Dietary flavonoids in the prevention of T2D: An overview

Nutrients

Volumn 10, Issue 4, 2018, Pages

  Alkhalidy, Hana ^a,b   Wang, Yao ^a   Liu, Dongmin ^a  

^a VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY   (United States)

^b JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Jordan)

Author keywords

Flavonoids; Insulin resistance; Type 2 diabetes

Indexed keywords

FLAVONOID; PLANT EXTRACT;

ANTIDIABETIC ACTIVITY; ANTIOXIDANT ACTIVITY; DIETARY INTAKE; DRUG MECHANISM; GLUCOSE BLOOD LEVEL; HUMAN; INFLAMMATION; INSULIN RELEASE; INSULIN RESISTANCE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; REVIEW; BLOOD; CHEMISTRY; DIET; EDIBLE PLANT; PHYTOTHERAPY;

DIABETES MELLITUS, TYPE 2; DIET; FLAVONOIDS; HUMANS; INSULIN RESISTANCE; PHYTOTHERAPY; PLANT EXTRACTS; PLANTS, EDIBLE;

EID: 85045005772     PISSN: None     EISSN: 20726643     Source Type: Journal    
DOI: 10.3390/nu10040438     Document Type: Review

References (365)

1. Centers of Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and its Burden in the United States, 2014; Centers of Disease Control and Prevention: Atlanta, GA, USA, 2014.
2. Boyle, J.P.; Thompson, T.J.; Gregg, E.W.; Barker, L.E.;Williamson, D.F. Projection of the year 2050 burden of diabetes in the us adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul. Health Metr. 2010, 8, 29.
3. Zimmet, P. The burden of type 2 diabetes: Are we doing enough? Diabetes Metab. 2003, 29, 6S9-6S18.
4. Assoc, A.D. Economic costs of diabetes in the U.. in 2012. Diabetes Care 2013, 36, 1033-1046.
5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010, 33, S62-S69.
6. Goldberg, I.J. Clinical review 124: Diabetic dyslipidemia: Causes and consequences. J. Clin. Endocrinol. Metab. 2001, 86, 965-971.
7. Gougeon, R.; Pencharz, P.B.; Sigal, R.J. Effect of glycemic control on the kinetics of whole-body protein metabolism in obese subjects with non-insulin-dependent diabetes mellitus during iso- and hypoenergetic feeding. Am. J. Clin. Nutr. 1997, 65, 861-870.
8. Lewis, G.F.; Carpentier, A.; Adeli, K.; Giacca, A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr. Rev. 2002, 23, 201-229.
9. Michael, D.J.; Ritzel, R.A.; Haataja, L.; Chow, R.H. Pancreatic beta-cells secrete insulin in fast- and slow-release forms. Diabetes 2006, 55, 600-607.
10. Bergman, R.N.; Ader, M.; Huecking, K.; Van Citters, G. Accurate assessment of beta-cell function: The hyperbolic correction. Diabetes 2002, 51 (Suppl. S1), S212-S220.
11. Ramlo-Halsted, B.A.; Edelman, S.V. The natural history of type 2 diabetes: Practical points to consider in developing prevention and treatment strategies. Clin. Diabetes 2000, 18, 80-84.
12. Ahmed, N. Advanced glycation endproducts-Role in pathology of diabetic complications. Diabetes Res. Clin. Pract. 2005, 67, 3-21.
13. Stratton, I.M.; Adler, A.I.; Neil, H.A.; Matthews, D.R.; Manley, S.E.; Cull, C.A.; Hadden, D.; Turner, R.C.; Holman, R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (ukpds 35): Prospective observational study. BMJ 2000, 321, 405-412.
14. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414, 813-820.
15. Rossetti, L. Glucose toxicity: The implications of hyperglycemia in the pathophysiology of diabetes mellitus. Clin. Investig. Med. 1995, 18, 255-260.
16. Ohkubo, Y.; Kishikawa, H.; Araki, E.; Miyata, T.; Isami, S.; Motoyoshi, S.; Kojima, Y.; Furuyoshi, N.; Shichiri, M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res. Clin. Pract. 1995, 28, 103-117.
17. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837-853.
18. Nazimek-Siewniak, B.; Moczulski, D.; Grzeszczak, W. Risk of macrovascular and microvascular complications in type 2 diabetes: Results of longitudinal study design. J. Diabetes Complicat. 2002, 16, 271-276.
19. Holman, R.R.; Paul, S.K.; Bethel, M.A.; Matthews, D.R.; Neil, H.A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 2008, 359, 1577-1589.
20. Groop, L.; Forsblom, C.; Lehtovirta, M. Characterization of the prediabetic state. Am. J. Hypertens. 1997, 10, 172S-180S.
