Effect of green tea polyphenol, EGCG, on insulin sensitivity

Insulin resistance contributes to and precedes the development of type 2 diabetes. Insulin-stimulated microvascular perfusion and glucose uptake in skeletal muscle are important components of glucose homeostasis, and are impaired during insulin resistance. Epidemiological studies suggest that regular green tea consumption may lower the risk for developing type 2 diabetes. Whether green tea or its components could be used as an alternative treatment for type 2 diabetes is not known. The primary aim of this thesis was to investigate the effects of epigallocatechin gallate (EGCG), a green tea polyphenol, on vascular function and glucose metabolism in skeletal muscle. The direct vascular and metabolic actions of EGCG in skeletal muscle were assessed in situ using the isolated, constant-flow perfused rat hindlimb. In this study, four different doses of EGCG were studied: 0.1, 1, 10, and 100 ˜í¬¿M. EGCG (1 ‚Äö- 10 ˜í¬¿M) caused nitric oxide synthase (NOS)-dependent vasodilation against 5-hydroxytryptamine (5-HT). However, EGCG-mediated vasodilation was independent of PI3-kinase or AMP-kinase activation. EGCG had no direct effects on muscle glucose uptake in the presence or absence of insulin at any of the doses tested. This indicates that EGCG has direct vascular, but not metabolic, actions in skeletal muscle. Since EGCG had direct vascular effects in muscle its effects on microvascular perfusion and insulin-mediated glucose metabolism in vivo were then investigated. The acute and chronic effects of EGCG on vascular function and glucose metabolism were investigated in normal healthy and diet-induced insulin resistant rats in vivo under anaesthesia. Hyperinsulinaemic euglycaemic clamp was used to determine the acute and chronic effects of EGCG on whole body insulin sensitivity. In the acute studies, EGCG was infused intravenously to increase plasma EGCG to 10 ˜í¬¿M. Acute EGCG stimulated muscle microvascular perfusion in both healthy and insulin resistant rats, but was not additive to insulin-stimulated microvascular perfusion. Acute EGCG did not stimulate muscle glucose uptake or enhance insulin-stimulated muscle glucose uptake. However, acute EGCG treatment improved whole body insulin sensitivity (glucose infusion rate, GIR) by 12% in insulin resistant rats but not healthy rats. In the chronic studies, high fat-fed rats were given EGCG in their drinking water (200 mg.kg-1.d-1) for 4 weeks to determine whether EGCG could prevent the development of insulin resistance. Chronic EGCG treatment improved whole body insulin sensitivity (GIR) by 21% and insulin-stimulated muscle glucose uptake by 67%. However, chronic EGCG treatment had no effect on muscle microvascular perfusion. This suggests that chronic EGCG treatment improved glucose metabolism, without altering vascular function of insulin resistant rats. The data from this thesis demonstrate that acute and chronic EGCG treatment exhibit distinct vascular and metabolic effects in vivo in rats. Acute EGCG treatment stimulated microvascular perfusion, but not glucose uptake in skeletal muscle. Chronic EGCG treatment improved whole body and muscle insulin sensitivity, but not muscle microvascular perfusion. Together these data provide a mechanistic insight into the potential anti-diabetic effects of chronic EGCG treatment, and support its development as a promising new therapeutic agent for prevention of insulin resistance and type 2 diabetes.