Mechanisms of muscle insulin resistance and the cross-talk with liver and adipose tissue

Abstract

Insulin resistance is a metabolic disorder affecting multiple tissues and is a precursor event to type 2 diabetes (T2D). As T2D affects over 425 million people globally, there is an imperative need for research into insulin resistance to better understand the underlying mechanisms. The proposed mechanisms involved in insulin resistance include both whole body aspects, such as inflammation and metabolic inflexibility; as well as cellular phenomena, such as lipotoxicity, ER stress, and mitochondrial dysfunction. Despite numerous studies emphasizing the role of lipotoxicity in the pathogenesis of insulin resistance, an understanding of the interplay between tissues and these proposed mechanisms is still emerging. Furthermore, the tissue-specific and unique responses each of the three major insulin target tissues and how each interconnect to regulate the whole body insulin response has become a new priority in metabolic research. With an emphasis on skeletal muscle, this mini-review highlights key similarities and differences in insulin signaling and resistance between different target-tissues, and presents the latest findings related to how these tissues communicate to control whole body metabolism.

Keywords: adipose tissue; insulin resistance; lipotoxicity; liver; mitochondrial dysfunction; skeletal muscle.

FIGURE 1

Overview of possible mechanisms leading to insulin resistance. Impaired mitochondrial functioning is a suggested mechanism through which insulin resistance develops. Several factors have been implicated in the development of mitochondrial dysfunction. Some of the most reported factors include: (a) an increased production of reactive oxidative species (ROS). ROSs are necessary by‐products of mitochondrial energy metabolism; however, if their production is not adequately coupled by intracellular antioxidants, then oxidative damage to mitochondrial DNA (mtDNA) can occur. (b) Impaired glucose oxidation and fatty acid oxidation may result from metabolic inflexibility, which is commonly described as an inability to adapt fuel oxidation to fuel availability. Ultimately, these events may lead to both the development of ROS and ectopic lipid accumulation, resulting in mitochondrial damage and removal through mitophagy pathways. Further investigation on the genes involved in mitophagy (i.e., Bnip3, Nix, Fundc1) may allow the discovery of pathways that explain the correlation between mitochondrial dysfunction and insulin resistance in adipose, hepatic, and skeletal muscle tissue. (c) Endoplasmic Reticulum (ER) stress is also involved in the pathogenesis of mitochondrial dysfunction. Lipotoxicity and glucotoxicity can induce ER stress, which may trigger an adaptive signaling pathway, known as the unfolded protein response (UPR). If ER stress fails to be relieved by this UPR, then this can lead to the provocation of both mitochondrial dependent and independent cell death pathways. Together, the ability of the mitochondria to respond to metabolic disruptions is essential for healthy cellular bioenergetics, and interference with this process may prompt unregulated mitochondrial biogenesis and mitophagy, thus contributing to insulin resistance. This figure was created using Servier Medical Art (available at https://smart.servier.com/) and PAGES software.

FIGURE 2

Overfed state and insulin resistance as central regulators in tissue‐crosstalk. An increase in adipokines causes augmentation in the inflammatory response and recruitment of macrophages and cytokines around dead adipocytes to discard them. The inflammatory mediators, tumor necrosis factor (TNF)‐⍺ or interleukin‐1 (IL‐1)‐β increase lipolysis and inhibit insulin receptor (INSR), therefore, impairing insulin signaling. Lipolysis is activated by protein kinase A (PKA) signaling, and, in a fed state, insulin activates Akt2 signaling, which via unknown mechanisms activates phosphodiesterase 3 (PDE3) and inhibits PKA in order to suppress lipolysis. However, during adipose tissue insulin resistance, there is a decrease in Akt2 phosphorylation, contributing to sustained lipolysis activation. As a result, non‐esterified fatty acid (NEFA) production and circulating fatty acids are increased, which are uptake by the liver and muscle, contributing to ectopic lipid accumulation in both tissues. Intrahepatic lipid accumulation triggers activation of the diacylglycerol (DAG)/protein kinase C (PKC)ε axis. PKCε directly phosphorylates and inhibits insulin receptor (INSR) at Thr1160, impairing insulin signaling. As a result, gluconeogenesis is increased, as insulin suppression of gluconeogenesis mediator, forkhead box protein 01 (FOXO1), is impaired. Furthermore, in a chronic overnutrition state, de novo lipogenesis (DNL) is increased, concurrent with its mediators mTORC1 and SREBP‐1c. Even though activation of SREBP‐1c by INSR is impaired in hepatic insulin resistance, other inputs such as amino‐acid mediated mTORC1 activation can increase the lipogenic flux. Additionally, a chronic increase in lipolysis contributes to IMCL accumulation and lipid‐induced insulin resistance. In contrast to the liver, in the skeletal muscle, lipid‐induced insulin resistance is initiated upon activation of the DAG‐PKCθ axis and inhibition of both phosphoinositide‐3 kinase (PI3k) and phosphorylation of IRS1. As a result, insulin signaling is impaired, preventing glucose transporter (GLUT)4 translocation to the plasma membrane and glucose uptake. As a compensatory mechanism during an overfed state, FGF21 plays a role as a hepatokine, adipokine, and myokine controlling insulin sensitivity in insulin‐resistant animals. Similarly, GFD15 is selectively upregulated as a stress response mechanism during high‐fat feeding, especially in liver and adipose tissue. This figure was created using Servier Medical Art (available at https://smart.servier.com/) and PAGES software.