Exploring the Therapeutic Mechanism of Jiangtang Sanhao Formula in Alleviating Insulin Resistance in Skeletal Muscle Cells: Involvement of AMPK/SIRT1/PGC-1α pathway？

Abstract Insulin resistance (IR) in skeletal muscle is a well-documented pathologic characteristic in the development of type 2 diabetes mellitus (T2DM), with GLUT4 being a key protein involved in this process. Jiangtang Sanhao formula, (JTSHF), a proven effective prescription for treating T2DM in clinic, has been shown to have a beneficial effect on alleviation of skeletal muscle IR. However, the underlying mechanism still need to be explored. Herein, we investigated the potential benefits and mechanism of JTSHF-containing serum in combating IR induced by palmitate in C2C12 skeletal muscle cells. The results demonstrated that JTSHF-containing serum significantly enhanced glucose consumption and uptake in IR-C2C12 cells at noncytotoxic concentration. Moreover, the JTSHF-containing serum reduced the malondialdehyde level and increase superoxide dismutase activity. Further investigations showed the function of JTSHF-containing serum in up-regulating the expression of key factors involved in glucose transport and metabolism, including GLUT4, phosphorylated AMPKα, SIRT1, PGC-1α, PPARα, PPARγ, and UCP3, as well as GLUT4 translocation. Notably, these positive effects were substantially diminished when we used an AMPK inhibitor, named Compound C, suggesting that AMPK/SIRT1/PGC-1α signaling pathway may be involved in JTSHF’s ability to rescue palmitate-induced reductions in GLUT4 expression and translocation in IR-C2C12 cells. In summary, our study provides evidence that JTSHF may effectively regulate GLUT4 and counteracte IR in skeletal muscle cells, and it highlights the potential involvement of the AMPK/SIRT1/PGC-1α signaling pathway in mediating these beneficial effects.