Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes

Abstract

Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low-grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass.

Keywords: insulin resistance; interorgan crosstalk; muscle atrophy; obesity.

Figure 1

Individuals with obesity and older individuals experience an increase in lipid deposition in visceral and ectopic fat depots. This may affect metabolism in key organs including adipose tissue, liver, and skeletal muscle, which may result in the development of muscle insulin resistance and a decrease in muscle mass. Patients often enter a vicious cycle in which decreased activity levels and increased incidence of falls lead to more muscle loss, a deterioration in quality of life, and premature death. Exercise (E) is an effective strategy to reduce obesity and improve lipid metabolism. It will ameliorate muscle mass loss and the development of insulin resistance, and it will reduce the incidence of falls and improve quality of life

Figure 2

Schematic overview of interorgan crosstalk between adipose tissue, liver, and skeletal muscle, leading to muscle insulin resistance and decrease of muscle mass. Increased lipid deposition in visceral and ectopic fat depots include skeletal muscle and liver. Increased lipid levels may lead to a change in the secretion pattern of cytokines, which may lead to muscle insulin resistance and a decrease in muscle mass via interorgan crosstalk. Lipids and cytokines may also affect mitochondrial function and vascularization in skeletal muscle, which contributes to the problem. Full arrows indicate pathways discussed in this review. Broken arrows indicate pathways outside the scope of this review