Neuregulin-1β increases glucose uptake and promotes GLUT4 translocation in palmitate-treated C2C12 myotubes by activating PI3K/AKT signaling pathway

Abstract

Insulin resistance (IR) is a feature of type 2 diabetes (T2DM) accompanied by reduced glucose uptake and glucose transporter 4 (GLUT4) translocation by skeletal muscle. Neuregulin-1β (NRG-1β) is essential for myogenesis and the regulation of skeletal muscle metabolism. Neuregulin-1β increases insulin sensitivity, promotes glucose uptake and glucose translocation in normal skeletal muscle. Here, we explored whether Neuregulin-1β increased glucose uptake and GLUT4 translocation in palmitate (PA)-treated C2C12 myotubes. After C2C12 myoblasts differentiated into myotubes, we used palmitate to induce cellular insulin resistance. Cells were incubated with or without Neuregulin-1β and glucose uptake was determined using the 2-NBDG assay. The expression level of glucose transporter 4 (GLUT4) was measured via immunofluorescence and Western blotting. MK2206, an inhibitor of AKT, was employed to reveal the important role played by AKT signaling in PA-treated C2C12 myotubes. We then established an animal model with T2DM and evaluated the effects of Neuregulin-1β on body weight and the blood glucose level. The GLUT4 level in the gastrocnemius of T2DM mice was also measured. NRG-1β not only increased glucose uptake by PA-treated myotubes but also promoted GLUT4 translocation to the plasma membrane. The effect of NRG-1β on PA-treated C2C12 myotubes was associated with AKT activation. In T2DM mice, Neuregulin-1β not only improved diabetes-induced weight loss and diabetes-induced hyperglycemia, but also promoted GLUT4 translocation in the gastrocnemius. In summary, Neuregulin-1β increased glucose uptake and promoted translocation of GLUT4 to the plasma membrane in PA-treated C2C12 myotubes by activating the PI3K/AKT signaling pathway.

Ginsenoside F4 Alleviates Skeletal Muscle Insulin Resistance by Regulating PTP1B in Type II Diabetes Mellitus

“…15 Insulin induces downstream IRS-1 phosphorylation by stimulating INSR phosphorylation on the cell surface of skeletal muscle, which subsequently activates the PI3K/AKT signaling pathway mediating GLUT4 membrane translocation. 31 Reduced GLUT4 translocation is the direct cause of insulin resistance, 19 and we found that F4-treated IR-L6 cells displayed a tremendous increase in glucose uptake and a significant increase in muscle glycogen content, as well as a rise in GLUT4 expression and membrane translocation in skeletal muscle cells. All these results suggest that F4 ameliorates insulin resistance in skeletal muscle.…”

“…Among the main target organs of insulin, skeletal muscle is responsible for the uptake and metabolism of up to 80% of postprandial glucose, indicating that it is necessary to regulate systemic glucose homeostasis . Insulin induces downstream IRS-1 phosphorylation by stimulating INSR phosphorylation on the cell surface of skeletal muscle, which subsequently activates the PI3K/AKT signaling pathway mediating GLUT4 membrane translocation . Reduced GLUT4 translocation is the direct cause of insulin resistance, and we found that F4-treated IR-L6 cells displayed a tremendous increase in glucose uptake and a significant increase in muscle glycogen content, as well as a rise in GLUT4 expression and membrane translocation in skeletal muscle cells.…”

Activation of POMC neurons to adiponectin participating in EA-mediated improvement of high-fat diet IR mice

“…Skeletal muscle is the main target of Adipo and a major location of AdipoR1. Although skeletal muscle is considered to be one of the targets of pharmacological treatment for IR or diabetes ( Dong et al, 2021 ; Wei et al, 2021 ; Yu et al, 2022 ), some studies have shown that acupuncture ST36 may stimulate skeletal muscle and improve the recovery of behavioral activity in rats subjected to cerebral ischemia or reperfusion injury ( Yang et al, 2022 ). Sun demonstrated that acupuncture at ST36 increased motor cortical excitation ( Sun et al, 2019 ).…”

Identification of Potential Mechanisms of Rk1 Combination with Rg5 in the Treatment of Type II Diabetes Mellitus by Integrating Network Pharmacology and Experimental Validation

“…Among the main target tissues of insulin resistance, skeletal muscles are responsible for ingesting and metabolizing over 80% of glucose, making it an important tissue for regulating glucose homeostasis [31]. Insulin stimulates the insulin receptor on the skeletal muscle cells, which subsequently activates the PI3K/Akt signaling pathway to mediate GLUT4 membrane translocation [32]. Reduction in GLUT4 was the direct cause of insulin resistance [33].…”