Data from: Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men

Insulin resistance is a well-known physiological adaptation to prolonged fasting in healthy skeletal muscle. Obesity is associated with insulin resistance and metabolic inflexibility in skeletal muscle, and a pronounced increase in the risk of metabolic complications. Under the hypothesis that the metabolic traits of insulin resistance associated with prolonged fasting are different from insulin resistance associated with obesity, we examined nine obese and nine lean participants during 12 and 72h of fasting, respectively. Insulin resistance in obese participants was associated with impaired insulin signaling, and reduced levels of glucose-6-phosphate and TCA-cycle intermediates. 72h of fasting in lean participants reduced insulin-stimulated glucose uptake to levels similar to obese participants fasted for 12h. This was associated with increased lipid oxidation, but not accumulation of diacylglycerol or acylcarnitines and impairment of insulin signaling. Prolonged fasting was associated with pronounced increases in β-hydroxybutyrate and β- hydroxybutyrylcarnitine levels in skeletal muscle suggesting augmented ketone body metabolism. Fasting induced insulin resistance may be a consequence of substrate competition. The underlying mechanism behind insulin resistance in obesity is thus not comparable to the physiological adaptations in skeletal muscle induced by prolonged fasting in lean participants.胰岛素抵抗（Insulin Resistance）是健康骨骼肌（Skeletal Muscle）对长期禁食的一种公认的生理性适应机制。肥胖与骨骼肌胰岛素抵抗及代谢灵活性受损相关，并会显著升高代谢并发症的发病风险。基于“长期禁食相关胰岛素抵抗的代谢特征与肥胖相关胰岛素抵抗存在差异”这一假说，我们分别对9名肥胖受试者与9名瘦体型受试者开展了12小时与72小时禁食状态下的检测。肥胖受试者的胰岛素抵抗与胰岛素信号通路受损、葡萄糖-6-磷酸（Glucose-6-Phosphate）及三羧酸循环（Tricarboxylic Acid Cycle, TCA）中间产物水平降低相关。瘦体型受试者经72小时禁食后，其胰岛素刺激下的葡萄糖摄取能力降至与禁食12小时的肥胖受试者相当的水平。该现象与脂质氧化增强相关，但未伴随二酰基甘油（Diacylglycerol, DAG）或酰基肉碱（Acylcarnitines）的蓄积，也未出现胰岛素信号通路受损。长期禁食会使骨骼肌内β-羟丁酸（β-Hydroxybutyrate）与β-羟丁酰肉碱（β-Hydroxybutyrylcarnitine）水平显著升高，提示酮体代谢增强。禁食诱导的胰岛素抵抗可能源于底物竞争。因此，肥胖相关胰岛素抵抗的潜在机制，与瘦体型受试者长期禁食诱导的骨骼肌生理性适应机制并不相同。