21. Perfetti, R.; Barnett, P.S.; Mathur, R.; Egan, J.M. Novel therapeutic strategies for the treatment of type 2 diabetes. Diabetes/Metab. Rev. 1998, 14, 207-225.
22. Schulze, M.B.; Hu, F.B. Primary prevention of diabetes: What can be done and how much can be prevented? Annu. Rev. Publ Health 2005, 26, 445-467.
23. Keservani, R.; Sharma, A. Flavonoids: Emerging trends and potential health benefits. J. Chin. Pharm. Sci. 2014, 23, 815-822.
24. Triplitt, C.L. Examining the mechanisms of glucose regulation. Am. J. Manag. Care 2012, 18, S4-S10.
25. Roder, P.V.; Geillinger, K.E.; Zietek, T.S.; Thorens, B.; Koepsell, H.; Daniel, H. The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS ONE 2014, 9, e89977.
26. Agius, L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem. J. 2008, 414, 1-18.
27. Pagliassotti, M.J.; Cherrington, A.D. Regulation of net hepatic glucose uptake in vivo. Annu. Rev. Physiol. 1992, 54, 847-860.
28. Mithieux, G. Role of glucokinase and glucose-6 phosphatase in the nutritional regulation of endogenous glucose production. Reprod. Nutr. Dev. 1996, 36, 357-362.
29. Ferrannini, E.; Bjorkman, O.; Reichard, G.A., Jr.; Pilo, A.; Olsson, M.;Wahren, J.; DeFronzo, R.A. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes 1985, 34, 580-588.
30. Efrat, S.; Tal, M.; Lodish, H.F. The pancreatic beta-cell glucose sensor. Trends Biochem. Sci. 1994, 19, 535-538.
31. Rutter, G.A. Nutrient-secretion coupling in the pancreatic islet beta-cell: Recent advances. Mol. Aspects Med. 2001, 22, 247-284.
32. Iezzi, M.; Kouri, G.; Fukuda, M.; Wollheim, C.B. Synaptotagmin V and IX isoforms control Ca2+-dependent insulin exocytosis. J. Cell Sci. 2004, 117, 3119-3127.
33. Newsholme, P.; Brennan, L.; Rubi, B.; Maechler, P. New insights into amino acid metabolism, beta-cell function and diabetes. Clin. Sci. 2005, 108, 185-194.
34. Edgerton, D.S.; Cardin, S.; Emshwiller, M.; Neal, D.; Chandramouli, V.; Schumann, W.C.; Landau, B.R.; Rossetti, L.; Cherrington, A.D. Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism. Diabetes 2001, 50, 1872-1882.
35. Sindelar, D.K.; Chu, C.A.; Venson, P.; Donahue, E.P.; Neal, D.W.; Cherrington, A.D. Basal hepatic glucose production is regulated by the portal vein insulin concentration. Diabetes 1998, 47, 523-529.
36. Capaldo, B.; Gastaldelli, A.; Antoniello, S.; Auletta, M.; Pardo, F.; Ciociaro, D.; Guida, R.; Ferrannini, E.; Sacca, L. Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans. Diabetes 1999, 48, 958-966.
37. Moore, M.C.; Cherrington, A.D.;Wasserman, D.H. Regulation of hepatic and peripheral glucose disposal. Best Pract. Res. Clin. Endocrinol. Metab. 2003, 17, 343-364.
38. Saccomani, M.P.; Bonadonna, R.C.; Bier, D.M.; DeFronzo, R.A.; Cobelli, C. A model to measure insulin effects on glucose transport and phosphorylation in muscle: A three-tracer study. Am. J. Physiol. 1996, 270, E170-E185.
39. Kelley, D.; Mitrakou, A.; Marsh, H.; Schwenk, F.; Benn, J.; Sonnenberg, G.; Arcangeli, M.; Aoki, T.; Sorensen, J.; Berger, M.; et al. Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J. Clin. Investig. 1988, 81, 1563-1571.
40. Taylor, R.; Price, T.B.; Katz, L.D.; Shulman, R.G.; Shulman, G.I. Direct measurement of change in muscle glycogen concentration after a mixed meal in normal subjects. Am. J. Physiol. 1993, 265, E224-E229.
41. Jiang, G.; Zhang, B.B. Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E671-E678.
42. Paolisso, G.; Scheen, A.J.; Albert, A.; Lefebvre, P.J. Effects of pulsatile delivery of insulin and glucagon in humans. Am. J. Physiol. 1989, 257, E686-E696.
43. Klover, P.J.; Mooney, R.A. Hepatocytes: Critical for glucose homeostasis. Int. J. Biochem. Cell Biol. 2004, 36, 753-758.
44. Cherrington, A.D. Banting lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes 1999, 48, 1198-1214.
45. Nilsson, L.H.; Hultman, E. Liver and muscle glycogen in man after glucose and fructose infusion. Scand. J. Clin. Lab. Investig. 1974, 33, 5-10.
