胰岛素抵抗（IR）是2型糖尿病等发病基础。申请人前期2个研究分别显示:中等强度持续有氧运动（MCT）上调小鼠骨骼肌AMPK表达和线粒体自噬，改善IR；高强度间歇运动（HIT）比MCT更显著改善患者糖脂代谢。目前有关HIT改善IR是否优效于MCT仍存争议，且机制不明。有报道AMPK表达与运动强度有关，并参与线粒体自噬调节。据此提出假说：HIT比MCT更有效刺激骨骼肌AMPKα2表达，上调PINK1/Parkin介导的线粒体自噬，提高线粒体功能，改善IR。本研究拟以高脂饲养诱导AMPK激酶失活转基因小鼠IR，予8周HIT或MCT干预，探讨两种运动形式改善IR的作用及其通过骨骼肌AMPKα2作用于PINK1/Parkin介导的线粒体自噬调节线粒体功能和IR；并应用C2C12骨骼肌细胞及siRNA技术进一步探讨AMPKα2/PINK1/Parkin通路与IR的关系，为IR运动治疗方案选择提供依据。

Insulin resistance (IR) is the primary pathogenesis of a multitude of diseases, such as type 2 diabetes mellitus (T2DM) and metabolic syndrome. We have previously demonstrated that moderate-intensity continuous training (MCT) can elevate the expression of AMPK mRNA and protein, activate mitophagy in skeletal muscle, and improve IR via mice model; recently, two retrospective cohort studies performed by our team additionally showed that high-intensity interval training (HIT) elicited greater improvements in abdominal obesity and impaired fasting blood glucose, two indicators of IR, in patients with metabolic syndrome and coronary vascular disease compared to MCT. However, there is a prodigious dispute on whether HIT is more effective than MCT in reducing IR, and the mechanism whereby HIT and MCT reduce IR remains unclear. Previous studies revealed that AMPK plays a key role as a master regulator of cellular energy homeostasis, and participates in regulating autophagy; the amount of exercise induced-expression of AMPK is closely associated with the exercise intensity. Based on the evidence described above, we hypothesize that HIT can lead to superior improvements in IR compared to MCT by significantly augmenting mitochondrial function in skeletal muscle that results from the better efficacy of HIT on activating AMPKα2, followed by activation of PINK1/Parkin pathway-mediated mitophagy. To attest this hypothesis, the present study plans to firstly apply AMPK kinase-dead transgenic mice with IR induced by high-fat feeding, and with the treatment of consecutive eight weeks of MCT or HIT, to determine the efficacy of MCT and HIT on improving IR, and to explore the role of AMPK α2 in both MCT and HIT on regulating PINK1/Parkin pathway, mitophagy, mitochondrial function, and IR. Secondly, we plan to employ techniques of small interfering RNA and transfection in C2C12 mouse myoblast cell line with IR induced by palmitic acid to explore the relationship between AMPK α2/PINK1/Parkin pathway and IR. The completion of this study will provide experimental evidence for patients with IR and IR-related disease to choose a better exercise regimen between MCT and HIT.