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Andrographis Paniculata Ameliorates Insulin Resistance in High Fat Diet-fed Mice and 3T3-L1 Adipocytes (P21-074-19).

Objectives
Previous studies have shown that Andrographis paniculata (AP) possesses antiinflammatory activity and is able to reduce blood glucose level in diabetes. The results suggested that AP reduced blood glucose level via activation of glucose transporter 4 (GLUT4) membrane translocation; however, the mechanism in adipocytes remained unclear. Proinflammatory cytokines have been shown to play a role in blood glucose dysregulation, which leads to hyperglycemia in vivo. The aims of the present study were to investigate the effects of bioactive compounds of AP on GLUT4 membrane translocation in 3T3-L1 cells and hyperglycemia in high fat diet-fed mice.


Methods
The ethanolic extract of AP (APE) was prepared and 14-deoxy-11,12-didehydroandrographolide (deAND) was purified from APE. The purity of deAND was identified by LC/MS, which showed the purity for deAND was 98%. The 6-weeks old C57BL/6JNarl mice were fed normal fat diet (ND, 12.1% kcal from fat), high fat diet (HFD, 60% kcal from fat), HFD plus 0.1% AND, 0.05% deAND, or 0.4% APE for 16 weeks. 3T3-L1 cells were treated with 10 ng/mL TNFα in the presence or absence of 20 μM AND, 20 μM deAND, or 100 μg/mL APE for 24 hours. The blood glucose and insulin levels were determined by commercial assay kits and the protein expression was assayed by Western blotting.


Results
HFD significantly induced hyperglycemia as compared with ND. Treatment with deAND and APE significantly decreased the fasting blood glucose and HOMA-IR as compared with HFD. TNFα, a proinflammatory cytokine, significantly inhibited glucose uptake in 3T3-L1 cells because impairment of IRS1-AKT-AS160 signaling pathway and GLUT4 membrane translocation. In contrast, treatment with AND, deAND, and APE attenuated the lower glucose uptake induced by TNFα. The protective effects of deAND and APE were associated with improvement of IRS1-AKT-AS160 signaling pathway, which resulted in more GLUT4 membrane translocation.


Conclusions
HFD induced hyperglycemia and elevated blood TNFα level in vivo. TNFα dysregulated insulin signaling pathway in vitro. Treatment with deAND and APE reversed defects in IRS1-AKT-AS160-GLUT4 signaling pathway induced by TNFα in 3T3-L1 cells, which accounted for the anti-diabetic effect of AP.


Funding Sources
This study was supported by Ministry of Science and Technology, Taiwan.