46. van Schaftingen, E.; Gerin, I. The glucose-6-phosphatase system. Biochem. J. 2002, 362, 513-532.
47. Maggs, D.G.; Jacob, R.; Rife, F.; Lange, R.; Leone, P.; During, M.J.; Tamborlane, W.V.; Sherwin, R.S. Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle. J. Clin. Investig. 1995, 96, 370-377.
48. Saltiel, A.R. Diverse signaling pathways in the cellular actions of insulin. Am. J. Physiol. 1996, 270, E375-E385.
49. Reaven, G.M. The insulin resistance syndrome: Definition and dietary approaches to treatment. Annu. Rev. Nutr. 2005, 25, 391-406.
50. Chung, S.T.; Hsia, D.S.; Chacko, S.K.; Rodriguez, L.M.; Haymond, M.W. Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes. Diabetologia 2014, 58, 596-603.
51. Bock, G.; Chittilapilly, E.; Basu, R.; Toffolo, G.; Cobelli, C.; Chandramouli, V.; Landau, B.R.; Rizza, R.A. Contribution of hepatic and extrahepatic insulin resistance to the pathogenesis of impaired fasting glucose: Role of increased rates of gluconeogenesis. Diabetes 2007, 56, 1703-1711.
52. Basu, R.; Barosa, C.; Jones, J.; Dube, S.; Carter, R.; Basu, A.; Rizza, R.A. Pathogenesis of prediabetes: Role of the liver in isolated fasting hyperglycemia and combined fasting and postprandial hyperglycemia. J. Clin. Endocrinol. Metab. 2013, 98, E409-E417.
53. Mykkanen, L.; Zaccaro, D.J.; Wagenknecht, L.E.; Robbins, D.C.; Gabriel, M.; Haffner, S.M. Microalbuminuria is associated with insulin resistance in nondiabetic subjects: The insulin resistance atherosclerosis study. Diabetes 1998, 47, 793-800.
54. Triplitt, C.L. Understanding the kidneys’ role in blood glucose regulation. Am. J. Manag. Care 2012, 18, S11-S16.
55. Meyer, C.; Dostou, J.M.; Welle, S.L.; Gerich, J.E. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 2002, 282, E419-E427.
56. Meyer, C.; Dostou, J.M.; Gerich, J.E. Role of the human kidney in glucose counterregulation. Diabetes 1999, 48, 943-948.
57. Gerich, J.E. Hepatorenal glucose reciprocity in physiologic and pathologic conditions. Diabetes Nutr. Metab. 2002, 15, 298-302.
58. Woerle, H.J.; Meyer, C.; Popa, E.M.; Cryer, P.E.; Gerich, J.E. Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: Further evidence for hepatorenal reciprocity. Diabetes 2003, 52, 1386-1392.
59. Marks, J.; Carvou, N.J.C.; Debnam, E.S.; Srai, S.K.; Unwin, R.J. Diabetes increases facilitative glucose uptake and glut2 expression at the rat proximal tubule brush border membrane. J. Physiol. 2003, 553, 137-145.
60. Noonan, W.T.; Shapiro, V.M.; Banks, R.O. Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci. 2001, 68, 2967-2977.
61. Rahmoune, H.; Thompson, P.W.; Ward, J.M.; Smith, C.D.; Hong, G.; Brown, J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005, 54, 3427-3434.
62. Weickert, M.O. Nutritional modulation of insulin resistance. Scientifica 2012, 2012, 424780.
63. Reaven, G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37, 1595-1607.
64. Grundy, S.M. Metabolic syndrome: Connecting and reconciling cardiovascular and diabetes worlds. J. Am. Coll. Cardiol. 2006, 47, 1093-1100.
65. Lebovitz, H.E. Insulin resistance: Definition and consequences. Exp. Clin. Endocrinol. Diabetes 2001, 109 (Suppl. S2), S135-S148.
66. Patti, M.E. Nutrient modulation of cellular insulin action. Ann. N. Y. Acad. Sci. 1999, 892, 187-203.
67. Krebs, M.; Roden, M. Nutrient-induced insulin resistance in human skeletal muscle. Curr. Med. Chem. 2004, 11, 901-908.
68. Lillioja, S.; Mott, D.M.; Spraul, M.; Ferraro, R.; Foley, J.E.; Ravussin, E.; Knowler, W.C.; Bennett, P.H.; Bogardus, C. Insulin-resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes-mellitus-Prospective studies of pima-indians. N. Engl. J. Med. 1993, 329, 1988-1992.
