Wang Jingxuan, Dai Lizhi, Yu Tong, Xiao Jianhua
Key Laboratory for Prevention and Control of Common Animal Diseases in General Higher Education Institutions of Heilongjiang Province, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
PLoS One. 2025 Jan 6;20(1):e0310458. doi: 10.1371/journal.pone.0310458. eCollection 2025.
This study aims to provide a theoretical foundation for the future management of diabetes at various stages induced by a high-fat diet. Specifically, it seeks to determine the appropriate pharmacological interventions for each phase of diabetes development and the targeted therapeutic directions at different stages of diabetes progression. This investigation employed C57BL6 mice as experimental subjects, successfully establishing an insulin resistance model through a 12-week high-fat diet. Clinical manifestations, weight, body composition, and overall health of each mouse group were observed on the first day of the 6th, 8th, 10th, and 12th week of high-fat feeding to analyze insulin resistance. Subsequently, open-field test of each mouse group, and histopathological changes in the skeletal muscle and myocardium of each mouse group, along with the detection of protein-level expression of relevant genes, were performed to assess alterations in mitochondrial energy metabolism during insulin resistance. This endeavor aims to contribute insights for future in-depth veterinary research. The outcomes demonstrated that a continuous 12-week high-fat diet successfully induced stable insulin resistance in C57BL6 mice. Following insulin resistance, the motor activity of mice decreased, gradual pathological damage and functional decline were observed in the skeletal muscle and myocardium. The insulin signaling pathway was inhibited, resulting in reduced glucose transport and increased gluconeogenesis. Additionally, mitochondrial dysfunction manifested as diminished ATP synthesis capacity, weakened mitochondrial biogenesis, reduced mitochondrial fusion, increased division, and diminished autophagy. Notably, during insulin resistance progression, skeletal muscles and myocardium in C57BL6 mice predominantly relied on glycolytic pathways for energy supply. In the early stages of insulin resistance, the glycogen synthesis pathway in C57BL6 mouse skeletal muscles was inhibited. Our findings underscore a distinct mechanism in skeletal muscle and myocardium that ensures the utilization of anaerobic fermentation to meet energy demands in instances of inadequate aerobic respiration (Fig 1).
本研究旨在为高脂饮食诱导的不同阶段糖尿病的未来管理提供理论基础。具体而言，它试图确定糖尿病发展各阶段的适当药物干预措施以及糖尿病进展不同阶段的靶向治疗方向。本研究以C57BL6小鼠作为实验对象，通过12周的高脂饮食成功建立了胰岛素抵抗模型。在高脂喂养的第6、8、10和12周的第一天观察每组小鼠的临床表现、体重、身体组成和整体健康状况，以分析胰岛素抵抗。随后，对每组小鼠进行旷场试验，并对每组小鼠的骨骼肌和心肌进行组织病理学变化分析，同时检测相关基因的蛋白水平表达，以评估胰岛素抵抗期间线粒体能量代谢的改变。这项工作旨在为未来深入的兽医研究提供见解。结果表明，连续12周的高脂饮食成功诱导了C57BL6小鼠稳定的胰岛素抵抗。胰岛素抵抗后，小鼠的运动活性下降，骨骼肌和心肌出现逐渐的病理损伤和功能衰退。胰岛素信号通路受到抑制，导致葡萄糖转运减少和糖异生增加。此外，线粒体功能障碍表现为ATP合成能力下降、线粒体生物发生减弱、线粒体融合减少、分裂增加和自噬减少。值得注意的是，在胰岛素抵抗进展过程中，C57BL6小鼠的骨骼肌和心肌主要依赖糖酵解途径供能。在胰岛素抵抗早期，C57BL6小鼠骨骼肌中的糖原合成途径受到抑制。我们的研究结果强调了骨骼肌和心肌中的一种独特机制，即在有氧呼吸不足的情况下确保利用无氧发酵来满足能量需求（图1）。
