Green tea polyphenols : a natural therapeutic approach for metabolic syndrome and diabetes prevention
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Metabolic syndrome (MetS) is a collection of interrelated disorders that increase the risk of type 2 diabetes (T2D) and cardiovascular disease. Abnormalities associated with MetS include, but are not limited to, central obesity, insulin resistance, glucose intolerance, hyperglycaemia, hyperlipidaemia and hypertension. MetS has caused an encumbrance to public health globally. Due to the complex nature of MetS and the lack of availability of effective medications, there is an urgent need for the implementation of novel oral agents to manage Mets and prevent T2D and cardiovascular complications. The beneficial effects of green tea polyphenols (GTP) for MetS have been recently reported. However, the direct effects and mechanisms of GTP on abnormalities of glucose and lipid metabolism are not fully understood. This thesis investigated effects and mechanisms of GTP in obesity, insulin resistant and metabolic dysfunctions through in vitro and in vivo studies. The effects of GTP on biochemical parameters and its actions in major organs involved in glucose homeostasis, fat metabolism and insulin sensitivity such as skeletal muscle, liver and adipose tissue were elucidated. The study was further extended to investigate the effect of GTP on a model of non-alcoholic fatty liver disease (NAFLD). In 3T3-L1 adipocytes, GTP-EGCG (epigallocatechin gallate) improved glucose uptake and inhibited lipolysis significantly. It was revealed that GTP-EGCG significantly increased glucose uptake by up-regulating expressions of IRS-1, PKB/Akt and GLUT4. The probable mechanism for decreased lipolysis with GTP-EGCG may be through down-regulation of PKA, as observed in this thesis. GTP-EGCG also enhanced glycogen synthesis in a dose-dependent manner and significantly increased glycogen synthesis two-fold compared with insulin alone in HepG2 cells. Western blotting revealed that phosphorylation of GSK3β and GS was significantly increased in GTP-EGCG treated HepG2 cells compared to non-treated cells. GTP-EGCG also significantly inhibited lipogenesis and the likely mechanism behind this inhibition involved enhanced expression of phosphorylated AMPKα and ACC in HepG2 cells. A marked state of insulin resistance was observed in high fat diet (HFD) fed obese Zuker fatty (ZF) rats compared to their lean littermates, which is associated with significant defects in the insulin-signalling/glucose transport system. GTP significantly improved fasting metabolic parameters, including glucose, insulin, TG, NEFA and cholesterol, and improved insulin sensitivity and glucose intolerance in HFD ZF rats. The likely molecular mechanisms involved are regulation of the elements of the insulin-signalling pathway such as PKB/Akt, GLUT4 translocation and regulation of PKC translocation in skeletal muscle of HFD ZF rats. Data from this thesis also strongly supports that GTP reduces fat accumulation in the liver and hepatic insulin resistance. This is evidenced by significant reduction in serum levels of ALT and AST hepatic TG and lipid content in HFD ZF rats administered GTP. Mechanisms are likely to up regulate GSK3β and GS expressions thereby enhancing glycogen synthesis and down-regulating de novo lipogenesis through regulation of AMPKα, ACC and PEPCK expressions. Overall, the results presented in this thesis provide insight into GTP as a potential therapeutic agent for MetS and related disorders such as T2D, obesity and NAFLD. GTP may be a valuable natural and cost-effective therapy for the treatment and prevention of metabolic disorders.
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