Mechanisms of Inonotus obliquus (Fr.) Pilát polysaccharides in ameliorating lipid-induced skeletal muscle insulin resistance via PI3K/AKT and AMPK/ACC1/CPT1 signaling pathways

Abstract

Ethnopharmacological relevance: Inonotus obliquus (Fr.) Pilát, a traditional medicinal fungi, has been used to treat diabetes in China and Russia since the 16th century. Recent studies show Inonotus obliquus (Fr.) Pilát polysaccharides (IOP) have hypoglycemic and lipid-lowering effects in type 2 diabetes mellitus (T2DM) mice and can recover liver insulin resistance.

Aim of the study: This study aims to assess the effect of IOP and its mechanisms in ameliorating insulin resistance and lipid metabolism disorders in T2DM.

Materials and methods: The potential targets of IOP for T2DM were identified by network pharmacology and molecular docking. In vitro, an insulin resistance model in C2C12 cells was induced, and IOP's effects on glucose uptake, glycogen, lipid content, and lipid metabolism-related mRNAs were assessed. In vivo, a T2DM mice model was established. Blood glucose, lipids, glucose tolerance, and insulin sensitivity were evaluated. Histopathology was used to assess morphological changes in mice skeletal muscle. Western blotting was utilized to evaluate the expression levels of PI3K/AKT and AMPK/ACC1/CPT1 signaling pathway proteins both in vivo and in vitro.

Results: Network pharmacology results showed IOP and T2DM targets were enriched in PI3K/AKT, insulin resistance, and lipid metabolism pathways. Cell experiments showed IOP enhanced glucose uptake and glycogen content, reduced lipid content, and improved lipid deposition in insulin-resistant C2C12 cells. Animal experiments showed IOP improved hyperglycemia and hyperlipidemia, enhanced glucose tolerance and insulin sensitivity, and reduced insulin resistance in T2DM mice. Western blot showed IOP activated PI3K/AKT and AMPK/ACC1/CPT1 pathways, promoting GLUT4 expression and translocation, and GSK3β phosphorylation.

Conclusions: In summary, the results indicated that IOP was able to ameliorate lipid-induced skeletal muscle insulin resistance in T2DM. The mechanism may be related to the PI3K/AKT and AMPK/ACC1/CPT1 signaling pathways.

Keywords: AMPK signaling pathway; Inonotus obliquus (Fr.) Pilát polysaccharides; Insulin resistance; Lipid metabolism; PI3K/AKT signaling pathway; Skeletal muscle; Type 2 diabetes mellitus.