Zapata Bustos Rocio, Coletta Dawn K, Galons Jean-Philippe, Davidson Lisa B, Langlais Paul R, Funk Janet L, Willis Wayne T, Mandarino Lawrence J
Division of Endocrinology, Department of Medicine, The University of Arizona, Tucson, AZ, United States.
Center for Disparities in Diabetes, Obesity, and Metabolism, University of Arizona, Tucson, AZ, United States.
Front Physiol. 2023 Jul 7;14:1208186. doi: 10.3389/fphys.2023.1208186. eCollection 2023.
Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔG) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. After showing calibrated P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO ( = 0.001) and the 2) slope of the relationship of ΔG with the rate of oxidative phosphorylation ( = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R = 0.55, = 0.001). Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔG, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content can explain fractional fat oxidation during mild exercise.
许多研究人员试图确定导致肌肉胰岛素抵抗变化的分子本质，但分子方法可能没有考虑到肌肉的整体生理背景。由于ATP的能量状态（ΔG）可能会影响胰岛素刺激的耗能过程的速率，因此开展了本研究，以确定骨骼肌的热力学状态是否能部分独立于分子变化来解释胰岛素敏感性和燃料选择。对16名志愿者使用磷磁共振波谱（P-MRS）结合葡萄糖钳夹、运动研究、肌肉活检和蛋白质组学来测量胰岛素敏感性、热力学变量、线粒体蛋白含量和有氧能力。在证明校准后的P-MRS测量结果符合肌肉非平衡热力学的线性电路模型后，我们将这些测量结果用于对胰岛素刺激的葡萄糖处置和燃料氧化速率的多元逐步回归分析。多元线性回归分析表明，胰岛素敏感性53%的变异可由以下因素解释：1）VO₂（P = 0.001）和2）ΔG与氧化磷酸化速率关系的斜率（P = 0.007）。该斜率代表线性模型中的电导率（线粒体的功能含量）。蛋白质组学测得的线粒体蛋白含量是轻度运动期间脂肪氧化分数的独立预测因子（R = 0.55，P = 0.001）。较高的线粒体功能含量与骨骼肌维持更大ΔG的能力有关，这可能导致胰岛素刺激过程的速率更快。线粒体蛋白含量可以解释轻度运动期间的脂肪氧化分数。
