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      Vascular and Metabolic Actions of the Green Tea Polyphenol Epigallocatechin Gallate

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          Abstract

          Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.

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          Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

          Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
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            Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study.

            Green tea polyphenols have been extensively studied as cardiovascular disease and cancer chemopreventive agents in vitro and in animal studies. However, the effects of green tea consumption in humans remain unclear. To investigate the associations between green tea consumption and all-cause and cause-specific mortality. The Ohsaki National Health Insurance Cohort Study, a population-based, prospective cohort study initiated in 1994 among 40,530 Japanese adults aged 40 to 79 years without history of stroke, coronary heart disease, or cancer at baseline. Participants were followed up for up to 11 years (1995-2005) for all-cause mortality and for up to 7 years (1995-2001) for cause-specific mortality. Mortality due to cardiovascular disease, cancer, and all causes. Over 11 years of follow-up (follow-up rate, 86.1%), 4209 participants died, and over 7 years of follow-up (follow-up rate, 89.6%), 892 participants died of cardiovascular disease and 1134 participants died of cancer. Green tea consumption was inversely associated with mortality due to all causes and due to cardiovascular disease. The inverse association with all-cause mortality was stronger in women (P = .03 for interaction with sex). In men, the multivariate hazard ratios of mortality due to all causes associated with different green tea consumption frequencies were 1.00 (reference) for less than 1 cup/d, 0.93 (95% confidence interval [CI], 0.83-1.05) for 1 to 2 cups/d, 0.95 (95% CI, 0.85-1.06) for 3 to 4 cups/d, and 0.88 (95% CI, 0.79-0.98) for 5 or more cups/d, respectively (P = .03 for trend). The corresponding data for women were 1.00, 0.98 (95% CI, 0.84-1.15), 0.82 (95% CI, 0.70-0.95), and 0.77 (95% CI, 0.67-0.89), respectively (P<.001 for trend). The inverse association with cardiovascular disease mortality was stronger than that with all-cause mortality. This inverse association was also stronger in women (P = .08 for interaction with sex). In women, the multivariate hazard ratios of cardiovascular disease mortality across increasing green tea consumption categories were 1.00, 0.84 (95% CI, 0.63-1.12), 0.69 (95% CI, 0.52-0.93), and 0.69 (95% CI, 0.53-0.90), respectively (P = .004 for trend). Among the types of cardiovascular disease mortality, the strongest inverse association was observed for stroke mortality. In contrast, the hazard ratios of cancer mortality were not significantly different from 1.00 in all green tea categories compared with the lowest-consumption category. Green tea consumption is associated with reduced mortality due to all causes and due to cardiovascular disease but not with reduced mortality due to cancer.
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              A receptor for green tea polyphenol EGCG.

              The major polyphenol in green tea, (-)-epigallocatechin-3-gallate (EGCG), has been shown to prevent carcinogenesis. We have identified a receptor that mediates the anticancer activity of EGCG. Expression of the metastasis-associated 67-kDa laminin receptor confers EGCG responsiveness to cancer cells at physiologically relevant concentrations. Experiments using surface plasmon resonance demonstrate binding of EGCG to the 67-kDa laminin receptor with a nanomolar K (d) value.
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                Author and article information

                Journal
                9440157
                20806
                Curr Med Chem
                Curr. Med. Chem.
                Current medicinal chemistry
                0929-8673
                1875-533X
                8 June 2016
                2015
                15 June 2016
                : 22
                : 1
                : 59-69
                Affiliations
                [1 ]Menzies Research Institute Tasmania, University of Tasmania, Australia
                [2 ]University of Alabama at Birmingham, USA
                [3 ]University of Maryland School of Medicine, Baltimore, USA
                Author notes
                [* ]Address correspondence to this author at the Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, 7000, Australia; Tel: (03) 62 26 2669; Fax: (03) 62 26 7704; Michelle.Keske@ 123456utas.edu.au
                [#]

                Author’s Profile: Dr. Keske is a Senior Research Fellow at the Menzies Research Institute Tasmania, University of Tasmania. Her research interests have focused on the control of microvascular blood flow in skeletal muscle. Her current research investigates interventions to prevent or reverse insulin resistance by regulating microvascular blood flow within skeletal muscle.

                Article
                NIHMS792718
                10.2174/0929867321666141012174553
                4909506
                25312214
                c7614533-0d34-4b53-82e9-818a94e12d82

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                Categories
                Article

                Pharmaceutical chemistry
                egcg,endothelial function,green tea,insulin action,insulin sensitivity,metabolism,muscle blood flow,type 2 diabetes

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