The Vicious Cycle of Type 2 Diabetes Mellitus and Skeletal Muscle Atrophy: Clinical, Biochemical, and Nutritional Bases

Abstract

Today, type 2 diabetes mellitus (T2DM) and skeletal muscle atrophy (SMA) have become increasingly common occurrences. Whether the onset of T2DM increases the risk of SMA or vice versa has long been under investigation. Both conditions are associated with negative changes in skeletal muscle health, which can, in turn, lead to impaired physical function, a lowered quality of life, and an increased risk of mortality. Poor nutrition can exacerbate both T2DM and SMA. T2DM and SMA are linked by a vicious cycle of events that reinforce and worsen each other. Muscle insulin resistance appears to be the pathophysiological link between T2DM and SMA. To explore this association, our review (i) compiles evidence on the clinical association between T2DM and SMA, (ii) reviews mechanisms underlying biochemical changes in the muscles of people with or at risk of T2DM and SMA, and (iii) examines how nutritional therapy and increased physical activity as muscle-targeted treatments benefit this population. Based on the evidence, we conclude that effective treatment of patients with T2DM-SMA depends on the restoration and maintenance of muscle mass. We thus propose that regular intake of key functional nutrients, along with guidance for physical activity, can help maintain euglycemia and improve muscle status in all patients with T2DM and SMA.

Keywords: diabetes mellitus; malnutrition; muscle mass; muscle strength; obesity; sarcopenia; skeletal muscle atrophy.

Figure 1

The vicious cycle of type 2 diabetes mellitus and skeletal muscle atrophy. Insulin resistance is the common and central element governing the association between T2DM and muscle atrophy. Low skeletal muscle mass and poor quality of skeletal muscle tissue result in impaired glucose uptake and increased blood glucose levels. Sustained elevation of blood glucose can lead to cardiovascular complications, which further impair blood circulation and glucose disposal.

Figure 2

Biochemical mechanisms of impaired glucose uptake and metabolism in T2DM and its association with SMA. Alterations in the cellular and molecular mechanisms in a state of insulin resistance include inhibition of IRS-PI3K-AKT-mTOR signaling cascade, disruption of GLUT4 trafficking, low mitochondrial content, reduced ATP synthesis, excess oxidative stress, elevated production of lipid intermediates like DAG and ceramides as well as proinflammatory cytokines due to intramyocellular lipid deposition. In addition, the accumulation of AGEs induces changes in the myofibrillar protein structure. Abbreviations: IRS, Insulin Receptor Substrate; PI3K, Phosphoinositide 3-kinase; Akt, Ak strain transforming protein kinase; Glut 4, Glucose Transporter Type 4; AGEs, Advanced Glycation End products; ROS, Reactive Oxygen Species; DAG, Diacylglycerol. IL-6, Interleukin-6; TNF-α, Tumor Necrosis Factor-alpha; CRP, C-reactive protein; NFkB, nuclear factor kappa light chain enhancer of activated B cells.