The Improvement And Mechanism Of Celastrol In Hepatic Insulin Resistance

Nowadays, type2diabetes is a serious threat to human health. Insulin resistance is one of the main reasons for type2diabetes and a series of complications of diabetes. So there is an important clinical significance to find a safe and effective drug to alleviate insulin resistance. Celastrol is a remedial ingredient isolated from the root extracts of Tripterygium Wilfordi(Thunder of God vine), previous studies showed that celastrol exhibited anti-inflammatory, antioxidant and anticancer activities both in vivo and in vitro. Nowadays, more effects of celastrol were evaluated and reported. Recent study showed that celastrol can lower blood pressure values and attenuate hypertension-induced inflammatory. And there was also a report suggestted that celastrol can down-regulate blood glucose when attenuating diabetic nephropathy in db/db mice. These studies suggested that celastrol may also play an important role in metabolic disorders, such as diabetes. However, the detailed mechanism involved was still not clear and needed to be explored.In this study, db/db mice, a obesity and type2diabetes model, were treated with different doses of celatrol (0.2mg/kg,0.4mg/kg) for two weeks. It showed that celastrol attenuated Endoplasmic reticulum stress (ER Stress) in liver of db/db mice, decreased lipid accumulation induced by ER Stress, and then improved insulin sensitivity, significantly decreased blood glucose. Moreover, the effect of celastrol on palmitate induced insulin resistance in primary hepatocytes was further evaluated. In vitro experiment results suggested that celastrol can improve the insulin signaling pathway by increasing Akt phosphorylation and finally increase the glucose uptake and glycogen content.In conclusion, this study has first explored the effect and possible mechanism of how celastrol improves the insulin sensitivity in diabetic mice. Our results suggested that treatment of celastrol can decrease lipid accumulation through inhibiting the ER stress and then enhance insulin sensitivity, accelerate the glucose uptake and glycogen synthesis in liver, finally decrease glucose blood in db/db mice. Therefore, our study may suggest celastrol as a candidate for the treatment of type2diabetes in the future.