Mixture of five herbal extracts ameliorates pioglitazone-induced aggravation of hepatic steatosis via activating the adiponectin receptor 2/AMP-activated protein kinase signal pathway in diabetic KKAy mice

4区 · 医学

Article

作者: Wang Dongchao ; Xu Tunhai ; Wang Haiyan ; Wu Xinli ; Qin Lingling ; Liu Tonghua ; Li Linyi ; Jiang Yueying

OBJECTIVETo assess the effect of a mixture of five herbal extracts (FT-5) on insulin resistance, glucose/lipid metabolism, hepatic steatosis, and to investigate whether the combination of FT-5 and pioglitazone would provide a robust effect on diabetes treatment, while may minimize undesirable side-effects of pioglitazone in diabetic Ay gene (KKAy) mice.METHODSSeven-week-old KKAy mice were randomly divided into five groups: control (CON) group, FT-5 (2.0 g/kg) group, pioglitazone (20 mg/kg) (PIO) group, pioglitazone (20 mg/kg) + FT-5 (2.0 g/kg) (P + F) group. Age-matched C57BL/6J mice were used as the control group. After seven weeks of continuous intragastric administration of medication, the glucose metabolism, insulin sensitivity and lipid metabolism of KKAy mice were evaluated by assessing the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), fasting serum insulin (FINS), insulin tolerance test (ITT), homeostasis model of assessment-insulin resistance index (HOMA-IR), total cholesterol (TC), total triglycerides (TG), and free fatty acids (FFA) in plasma and liver. Plasma and hepatic adiponectin were measured via enzyme-linked immunosorbent assays. Genes related to adipogenesis and lipolysis in white adipose tissues (WAT) and liver were examined by real-time polymerase chain reaction. Lipid metabolism-related protein expression in the liver of KKAy mice were detected by Western blotting.RESULTSPIO treatment remarkably improved insulin resistance. However, it also showed substantial side effects. FT-5 group exhibited no significant decrease in serum glucose. However, it reduced fasting plasma TG levels and improved hepatic steatosis of KKAy mice. P + F group showed improved insulin resistance and similar body weight gain, as compared with control group. The mRNA expression of genes related to fatty acid oxidation was markedly up-regulated in the liver of P + F group. Pioglitazone administration markedly decreased the phosphorylation levels of AMPK, as compared with all other groups. Besides, even though plasma adiponectin increased in PIO, FT-5, P + F group, adipoR2 gene expression significantly decreased in the liver of PIO group.CONCLUSIONFT-5 decreased plasma TG and alleviated aggravating hepatic steatosis induced by pioglitazone in KKAy mice. FT-5's mechanism might be associated with its ability to activate the AdipoR2/AMPK pathway.

2002-08-01·British Journal of Pharmacology2区 · 医学

Evidence that the novel imidazoline compound FT005 is anα₂‐adrenoceptor agonist

2区 · 医学

Article

作者: Peter V Taberner ; Scott Slough ; Gerald Guillaumet

The aim of this study was to determine whether the hyperglycaemic action of the novel imidazoline compound FT005 could be mediated by activation of α2‐adrenoceptors, using a variety of in vivo and in vitro methods including radioligand binding.

FT005 produced a dose‐dependent increase in blood glucose levels of CBA/Ca mice (0.125–25 mg kg−1, i.p.). The time course of this hyperglycaemic effect matched that of adrenaline (1 mg kg−1) more closely than glucagon (1 mg kg−1) or the KATP channel opener diazoxide (25 mg kg−1). The hyperglycaemic effect of FT005 (1 mg kg−1) was significantly reduced by the α2‐adrenoceptor antagonist rauwolscine (0.5 mg kg−1).

FT005 produced a significant reduction in plasma insulin levels of mice 30 min after administration. The hyperglycaemic effect of FT005 (25 mg kg−1), although still present, was significantly less in fasted mice in which insulin levels are lower, suggesting that a reduction of insulin secretion contributes to the action of FT005.

When studied in the mouse isolated vas deferens preparation, FT005 produced a complete inhibition of neurogenic contractions, which was blocked by rauwolscine. This is consistent with activation of pre‐synaptic α2‐adrenoceptors.

In radioligand binding studies FT005 completely displaced the α2‐adrenoceptor antagonist [3H]‐RX821002 from mouse whole brain homogenates. The displacement was best described by a two‐site model of interaction comprising high and low affinity components.

The results indicate that FT005 is an agonist at α2‐adrenoceptors. A reduction in insulin secretion contributes to the hyperglycaemic action of FT005, although an additional mechanism can not be excluded.

British Journal of Pharmacology (2002) 136, 1049–1057. doi:10.1038/sj.bjp.0704810

项与 FT-005 相关的新闻（医药）

2023-08-21

·创鉴汇

超1.5亿美元助力潜在“first-in-class”抗体开发；强生创新看好这家中国RNA疗法新锐… | 一周融资

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