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Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70s6kactivity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent. Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70s6kactivity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent. For centuries, folk medicine has employed plants and herbs for their medicinal and protective abilities. Recent epidemiologic research shows a positive correlation between the consumption of fruits, vegetables, grains, and legumes and the prevention of chronic illnesses. Phytochemicals, naturally occurring plant biochemicals that give plants their color and flavor, may improve or prevent a number of chronic diseases because of their anti-inflammatory, antithrombotic, antioxidant, and anticarcinogenic activity (1Craig W.J. Am. J. Clin. Nutr. 1999; 70: 491S-499SCrossref PubMed Scopus (800) Google Scholar). The polyphenols, which include more than 4000 identified flavonoids, comprise one of the largest groups of active phytochemicals (2Hollman P.C. Eur. J. Clin. Nutr. 1997; 51: S66-S69PubMed Google Scholar). Green tea, a beverage commonly consumed in Asian countries, is a significant source of a type of flavonoids called catechins. The green tea catechins include (−)-epigallocatechin gallate (EGCG), 1The abbreviations used are: EGCG, (−)-epigallocatechin gallate; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; DMEM, Dulbecco's modified Eagle's medium; PTP, protein-tyrosine phosphatase; DCFH, 2′,7′-dichlorofluorescein diacetate; DCF, 2′,7′-dichlorofluorescein; IRS-1, insulin receptor substrate-1; IGF, insulin-like growth factor; IGF-1R, IGF-1 receptor; Dex, dexamethasone; NAC, N-acetylcysteine; SOD, superoxide dismutase; ROS, reactive oxygen species; IR-β, β-subunit of the insulin receptor; MAPK, mitogen-activated protein kinase; MOPS, 4-morpholinepropanesulfonic acid. (−)-epigallocatechin, (−)-epicatechin gallate, and (−)-epicatechin (Fig. 1) (3Guo Q. Zhao B. Shen S. Hou J., Hu, J. Xin W. Biochim. Biophys. Acta. 1999; 1427: 13-23Crossref PubMed Scopus (396) Google Scholar). EGCG is the most abundant of these catechins, and many healthful benefits, including anticarcinogenic, antioxidant, antiangiogenic, and antiviral activities, have been attributed to EGCG (4Katiyar S.K. Mukhtar H. J. Cell. Biochem. Suppl. 1997; 27: 59-67Crossref PubMed Scopus (214) Google Scholar, 5Yang C.S. Wang Z.Y. J. Natl. Cancer Inst. 1993; 85: 1038-1049Crossref PubMed Scopus (1016) Google Scholar, 6Cao Y. Cao R. Nature (Lond.). 1999; 398: 381Crossref PubMed Scopus (615) Google Scholar, 7Nakayama M. Suzuki K. Toda M. Okubo S. Hara Y. Antivir. Res. 1993; 21: 289-299Crossref PubMed Scopus (358) Google Scholar). EGCG may also possess antidiabetic activity. In a recent report, injection of EGCG into lean and obese Zucker rats significantly lowered blood glucose and insulin levels, and green tea extract increased glucose metabolism in adipocytes (8Kao Y.H. Hiipakka R.A. Liao S. Endocrinology. 2000; 141: 980-987Crossref PubMed Scopus (370) Google Scholar, 9Broadhurst C.L. Polansky M.M. Anderson R.A. J. Agric. Food Chem. 2000; 48: 849-852Crossref PubMed Scopus (347) Google Scholar). Additionally, (−)-epicatechin, which is structurally similar to EGCG, is the active compound in the extract ofPterocarpus marsupium Roxb bark, which is traditionally used in Indian folk medicine to treat diabetes (10Ahmad F. Khalid P. Khan M.M. Rastogi A.K. Kidwai J.R. Acta Diabetol. Lat. 1989; 26: 291-300Crossref PubMed Scopus (76) Google Scholar). One of the hallmarks of diabetes is the inability of insulin to inhibit hepatic glucose production. It has been suggested that increased gluconeogenesis is a main source of increased hepatic glucose production and that the ability of insulin to regulate transcription of the rate-controlling gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), may contribute to this problem. This point is underscored by the observation that in several animal models of type II diabetes and obesity, PEPCK mRNA levels are increased 2–3-fold over that observed in non-diabetic animals, despite the higher circulating insulin levels observed in the diabetic animals (11Hofmann C.A. Edwards III, C.W. Hillman R.M. Colca J.R. Endocrinology. 1992; 130: 735-740PubMed Google Scholar, 12Noguchi T. Matsuda T. Tomari Y. Yamada K. Imai E. Wang Z. Ikeda H. Tanaka T. FEBS Lett. 1993; 328: 145-148Crossref PubMed Scopus (23) Google Scholar, 13Shafrir E. Barash V. Zederman R. Kissilevitz R. Diamant Y.Z. Isr. J. Med. Sci. 1994; 30: 32-41PubMed Google Scholar). Also, transgenic mice that over-express PEPCK display a diabetes-like syndrome (14Valera A. Pujol A. Pelegrin M. Bosch F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9151-9154Crossref PubMed Scopus (256) Google Scholar). The rate of transcription of the hepatic PEPCK gene is increased by several hormones, including glucocorticoids, retinoic acid, and glucagon (via its second messenger, cAMP) (15Granner D. Pilkis S. J. Biol. Chem. 1990; 265: 10173-10176Abstract Full Text PDF PubMed Google Scholar, 16Lucas P.C. Granner D.K. Annu. Rev. Biochem. 