SHP2 knockdown ameliorates liver insulin resistance by activating IRS-2 phosphorylation through the AKT and ERK1/2 signaling pathways.

Diabetes is a chronic metabolic disease characterized by insulin resistance (IR). SHP2 has previously been identified as a potential target to reduce IR in diabetes. Here, we examined the effects of SHP2 on glucose consumption (GC), IR level, and the expression of IRS, AKT and ERK1/2 proteins in a cellular and animal model of diabetes. IR was induced in hepatocellular carcinoma (HCC) cells, and SHP2 was up- or down-regulated in cells. Diabetic rats were treated with SHP2 inhibitor. GC of cells， and the weight, total cholesterol (TC), triglycerides (TG), fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment-insulin resistance index (HOMA-IR) and insulin sensitivity (ISI) of the rats were analyzed. The levels of SHP2, the activation of insulin receptor substrate (IRS)-2, AKT and ERK1/2 in cells and rats were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot (WB). GC was reduced, but expression of SHP2 was enhanced in IR HCC cells. Phosphorylation of IRS-2 and AKT in IR HCC cells and diabetic rats was decreased, while phosphorylation of ERK1/2 was enhanced. In both the cell and animal model, SHP2 knockdown enhanced GC, ameliorated IR, activated IRS-2 and AKT, and inhibited ERK1/2 phosphorylation, in contrast to the effects of SHP2 overexpression. SHP2 knockdown may enhance GC and ameliorate IR through phosphorylation of IRS-2 via regulating AKT and ERK1/2 in liver.