69. DeFronzo, R.A.; Tripathy, D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009, 32, S157-S163.
70. Krook, A.; Bjornholm, M.; Galuska, D.; Jiang, X.J.; Fahlman, R.; Myers, M.G., Jr.;Wallberg-Henriksson, H.; Zierath, J.R. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000, 49, 284-292.
71. Pratipanawatr, W.; Pratipanawatr, T.; Cusi, K.; Berria, R.; Adams, J.M.; Jenkinson, C.P.; Maezono, K.; DeFronzo, R.A.; Mandarino, L.J. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001, 50, 2572-2578.
72. Cusi, K.; Maezono, K.; Osman, A.; Pendergrass, M.; Patti, M.E.; Pratipanawatr, T.; DeFronzo, R.A.; Kahn, C.R.; Mandarino, L.J. Insulin resistance differentially affects the pi 3-kinase- and map kinase-mediated signaling in human muscle. J. Clin. Investig. 2000, 105, 311-320.
73. Perseghin, G.; Price, T.B.; Petersen, K.F.; Roden, M.; Cline, G.W.; Gerow, K.; Rothman, D.L.; Shulman, G.I. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N. Engl. J. Med. 1996, 335, 1357-1362.
74. Kahn, B.B.; Flier, J.S. Obesity and insulin resistance. J. Clin. Investig. 2000, 106, 473-481.
75. Itani, S.I.; Zhou, Q.; Pories,W.J.; MacDonald, K.G.; Dohm, G.L. Involvement of protein kinase c in human skeletal muscle insulin resistance and obesity. Diabetes 2000, 49, 1353-1358.
76. Itani, S.I.; Ruderman, N.B.; Schmieder, F.; Boden, G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and I kappa B-alpha. Diabetes 2002, 51, 2005-2011.
77. Lara-Castro, C.; Garvey, W.T. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol. Metab. Clin. N. Am. 2008, 37, 841-856.
78. Laybutt, D.R.; Schmitz-Peiffer, C.; Saha, A.K.; Ruderman, N.B.; Biden, T.J.; Kraegen, E.W. Muscle lipid accumulation and protein kinase c activation in the insulin-resistant chronically glucose-infused rat. Am. J. Physiol. 1999, 277, E1070-E1076.
79. Pan, D.A.; Lillioja, S.; Kriketos, A.D.; Milner, M.R.; Baur, L.A.; Bogardus, C.; Jenkins, A.B.; Storlien, L.H. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997, 46, 983-988.
80. Ikeda, Y.; Olsen, G.S.; Ziv, E.; Hansen, L.L.; Busch, A.K.; Hansen, B.F.; Shafrir, E.; Mosthaf-Seedorf, L. Cellular mechanism of nutritionally induced insulin resistance in psammomys obesus: Overexpression of protein kinase cepsilon in skeletal muscle precedes the onset of hyperinsulinemia and hyperglycemia. Diabetes 2001, 50, 584-592.
81. Qu, X.; Seale, J.P.; Donnelly, R. Tissue and isoform-selective activation of protein kinase c in insulin-resistant obese zucker rats-effects of feeding. J. Endocrinol. 1999, 162, 207-214.
82. Mayer, B.; Oberbauer, R. Mitochondrial regulation of apoptosis. News Physiol. Sci. 2003, 18, 89-94.
83. Kelley, D.E.; Mokan, M.; Mandarino, L.J. Intracellular defects in glucose metabolism in obese patients with niddm. Diabetes 1992, 41, 698-706.
84. Reaven, G.M.; Hollenbeck, C.; Jeng, C.Y.;Wu, M.S.; Chen, Y.D. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with niddm. Diabetes 1988, 37, 1020-1024.
85. Petersen, K.F.; Dufour, S.; Shulman, G.I. Decreased insulin-stimulated atp synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2005, 2, e233.
86. Patti, M.E.; Butte, A.J.; Crunkhorn, S.; Cusi, K.; Berria, R.; Kashyap, S.; Miyazaki, Y.; Kohane, I.; Costello, M.; Saccone, R.; et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl. Acad. Sci. USA 2003, 100, 8466-8471.
87. Lefort, N.; Glancy, B.; Bowen, B.; Willis, W.T.; Bailowitz, Z.; De Filippis, E.A.; Brophy, C.; Meyer, C.; Hojlund, K.; Yi, Z.; et al. Increased reactive oxygen species production and lower abundance of complex i subunits and carnitine palmitoyltransferase 1b protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 2010, 59, 2444-2452.
88. Szendroedi, J.; Phielix, E.; Roden, M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2012, 8, 92-103.
89. Hsueh,W.A.; Quinones, M.J. Role of endothelial dysfunction in insulin resistance. Am. J. Cardiol. 2003, 92, 10J-17J.
90. Pinkney, J.H.; Stehouwer, C.D.; Coppack, S.W.; Yudkin, J.S. Endothelial dysfunction: Cause of the insulin resistance syndrome. Diabetes 1997, 46 (Suppl. S2), S9-S13.