1992; 61: 1131-1173Crossref PubMed Scopus (163) Google Scholar, 17Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar, 18Hall R.K. Scott D.K. Noisin E.L. Lucas P.C. Granner D.K. Mol. Cell. Biol. 1992; 12: 5527-5535Crossref PubMed Scopus (77) Google Scholar). Insulin dominantly represses PEPCK gene transcription (19Granner D. Andreone T. Sasaki K. Beale E. Nature (Lond.). 1983; 305: 549-551Crossref PubMed Scopus (247) Google Scholar, 20Sasaki K. Cripe T.P. Koch S.R. Andreone T.L. Petersen D.D. Beale E.G. Granner D.K. J. Biol. Chem. 1984; 259: 15242-15251Abstract Full Text PDF PubMed Google Scholar, 21O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (439) Google Scholar). The use of specific kinase inhibitors revealed that PI3K, but neither MAPK nor p70s6k, is involved in the insulin response of the PEPCK gene (22Sutherland C. O'Brien R.M. Granner D.K. J. Biol. Chem. 1995; 270: 15501-15506Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). A variety of other agents is insulinomimetic in the sense that these compounds reduce PEPCK mRNA levels. Such compounds include phorbol esters, compounds that elicit oxidative and cellular stress (such as H2O2 and sodium arsenite), and the cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1. These agents differ from insulin, however, in that they repress PEPCK gene transcription in a PI3K-independent manner (20Sasaki K. Cripe T.P. Koch S.R. Andreone T.L. Petersen D.D. Beale E.G. Granner D.K. J. Biol. Chem. 1984; 259: 15242-15251Abstract Full Text PDF PubMed Google Scholar, 23Sutherland C. Tebbey P.W. Granner D.K. Diabetes. 1997; 46: 17-22Crossref PubMed Scopus (37) Google Scholar, 24Christ B. Nath A. Biochem. J. 1996; 320: 161-166Crossref PubMed Scopus (27) Google Scholar, 25Christ B. Nath A. Heinrich P.C. Jungermann K. Hepatology. 1994; 20: 1577-1583Crossref PubMed Scopus (31) Google Scholar, 26Hill M.R. McCallum R.E. Infect. Immun. 1992; 60: 4040-4050Crossref PubMed Google Scholar). Vanadate, a potent protein-tyrosine phosphatase inhibitor, also mimics several of the metabolic actions of insulin. For instance, vanadate lowers blood glucose in streptozotocin-induced diabetic rats, inhibits lipolysis in adipocytes, and increases glucose transport into L6 myotubes (27Valera A. Rodriguez-Gil J.E. Bosch F. J. Clin. Investig. 1993; 92: 4-11Crossref PubMed Scopus (65) Google Scholar, 28Brichard S.M. Desbuquois B. Girard J. Mol. Cell. Endocrinol. 1993; 91: 91-97Crossref PubMed Scopus (73) Google Scholar, 29Bosch F. Hatzoglou M. Park E.A. Hanson R.W. J. Biol. 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Biochem. 1998; 182: 109-119Crossref PubMed Scopus (95) Google Scholar). Furthermore, vanadate directly inhibits the activity of two key gluconeogenic enzymes, PEPCK and G6Pase, which also contributes to decreased blood glucose levels in diabetic animals (33Mosseri R. Waner T. Shefi M. Shafrir E. Meyerovitch J. Metabolism. 2000; 49: 321-325Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 34Westergaard N. Brand C.L. Lewinsky R.H. Andersen H.S Carr R.D. Burchell A. Lundgren K. Arch. Biochem. Biophys. 1999; 366: 55-60Crossref PubMed Scopus (30) Google Scholar). The above-listed observations reveal that, although many diverse signals regulate glucose metabolism, an understanding of these signaling pathways should aid in the development of pharmacological agents to treat diabetes. A suitable antidiabetic agent should have actions similar to insulin, or it should bypass the defects in insulin action characterized by insulin resistance. Since EGCG reduces blood glucose by an unknown mechanism, the purpose of this study is to examine the effect of green tea compounds on insulin signaling pathways, gene expression, and glucose production. Our experiments reveal that EGCG has some insulinomimetic activities in hepatoma and that it differs from many other identified of PEPCK gene expression in that it in a PI3K-dependent manner. In to insulin, however, the metabolic effects of EGCG are and seem to on changes in the cell. hepatoma with a of and in the or of insulin or EGCG for for an in glucose production Dulbecco's modified containing sodium and sodium with and in the or of insulin or EGCG. the of this of to the glucose in the a glucose Scott D.K. C. Granner