Bengal Eyal, Aviram Sharon
Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, P.O. Box 9649, Bat Galim, Haifa 31096, Israel.
Cells. 2025 Aug 18;14(16):1277. doi: 10.3390/cells14161277.
Type 2 diabetes (T2D), a growing global health concern, is closely linked to obesity and sedentary behavior. Central to its development are insulin resistance and impaired glucose metabolism in peripheral tissues, particularly skeletal muscle, which plays a key role in energy expenditure, glucose uptake, and insulin sensitivity. Notably, increased accumulation of lipid metabolites in skeletal muscle is observed both in endurance exercise-associated with improved insulin sensitivity-and in high-fat diets that induce insulin resistance. The review examines the contrasting metabolic adaptations of skeletal muscle to these opposing conditions and highlights the key signaling molecules involved. The focus then shifts to the role of the stress kinase p38α mitogen-activated protein kinase (MAPK) in skeletal muscle adaptation to overnutrition and endurance exercise. p38α enhances mitochondrial oxidative capacity and regulates nutrient utilization, both critical for maintaining metabolic homeostasis. During exercise, it cooperates with AMP-activated protein kinase (AMPK) to boost glucose uptake and fatty acid oxidation, key mechanisms for improving insulin sensitivity. The co-activation of p38α and AMPK in skeletal muscle emerges as a promising therapeutic avenue to combat insulin resistance and T2D. The review explores strategies for selectively enhancing p38α activity in skeletal muscle. In conclusion, it advocates a comprehensive approach to T2D prevention and treatment, combining established caloric intake-reducing therapies, such as GLP-1 receptor agonists, with interventions aimed at increasing energy expenditure via activation of p38α and AMPK signaling pathways.
2型糖尿病（T2D）是一个日益引起全球健康关注的问题，与肥胖和久坐行为密切相关。其发病的核心是胰岛素抵抗以及外周组织，特别是骨骼肌中葡萄糖代谢受损，而骨骼肌在能量消耗、葡萄糖摄取和胰岛素敏感性方面起着关键作用。值得注意的是，在与胰岛素敏感性改善相关的耐力运动以及诱导胰岛素抵抗的高脂饮食中，均观察到骨骼肌中脂质代谢产物的积累增加。本综述探讨了骨骼肌对这些相反状况的不同代谢适应性，并强调了其中涉及的关键信号分子。随后重点转向应激激酶p38α丝裂原活化蛋白激酶（MAPK）在骨骼肌适应营养过剩和耐力运动中的作用。p38α增强线粒体氧化能力并调节营养物质利用，这两者对于维持代谢稳态都至关重要。在运动过程中，它与AMP活化蛋白激酶（AMPK）协同作用以促进葡萄糖摄取和脂肪酸氧化，这是改善胰岛素敏感性的关键机制。骨骼肌中p38α和AMPK的共同激活成为对抗胰岛素抵抗和T2D的一条有前景的治疗途径。本综述探索了选择性增强骨骼肌中p38α活性的策略。总之，它提倡一种综合的T2D预防和治疗方法，将已有的减少热量摄入的疗法，如胰高血糖素样肽-1受体激动剂，与旨在通过激活p38α和AMPK信号通路来增加能量消耗的干预措施相结合。