91. Cersosimo, E.; DeFronzo, R.A. Insulin resistance and endothelial dysfunction: The road map to cardiovascular diseases. Diabetes/Metab. Res. Rev. 2006, 22, 423-436.
92. Rizza, R.A. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: Implications for therapy. Diabetes 2010, 59, 2697-2707.
93. Basu, R.; Chandramouli, V.; Dicke, B.; Landau, B.; Rizza, R. Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Diabetes 2005, 54, 1942-1948.
94. Lin, H.V.; Accili, D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 2011, 14, 9-19.
95. Fisher, S.J.; Kahn, C.R. Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production. J. Clin. Investig. 2003, 111, 463-468.
96. Ishihara, H.; Maechler, P.; Gjinovci, A.; Herrera, P.L.; Wollheim, C.B. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nat. Cell Biol. 2003, 5, 330-335.
97. Granner, D.; Andreone, T.; Sasaki, K.; Beale, E. Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin. Nature 1983, 305, 549-551.
98. Dickens, M.; Svitek, C.A.; Culbert, A.A.; O’Brien, R.M.; Tavare, J.M. Central role for phosphatidylinositide 3-kinase in the repression of glucose-6-phosphatase gene transcription by insulin. J. Biol. Chem. 1998, 273, 20144-20149.
99. Li, X.; Monks, B.; Ge, Q.; Birnbaum, M.J. Akt/PKB regulates hepatic metabolism by directly inhibiting pgc-1alpha transcription coactivator. Nature 2007, 447, 1012-1016.
100. Cross, D.A.E.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen-synthase kinase-3 by insulin-mediated by protein-kinase-b. Nature 1995, 378, 785-789.
101. van Weeren, P.C.; de Bruyn, K.M.T.; de Vries-Smits, A.M.M.; van Lint, J.; Burgering, B.M.T. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation-Characterization of dominant-negative mutant of pkb. J. Biol. Chem. 1998, 273, 13150-13156.
102. Arden, K.C.; Biggs,W.H. Regulation of the foxo family of transcription factors by phosphatidylinositol-3 kinase-activated signaling. Arch. Biochem. Biophys. 2002, 403, 292-298.
103. Samuel, V.T.; Beddow, S.A.; Iwasaki, T.; Zhang, X.M.; Chu, X.; Still, C.D.; Gerhard, G.S.; Shulman, G.I. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with type 2 diabetes. Proc. Natl. Acad. Sci. USA 2009, 106, 12121-12126.
104. Clore, J.N.; Stillman, J.; Sugerman, H. Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes 2000, 49, 969-974.
105. Barthel, A.; Schmoll, D.; Unterman, T.G. Foxo proteins in insulin action and metabolism. Trends Endocrinol. Metab. 2005, 16, 183-189.
106. Zhang,W.; Patil, S.; Chauhan, B.; Guo, S.; Powell, D.R.; Le, J.; Klotsas, A.; Matika, R.; Xiao, X.; Franks, R.; et al. Foxo1 regulates multiple metabolic pathways in the liver: Effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 2006, 281, 10105-10117.
107. Haeusler, R.A.; Kaestner, K.H.; Accili, D. Foxos function synergistically to promote glucose production. J. Biol. Chem. 2010, 285, 35245-35248.
108. Puigserver, P.; Rhee, J.; Donovan, J.;Walkey, C.J.; Yoon, J.C.; Oriente, F.; Kitamura, Y.; Altomonte, J.; Dong, H.J.; Accili, D.; et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1 alpha interaction. Nature 2003, 423, 550-555.
109. Wang, M.; Wang, X.C.; Zhang, Z.Y.; Mou, B.; Hu, R.M. Impaired mitochondrial oxidative phosphorylation in multiple insulin-sensitive tissues of humans with type 2 diabetes mellitus. J. Int. Med. Res. 2010, 38, 769-781.
110. Kim, D.H.; Perdomo, G.; Zhang, T.; Slusher, S.; Lee, S.; Phillips, B.E.; Fan, Y.; Giannoukakis, N.; Gramignoli, R.; Strom, S.; et al. Foxo6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes 2011, 60, 2763-2774.
111. Perry, R.J.; Samuel, V.T.; Petersen, K.F.; Shulman, G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510, 84-91.
112. Abdelmalek, M.F.; Diehl, A.M. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med. Clin. N. Am. 2007, 91, 1125-1149.
113. Brons, C.; Jensen, C.B.; Storgaard, H.; Hiscock, N.J.; White, A.; Appel, J.S.; Jacobsen, S.; Nilsson, E.; Larsen, C.M.; Astrup, A.; et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J. Physiol. 2009, 587, 2387-2397.