D.K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). and and the protein to for for and with the by the The and which are to the of the PEPCK and genes and used in as (22Sutherland C. O'Brien R.M. Granner D.K. J. Biol. Chem. 1995; 270: 15501-15506Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). to the with the as Scott D.K. C. Granner D.K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The glucose-6-phosphatase from in which the the A of the directly to the of the with to or hepatoma to in Dulbecco's modified Eagle's containing and for and in in the or of insulin or of EGCG. with a and to in of the specific used to the β-subunit of the insulin receptor IRS-1, or The in containing of and of for or protein for an by two of the in The in of for and by The to and with specific for by with an or to the from to the as and directly in for of p70s6k, and by One of protein from with of specific for and the with of protein in and two in MOPS, and of in kinase to the in a of with the of of containing of to for and with the of of acid. of the to and with for by one with for of and by from of cellular protein with of for The with A sodium and and with and and with MOPS, sodium and of to the by the of of protein kinase and of by the of of containing of and for by the of of and and as for from of cellular protein with of a and the with of protein with containing and two with and two with kinase and The in of kinase by the of of and of The in a containing and to the The by the of of an containing of and and for by the of of and of and a with The by in reactive oxygen production 2′,7′-dichlorofluorescein which is to the 2′,7′-dichlorofluorescein by J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). with or EGCG for and two with containing and a to a to that from in The production of glucose in response to insulin or EGCG in hepatoma in containing and as for for these experiments because they glucose in response to in a and manner. The with a of and in the or of insulin or EGCG, for to glucose production for an with with or insulin or EGCG, in glucose production the of this of to the glucose in the a glucose of and EGCG in glucose production to levels (Fig. of EGCG glucose-lowering effect inhibition of glucose production observed in EGCG treatment but insulin treatment have that insulin inhibit glucose from gluconeogenic in or Y. K. H. M. M. H. Sasaki H. J. Clin. Med. 138: Full Text Full Text PDF PubMed Scopus Google Scholar). the for this is it is that of the insulin signaling for of gluconeogenesis are the these that EGCG may by a than insulin, as The decreased glucose production observed EGCG treatment be related to expression of genes that encode gluconeogenic PEPCK gene expression is increased by and is dominantly by insulin in P.C. Granner D.K. Annu. Rev. Biochem. 1992; 61: 1131-1173Crossref PubMed Scopus (163) Google Scholar, 17Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar, D. Andreone T. Sasaki K. Beale E. Nature (Lond.). 1983; 305: 549-551Crossref PubMed Scopus (247) Google Scholar, 20Sasaki K. Cripe T.P. Koch S.R. Andreone T.L. Petersen D.D. Beale E.G. Granner D.K. J. Biol. Chem. 1984; 259: 15242-15251Abstract Full Text PDF PubMed Google Scholar). with in the or of of EGCG for and for to PEPCK and a mRNA levels. EGCG, in a PEPCK as in Insulin reduces PEPCK gene expression by a PI3K-dependent mechanism, and the effect of insulin is by the PI3K inhibitors and MAPK is however, kinase kinase inhibitors the regulation of PEPCK gene expression by insulin (22Sutherland C. O'Brien R.M. Granner D.K. J. Biol. Chem. 1995; 270: 15501-15506Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). with EGCG in the of or a kinase kinase inhibitor, to PI3K or MAPK is involved in PEPCK gene observed with insulin, the effect of EGCG on PEPCK gene expression (Fig. the of PI3K, but MAPK, in of the PEPCK The gene is in a manner similar to that of the PEPCK and insulin also represses this gene by a PI3K-dependent M. C.A. O'Brien R.M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The effect of EGCG on gene expression also with expression of the gene as a (Fig. Insulin and EGCG repress expression of the gene in a PI3K-dependent manner. These results suggest that EGCG mimics insulin action by glucose production and the expression of genes that hepatic Insulin PI3K, PKB, and in (22Sutherland C. O'Brien R.M. Granner D.K. J. Biol. Chem. 1995; 270: 15501-15506Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). The effect of EGCG on these kinases in kinase with insulin or EGCG for or and of these kinases and its activity Insulin and EGCG PI3K The by insulin more and in the of EGCG, PI3K activity to Insulin a 2–3-fold in whereas EGCG a