeletal muscle to insulin represents one of the earliest maladies associated with high dietary fat intake and weight gain. Considerable evidence has accumulated to suggest that the cytosolic ectopic accumulation of fatty acid metabolites, including diacylglycerol and ceramides, underlies the development of insulin resistance in skeletal muscle. However, an alternative mechanism has recently been evolving, which places the etiology of insulin resistance in the context of cellular/mitochondrial bioenergetics and redox systems biology. Overnutrition, particularly from high-fat diets, generates fuel overload within the mitochondria, resulting in the accumulation of partially oxidized acylcarnitines, increased mitochondrial hydrogen peroxide (H₂O₂) emission and a shift to a more oxidized intracellular redox environment. Blocking H₂O₂ emission prevents the shift in redox environment and preserves insulin sensitivity, providing evidence that the mitochondrial respiratory system is able to sense and respond to cellular metabolic imbalance. Mitochondrial H₂O₂ emission is a major regulator of protein redox state, as well as the overall cellular redox environment, raising the intriguing possibility that elevated H₂O₂ emission from nutrient overload may represent the underlying basis for the development of insulin resistance due to disruption of normal redox control mechanisms regulating protein function, including the insulin signaling and glucose transport processes.

久坐的肥胖患者的骨骼肌的特征是电子传递活性降低、氧化代谢所需基因表达减少、线粒体形态改变和线粒体总含量降低。这些发现意味着肥胖，或者更可能是导致肥胖的代谢失衡，导致线粒体功能进行性下降，最终导致线粒体溶解或有丝分裂。骨骼肌对胰岛素的敏感性降低是与高膳食脂肪摄入和体重增加相关的最早疾病之一。大量证据表明，包括甘油二酯和神经酰胺在内的脂肪酸代谢物的细胞溶质异位积累是骨骼肌胰岛素抵抗发展的基础。然而，最近正在发展一种替代机制，它将胰岛素抵抗的病因置于细胞/线粒体生物能量学和氧化还原系统生物学的背景下。营养过剩，特别是来自高脂肪饮食的营养过剩，会在线粒体内产生燃料过载，导致部分氧化的酰基肉碱的积累，线粒体过氧化氢（H₂ O ₂ ) 排放和向更氧化的细胞内氧化还原环境的转变。阻断 H ₂ O ₂排放可防止氧化还原环境的变化并保持胰岛素敏感性，从而证明线粒体呼吸系统能够感知和响应细胞代谢失衡。线粒体 H ₂ O ₂排放是蛋白质氧化还原状态以及整个细胞氧化还原环境的主要调节剂，这增加了 H ₂ O _{2升高的有趣可能性。}由于调节蛋白质功能的正常氧化还原控制机制（包括胰岛素信号传导和葡萄糖转运过程）的破坏，营养超负荷的排放可能代表了胰岛素抵抗发展的潜在基础。