114. Samuel, V.T.; Liu, Z.X.; Qu, X.; Elder, B.D.; Bilz, S.; Befroy, D.; Romanelli, A.J.; Shulman, G.I. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 2004, 279, 32345-32353.
115. Magkos, F.; Su, X.; Bradley, D.; Fabbrini, E.; Conte, C.; Eagon, J.C.; Varela, J.E.; Brunt, E.M.; Patterson, B.W.; Klein, S. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology 2012, 142, 1444-1446.
116. Mantena, S.K.; Vaughn, D.P.; Andringa, K.K.; Eccleston, H.B.; King, A.L.; Abrams, G.A.; Doeller, J.E.; Kraus, D.W.; Darley-Usmar, V.M.; Bailey, S.M. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem. J. 2009, 417, 183-193.
117. Seidell, J.C. Obesity, insulin resistance and diabetes-A worldwide epidemic. Br. J. Nutr. 2000, 83 (Suppl. S1), S5-S8.
118. Colditz, G.A.;Willett, W.C.; Stampfer, M.J.; Manson, J.E.; Hennekens, C.H.; Arky, R.A.; Speizer, F.E.Weight as a risk factor for clinical diabetes in women. Am. J. Epidemiol. 1990, 132, 501-513.
119. Xu, H.; Barnes, G.T.; Yang, Q.; Tan, G.; Yang, D.; Chou, C.J.; Sole, J.; Nichols, A.; Ross, J.S.; Tartaglia, L.A.; et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821-1830.
120. Berg, A.H.; Scherer, P.E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005, 96, 939-949.
121. Ferroni, P.; Basili, S.; Falco, A.; Davi, G. Inflammation, insulin resistance, and obesity. Curr. Atheroscler. Rep. 2004, 6, 424-431.
122. Permana, P.A.; Menge, C.; Reaven, P.D. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem. Biophys. Res. Commun. 2006, 341, 507-514.
123. Boutens, L.; Stienstra, R. Adipose tissue macrophages: Going off track during obesity. Diabetologia 2016, 59, 879-894.
124. Tsigos, C.; Kyrou, I.; Chala, E.; Tsapogas, P.; Stavridis, J.C.; Raptis, S.A.; Katsilambros, N. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metab. Clin. Exp. 1999, 48, 1332-1335.
125. Weisberg, S.P.; McCann, D.; Desai, M.; Rosenbaum, M.; Leibel, R.L.; Ferrante, A.W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003, 112, 1796-1808.
126. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87-91.
127. Hotamisligil, G.S.; Murray, D.L.; Choy, L.N.; Spiegelman, B.M. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc. Natl. Acad. Sci. USA 1994, 91, 4854-4858.
128. Uysal, K.T.; Wiesbrock, S.M.; Marino, M.W.; Hotamisligil, G.S. Protection from obesity-induced insulin resistance in mice lacking tnf-alpha function. Nature 1997, 389, 610-614.
129. Hotamisligil, G.S. Inflammatory pathways and insulin action. Int. J. Obes. Relat. Metab. Disord. 2003, 27 (Suppl. S3), S53-S55.
130. Steinberg, G.R. Inflammation in obesity is the common link between defects in fatty acid metabolism and insulin resistance. Cell Cycle 2007, 6, 888-894.
131. Bergeron, R.; Previs, S.F.; Cline, G.W.; Perret, P.; Russell, R.R., 3rd; Young, L.H.; Shulman, G.I. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese zucker rats. Diabetes 2001, 50, 1076-1082.
132. Steinberg, G.R.; Kemp, B.E. AMPK in health and disease. Physiol. Rev. 2009, 89, 1025-1078.
133. Carling, D.; Sanders, M.J.;Woods, A. The regulation of amp-activated protein kinase by upstream kinases. Int. J. Obes. 2008, 32 (Suppl. S4), S55-S59.
134. Witczak, C.A.; Sharoff, C.G.; Goodyear, L.J. Amp-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism. Cell. Mol. Life Sci. 2008, 65, 3737-3755.
135. Jorgensen, S.B.;Wojtaszewski, J.F.; Viollet, B.; Andreelli, F.; Birk, J.B.; Hellsten, Y.; Schjerling, P.; Vaulont, S.; Neufer, P.D.; Richter, E.A.; et al. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J. 2005, 19, 1146-1148.
136. Canto, C.; Gerhart-Hines, Z.; Feige, J.N.; Lagouge, M.; Noriega, L.; Milne, J.C.; Elliott, P.J.; Puigserver, P.; Auwerx, J. AMPK regulates energy expenditure by modulating nad+ metabolism and sirt1 activity. Nature 2009, 458, 1056-1060.
137. Holmes, B.F.; Kurth-Kraczek, E.J.; Winder, W.W. Chronic activation of 50-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J. Appl. Physiol. 1999, 87, 1990-1995.
