Down-regulation of betatrophin enhances insulin sensitivity in type 2 diabetes mellitus through activation of the GSK-3β/PGC-1α signaling pathway.

OBJECTIVE

The incidence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising. Accumulating evidences have noted the significant role of betatrophin in the regulation of lipid metabolism and glucose homeostasis. In our study, we tried to figure out the underlying mechanism of betatrophin in insulin resistance (IR) in type 2 diabetes mellitus (T2DM).

METHODS

First, fasting serum betatrophin, fasting blood glucose (FBG), insulin, total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were detected in T2DM children. The homeostasis model assessment of insulin resistance (HOMA-IR), Gutt insulin sensitivity index (ISI) and Matsuda insulin sensitivity index (ISI) were calculated. A T2DM-IR mouse model was induced by high-fat diet, with the expression of GSK-3β and PGC-1α detected. Besides, HepG2 cells were induced by a high concentration of insulin to establish an IR cell model (HepG2-IR). The cell viability, glucose consumption, liver glycogen content, inflammation, and fluorescence level of GSK-3β and PGC-1α were analyzed.

RESULTS

Betatrophin was highly expressed in serum of T2DM children and was positively correlated with FBG, insulin, TC, TG, LDL-C and HOMA-IR, while negatively correlated with ISI and ISI. Betatrophin and GSK-3β in the liver tissues of T2DM-IR mice were increased, while the PGC-1α expression was decreased. Betatrophin expression was negatively correlated with PGC-1α and positively correlated with GSK-3β. Silencing of betatrophin enhanced insulin sensitivity through the activation of GSK-3β/PGC-1α signaling pathway. In vitro experiments also found that silencing of betatrophin promoted glucose consumption and glycogen synthesis while inhibited inflammation.

CONCLUSION

Our findings concluded that silencing of betatrophin could enhance insulin sensitivity and improve histopathological morphology through the activation of GSK-3β/PGC-1α signaling pathway.