Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy

Abstract

Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.

Keywords: disuse muscle atrophy; muscle fibers; muscle loss; sarcopenia; type 2 diabetes mellitus.

Figure 1

Comparison of the Potential Mechanisms of Sarcopenia and Disuse Muscle Atrophy. ① Aging leads to nutrient deficiency, chronic inflammation, endocrine imbalance, and oxidative stress, inhibiting mTOR pathway synthesis of muscle protein; ② Chronic inflammation and oxidative stress caused by aging promote FOXO3 leading to muscle protein degradation; ③ Reduced muscle stimulation caused by disuse results in hormone (such as testosterone) imbalance, chronic low-grade inflammation state causing muscle protein degradation through FOXO1; ④ FOXO1 can inhibit mTOR affecting muscle protein synthesis. ROS, Reactive Oxygen Species; FOXO, Forkhead Box O; PI3K, Phosphoinositide 3-kinase; AKT, Protein Kinase B; mTOR, Mammalian Target of Rapamycin.

Figure 2

The possible effects of FOXO1 and FOXO3 on different types of muscle atrophy. T2DM, Type 2 Diabetes Mellitus; FOXO, Forkhead Box O.

Figure 3

The possible endocrine mechanisms of muscle wasting associated with T2DM. ① Insulin, IGF-1, and other factors can activate the mTOR signaling pathway to promote muscle protein synthesis, thereby enhancing muscle growth and repair; ② Insulin and GH can inhibit the impact of FOXO on muscle protein degradation; ③ GH activates downstream mTOR through the Akt signaling pathway mediated by IGF-I, promoting protein synthesis; ④ Inflammatory conditions in T2DM induce insulin resistance, inhibiting protein synthesis as in mechanism①; ⑤ Inflammatory conditions in T2DM induce IGF-1 resistance, inhibiting protein synthesis as in mechanism①; ⑥Elevated levels of cortisol in T2DM suppress muscle protein synthesis by inhibiting the mTOR signaling pathway; ⑦ Inflammation triggers cell autophagy via the FOXO pathway leading to muscle protein degradation; ⑧ Inflammation activates FOXO proteins leading to muscle protein degradation. T2DM, Type 2 Diabetes Mellitus; mTOR, Mammalian Target of Rapamycin; FOXO, Forkhead box O; Akt, Protein Kinase B; PI3K, Phosphoinositide 3-kinase; IGF-I, Insulin-like Growth Factor-I; GH, Insulin and Growth Hormone; IL-6, Interleukin-6.