Antidiabetic Effect Of Xanthones From Garcinia Xanthochymus And Its Mechanism

To furtherdevelop and utilize traditional medicine plants, xanthones isolated from Garcinia xanthochymus were studied to explore their effect on Type 2 Diabetes mellitus?T2DM?.Five new xanthones compounds isolated from Garcinia xanthochymus were studied. A reliable insulin resistance cell model was established by treating HepG2 cells with high concentration of insulin. Cell survival rate was measured by MTT assay. Compounds 1, 2, 5(50 ?mol·L^-1,100 ?mol·L^-1,200 ?mol·L^-1,400 ?mol·L^-1), and Compound 3,4(25 ?mol·L^-1,50 ?mol·L^-1,100 ?mol·L^-1,200 ?mol·L^-1) were used to test their effect on HepG2 viability. Result showed that cell survival rate reached about 85% in 25 ?mol·L^-1 of Compound 1-5. Therefore, 6.25²5 ?mol·L^-1 were used as the experimental concentration range of these compounds.The effect of Compounds 1⁵ on glucose consumption of HepG2/IR cells were studied with the method of glucose oxidizes peroxides?GOD-POD?. Results showed that 3 of the 5 xanthones?Compounds 1, 3 and 4? isolated from Garcinia xanthochymus could promote glucose consumption could significantly improve the glucose consumption on HepG2/IR cells in a dose-dependent manner, while Compounds 2 and 5 did not. The glucose consumption for Compounds 1 group(25 ?mol·L^-1 and 12.5 ?mol·L^-1) increased to 8.15± 0.04 mmol·L^-1 and 7.56 ± 0.20 mmol·L^-1, which were higher than metformin group?***P<0.001?. All concentrations of Compound 3 showed stronger promotion effect on glucose consumption than metformin group?***P<0.001?. Compound 4 also showed activity of improving glucose consumption in Hep2/IR. In conclusion, xanthones isolated from Garcinia xanthochymus plays an important role in improving carbohydrate metabolism.To explore the mechanism of glucose metabolism promotion by xanthones compound from the Garcinia xanthochymus, the related signal transduction pathway were explored using another xanthones isolated from Garcinia xanthochymus, 12b-hydroxy-des-D-garcigerin A?DGA?. The effect of DGA on the glucose consumption, the bioactivity of hexokinase?HK? and pyruvate kinase?PK?, the mRNA expression of Insulin receptor?InsR?, Insulin receptor substrate 1?IRS-1? and phosphatidyl inositol 3-kinase?PI3-K?, and the protein expression of InsR, IRS-1, PI3-K, AKT, AMPK, p-AMPK?Thr172? in HepG2/IR cell were studied. It was found that DGA could significantly promote glucose consumption in HepG2/IR. DGA could also enhance bioactivity of HK and PK in HepG2/IR in a dose-response manner. High concentrations(25 ?mol ? L^-1) of the DGA could significantly increase the mRNA expression of InsR in a dose-dependent manner; in concentrations 12.5?mol ? L^-1 and 25 ?mol ? L^-1, DGA also could stimulate the mRNA expression of IRS-1; DGA tretament(12.5?mol ? L^-1 and 25 ?mol ? L^-1) could also significantly increase the mRNA expression of PI3-K. In addition, DGA could promote the expression of the proteins of InsR, p-IRS-1, p-PI3-K, p-AKTser473, However, DGA had no impact on the phosphorylation of AMPK?p-AMPK?. It suggested that DGA could stimulate the gloucose comsumption of HepG2/IR via InsR/IRS-1/PI3K/AKT pathway.