but in activity. Insulin also a in whereas the by EGCG and significant The effect of EGCG on the of these kinases is to that observed treatment of with which an in PEPCK mRNA levels These with the that shows that of PEPCK and gene expression, suggest that a of PI3K activity may be to repress these of insulin and EGCG on kinase for with insulin or EGCG. and with specific to IRS-1, PKB, or for of PI3K, PKB, or p70s6k, The to is for The results to in a for with insulin or EGCG. and with specific to IRS-1, PKB, or for of PI3K, PKB, or p70s6k, The to is for The results to The observed effects of EGCG on enzymes in the insulin kinase may be by the inhibition of protein-tyrosine phosphatase activity or by increased protein-tyrosine kinase activity. EGCG increases the of tyrosine for with EGCG. and by for a in insulin and EGCG a number of in EGCG increased the tyrosine phosphorylation of some of the as insulin, and it some EGCG also to the of tyrosine phosphorylation over a because some whereas modified between and Insulin increases tyrosine phosphorylation on IR-β, IRS-1, and and and for tyrosine phosphorylation to EGCG affects the phosphorylation of these in These of for Insulin and EGCG the tyrosine phosphorylation of and (Fig. Insulin increased the tyrosine phosphorylation of as EGCG also increased the levels of tyrosine phosphorylation but increases to The of tyrosine phosphorylation of these by EGCG as as that observed with insulin. EGCG the of active PI3K with IRS-1, as in The effect of EGCG on tyrosine phosphorylation of the IGF-1 receptor also levels of IGF-1R, used for this with IGF-1 or EGCG, and the β-subunit of the for with the observed with the insulin EGCG a in tyrosine phosphorylation of the have been in the regulation of protein kinase and in the inhibition of C.A. Q. R.A. K. Arch. Biochem. Biophys. 1999; PubMed Scopus Google Scholar, L. S. R.A. K. J. Res. 1999; PubMed Scopus Google Scholar). It is that activity of EGCG in hepatoma the increased levels of observed in these with to EGCG increases production. in of DCFH, the J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). in the or of EGCG, and (Fig. A of EGCG most of which in the This that EGCG has activity in hepatoma Insulin effect on The in because the with EGCG with EGCG with by a It to the EGCG The in by the with a and of (Fig. a of superoxide also decreased the number of that These results suggest that EGCG increases production in the in ROS, treatment of with to EGCG effects on as by production increased treatment of with EGCG, the effect of and on tyrosine phosphorylation of cellular with or for treatment with insulin or EGCG for and as in A. and the effect of EGCG on protein-tyrosine phosphorylation effect on protein-tyrosine the tyrosine phosphorylation of but the tyrosine phosphorylation of (Fig. The effect of and on PEPCK and gene expression also and PEPCK and gene the effect on of the PEPCK but the gene (Fig. These results show that EGCG regulates tyrosine phosphorylation and gene expression by a and that the PEPCK and genes are by signaling the is to contribute to an increased of as and diabetes, protective effects M. 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The here suggest that EGCG regulates protein-tyrosine phosphorylation by modulating the redox state of the cell. One for the observed actions of EGCG in hepatoma is the inhibition of which an in their active C.A. Q. R.A. K. Arch. Biochem. Biophys. 1999; PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar). It is that EGCG of this in and and this including and the insulin receptor and IRS-1, these for by in response to EGCG A. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A Andersen D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R.A. Biochem. Biophys. Res. 1997; PubMed Scopus (37) Google Scholar). It is that of the gene in mice to similar to observed in Zucker rats with EGCG, as decreased and blood glucose levels and increased insulin sensitivity (8Kao Y.H. Hiipakka R.A. Liao S. Endocrinology. 2000; 141: 980-987Crossref PubMed Scopus (370) Google Scholar, M. P. E. W. S. D. A. J. C. D. 1999; PubMed Scopus Google Scholar, N. M. A. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). We are the effect of EGCG on to this This study that EGCG many of the cellular effects as insulin, including of glucose production and PEPCK and gene EGCG, however, to these effects by of the redox state of the cell. EGCG or other phytochemicals may be identified that have insulin-like experiments the of EGCG action may to the of for the of agents in the treatment of diabetes. We for and for
Waltner‐Law et al. (Sun,) studied this question.
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