综述：2型糖尿病肌肉萎缩机制：调节肌肉蛋白质合成与分解失调的因素

《Applied Physiology, Nutrition, and Metabolism》：Mechanisms of muscle atrophy in type 2 diabetes mellitus: factors dysregulating muscle protein synthesis and breakdown

本综述深入探讨2型糖尿病（T2DM）中骨骼肌萎缩的调控机制，聚焦胰岛素抵抗对肌肉蛋白质合成（MPS）与分解（MPB）的关键影响。文章系统分析了胰岛素（Insulin）和亮氨酸（Leucine）信号通路失调的核心作用，并指出整合实验与计算模型的研究策略对开发靶向干预措施的重要意义。

　　

Abstract

Type 2 diabetes mellitus (T2DM) poses a growing global health challenge, with its less recognized complication—accelerated skeletal muscle loss—significantly impairing patients' quality of life and exacerbating disease progression. Central to this process is insulin resistance, which disrupts the delicate balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Insulin normally promotes anabolic processes via the PI3K/Akt/mTOR signaling pathway, while leucine acts as a potent activator of mTOR complex 1 (mTORC1). In T2DM, impaired insulin- and leucine-mediated signaling leads to reduced MPS and heightened MPB, though the exact molecular interplay remains complex due to numerous dysregulated components.

Key Regulatory Pathways

The PI3K/Akt pathway serves as a critical node in insulin signaling. Insulin binding to its receptor activates IRS-1, which in turn recruits and activates PI3K, generating PIP₃ to phosphorylate Akt. Activated Akt suppresses the FOXO transcription factors that upregulate atrophy-related genes (e.g., Atrogin-1 and MuRF-1), while simultaneously stimulating mTORC1 to enhance protein synthesis. In T2DM, defects in IRS-1 phosphorylation and elevated inflammatory cytokines (e.g., TNF-α) inhibit this pathway, leading to unchecked proteolysis and diminished synthesis.

Leucine, a branched-chain amino acid, potentiates mTORC1 activation independently of insulin. It is sensed by intracellular transporters and sensors like Sestrin2, which disinhibits mTORC1 when leucine is abundant. T2DM may impair leucine sensing or availability, further compromising anabolic signals.

Experimental and Computational Insights

Human and animal models indicate that hyperinsulinemia often fails to normally stimulate MPS in T2DM, highlighting profound anabolic resistance. Proteomic and transcriptomic studies reveal upregulation of ubiquitin-proteasome and autophagy-lysosomal systems in atrophying muscle. Computational models help integrate multi-omics data to map dynamic interactions between nutrients, hormones, and proteolytic pathways, offering predictive insights into disease progression.

Conclusions and Future Directions

The causal links between T2DM and muscle atrophy involve multifaceted disruptions in anabolic and catabolic signaling. Key underexplored areas include the temporal sequence of these disruptions and their sex-specific differences. Combining targeted experiments with prospective human studies and in silico modeling will enable precise characterization of mechanisms and foster development of personalized therapies to combat muscle wasting in T2DM.