138. Steinberg, G.R.; Michell, B.J.; van Denderen, B.J.; Watt, M.J.; Carey, A.L.; Fam, B.C.; Andrikopoulos, S.; Proietto, J.; Gorgun, C.Z.; Carling, D.; et al. Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of amp-kinase signaling. Cell Metab. 2006, 4, 465-474.
139. Mohamed-Ali, V.; Goodrick, S.; Bulmer, K.; Holly, J.M.; Yudkin, J.S.; Coppack, S.W. Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am. J. Physiol. 1999, 277, E971-E975.
140. Natali, A.; Toschi, E.; Baldeweg, S.; Ciociaro, D.; Favilla, S.; Sacca, L.; Ferrannini, E. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Diabetes 2006, 55, 1133-1140.
141. Bataille, R.; Klein, B. C-reactive protein-levels as a direct indicator of interleukin-6 levels in humans in vivo. Arthritis Rheum. 1992, 35, 982-983.
142. Yudkin, J.S.; Stehouwer, C.D.; Emeis, J.J.; Coppack, S.W. C-reactive protein in healthy subjects: Associations with obesity, insulin resistance, and endothelial dysfunction: A potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 1999, 19, 972-978.
143. Carey, A.L.; Steinberg, G.R.; Macaulay, S.L.; Thomas, W.G.; Holmes, A.G.; Ramm, G.; Prelovsek, O.; Hohnen-Behrens, C.; Watt, M.J.; James, D.E.; et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via amp-activated protein kinase. Diabetes 2006, 55, 2688-2697.
144. Yuen, D.Y.; Dwyer, R.M.; Matthews, V.B.; Zhang, L.; Drew, B.G.; Neill, B.; Kingwell, B.A.; Clark, M.G.; Rattigan, S.; Febbraio, M.A. Interleukin-6 attenuates insulin-mediated increases in endothelial cell signaling but augments skeletal muscle insulin action via differential effects on tumor necrosis factor-alpha expression. Diabetes 2009, 58, 1086-1095.
145. Harder-Lauridsen, N.M.; Krogh-Madsen, R.; Holst, J.J.; Plomgaard, P.; Leick, L.; Pedersen, B.K.; Fischer, C.P. Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2014, 306, E769-E778.
146. Hu, E.; Liang, P.; Spiegelman, B.M. Adipoq is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 1996, 271, 10697-10703.
147. Fargnoli, J.L.; Sun, Q.; Olenczuk, D.; Qi, L.; Zhu, Y.; Hu, F.B.; Mantzoros, C.S. Resistin is associated with biomarkers of inflammation while total and high-molecular weight adiponectin are associated with biomarkers of inflammation, insulin resistance, and endothelial function. Eur. J. Endocrinol. 2010, 162, 281-288.
148. Swarbrick, M.M.; Havel, P.J. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Metab. Syndr. Relat. Disord. 2008, 6, 87-102.
149. Kopp, H.P.; Krzyzanowska, K.; Mohlig, M.; Spranger, J.; Pfeiffer, A.F.; Schernthaner, G. Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women. Int. J. Obes. 2005, 29, 766-771.
150. Yamauchi, T.; Kamon, J.; Waki, H.; Terauchi, Y.; Kubota, N.; Hara, K.; Mori, Y.; Ide, T.; Murakami, K.; Tsuboyama-Kasaoka, N.; et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 2001, 7, 941-946.
151. Koch, C.E.; Lowe, C.; Legler, K.; Benzler, J.; Boucsein, A.; Bottiger, G.; Grattan, D.R.; Williams, L.M.; Tups, A. Central adiponectin acutely improves glucose tolerance in male mice. Endocrinology 2014, 155, 1806-1816.
152. Yamauchi, T.; Kamon, J.; Ito, Y.; Tsuchida, A.; Yokomizo, T.; Kita, S.; Sugiyama, T.; Miyagishi, M.; Hara, K.; Tsunoda, M.; et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003, 423, 762-769.
153. Yamauchi, T.; Nio, Y.; Maki, T.; Kobayashi, M.; Takazawa, T.; Iwabu, M.; Okada-Iwabu, M.; Kawamoto, S.; Kubota, N.; Kubota, T.; et al. Targeted disruption of adipor1 and adipor2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 2007, 13, 332-339.
154. Yadav, A.; Kataria, M.A.; Saini, V.; Yadav, A. Role of leptin and adiponectin in insulin resistance. Clin. Chim. Acta Int. J. Clin. Chem. 2013, 417, 80-84.
155. Awazawa, M.; Ueki, K.; Inabe, K.; Yamauchi, T.; Kaneko, K.; Okazaki, Y.; Bardeesy, N.; Ohnishi, S.; Nagai, R.; Kadowaki, T. Adiponectin suppresses hepatic srebp1c expression in an adipor1/lkb1/AMPK dependent pathway. Biochem. Biophys. Res. Commun. 2009, 382, 51-56.
