Pro-inflammatory cytokines interfere with blood glucose homeostasis, which leads to hyperglycemia. Andrographis paniculata (AP) has been shown to possess anti-inflammatory activity and to reduce blood glucose levels in diabetes. The two major bioactive diterpenoids in AP, andrographolide (AND) and 14-deoxy-11,12-didehydroandrographolide (deAND), have potent anti-inflammatory activity. We studied whether APE (an ethanolic extract of AP), AND, and deAND could improve a high-fat diet (HFD)-induced hyperglycemia in vivo and TNF[Formula: see text]-induced impairment of insulin signaling in vitro. Male C57BL/6JNarl mice were fed a normal diet (ND) or the HFD, and the fatty mice were treated with APE, deAND, or AND for 16 weeks. 3T3-L1 cells were used to study the underlying mechanisms by which APE, deAND, or AND attenuated TNF[Formula: see text]-induced insulin resistance. The HFD significantly induced obesity, hyperglycemia, insulin resistance, and inflammation, whereas APE and deAND significantly ameliorated HFD-induced obesity, hyperglycemia, insulin resistance, and TNF[Formula: see text] production. The HFD significantly impaired insulin signaling by decreasing the protein expression of p-IRS1 tyr632 and p-AKT ser473, as well as the membrane translocation of GLUT4 in response to insulin stimulation in epididymal adipose tissue. HFD-impaired the membrane translocation of GLUT4 was significantly reversed by deAND and APE. In addition, deAND and APE markedly reversed the detrimental effect of TNF[Formula: see text] on the insulin signaling pathway and glucose uptake in 3T3-L1 cells. Despite no significant positive effect on p-AS160, a trend for recovery by deAND and APE was observed. These results suggest that deAND and APE protect against HFD-induced insulin resistance by ameliorating inflammation-driven impairment of insulin sensitivity.
Keywords: 14-Deoxy-11,12-didehydroandrographolide (deAND); Andrographis paniculata Ethanolic Extract (APE); Andrographolide (AND); Inflammation; Insulin Resistance; Tumor Necrosis Factor Alpha (TNF[Formula: see text]).