156. Yamauchi, T.; Kamon, J.;Minokoshi, Y.; Ito, Y.;Waki, H.; Uchida, S.; Yamashita, S.; Noda,M.; Kita, S.; Ueki, K.; et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating amp-activated protein kinase. Nat. Med. 2002, 8, 1288-1295.
157. Awazawa, M.; Ueki, K.; Inabe, K.; Yamauchi, T.; Kubota, N.; Kaneko, K.; Kobayashi, M.; Iwane, A.; Sasako, T.; Okazaki, Y.; et al. Adiponectin enhances insulin sensitivity by increasing hepatic irs-2 expression via a macrophage-derived IL-6-dependent pathway. Cell Metab. 2011, 13, 401-412.
158. Clark, A.; Jones, L.C.; de Koning, E.; Hansen, B.C.; Matthews, D.R. Decreased insulin secretion in type 2 diabetes: A problem of cellular mass or function? Diabetes 2001, 50 (Suppl. S1), S169-S171.
159. Kahn, S.E.; Zraika, S.; Utzschneider, K.M.; Hull, R.L. The beta cell lesion in type 2 diabetes: There has to be a primary functional abnormality. Diabetologia 2009, 52, 1003-1012.
160. Donath, M.Y.; Ehses, J.A.; Maedler, K.; Schumann, D.M.; Ellingsgaard, H.; Eppler, E.; Reinecke, M. Mechanisms of beta-cell death in type 2 diabetes. Diabetes 2005, 54, S108-S113.
161. Meier, J.J.; Bonadonna, R.C. Role of reduced beta-cell mass versus impaired beta-cell function in the pathogenesis of type 2 diabetes. Diabetes Care 2013, 36, S113-S119.
162. Vijayalingam, S.; Parthiban, A.; Shanmugasundaram, K.R.; Mohan, V. Abnormal antioxidant status in impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Diabet. Med. J. Br. Diabet. Assoc. 1996, 13, 715-719.
163. Bast, A.; Wolf, G.; Oberbaumer, I.; Walther, R. Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells. Diabetologia 2002, 45, 867-876.
164. Robertson, R.P.; Harmon, J.; Tran, P.O.; Tanaka, Y.; Takahashi, H. Glucose toxicity in beta-cells: Type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003, 52, 581-587.
165. Kashyap, S.; Belfort, R.; Gastaldelli, A.; Pratipanawatr, T.; Berria, R.; Pratipanawatr,W.; Bajaj,M.;Mandarino, L.; DeFronzo, R.; Cusi, K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003, 52, 2461-2474.
166. Santomauro,A.T.; Boden,G.; Silva,M.E.; Rocha,D.M.; Santos, R.F.;Ursich,M.J.; Strassmann, P.G.;Wajchenberg, B.L. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 1999, 48, 1836-1841.
167. Poitout, V.; Robertson, R.P. Minireview: Secondary beta-cell failure in type 2 diabetes-A convergence of glucotoxicity and lipotoxicity. Endocrinology 2002, 143, 339-342.
168. Havsteen, B. Flavonoids, a class of natural products of high pharmacological potency. Biochem. Pharmacol. 1983, 32, 1141-1148.
169. Harborne, J.B. Plant Flavonoids in Biology and Medicine; Alan R. Liss: New York, NY, USA, 1986; pp. 15-24.
170. Stevenson, D.E.; Hurst, R.D. Polyphenolic phytochemicals-Just antioxidants or much more? Cell. Mol. Life Sci. 2007, 64, 2900-2916.
171. Moore, J.P.; Westall, K.L.; Ravenscroft, N.; Farrant, J.M.; Lindsey, G.G.; Brandt, W.F. The predominant polyphenol in the leaves of the resurrection plant myrothamnus flabellifolius, 3,4,5 tri-O-galloylquinic acid, protects membranes against desiccation and free radical-induced oxidation. Biochem. J. 2005, 385, 301-308.
172. Ryan, K.G.; Swinny, E.E.; Markham, K.R.; Winefield, C. Flavonoid gene expression and uv photoprotection in transgenic and mutant petunia leaves. Phytochemistry 2002, 59, 23-32.
173. Petrussa, E.; Braidot, E.; Zancani, M.; Peresson, C.; Bertolini, A.; Patui, S.; Vianello, A. Plant flavonoids-Biosynthesis, transport and involvement in stress responses. Int. J. Mol. Sci. 2013, 14, 14950-14973.
174. Webster, G.; Jain, V.; Davey, M.R.; Gough, C.; Vasse, J.; Denarie, J.; Cocking, E.C. The flavonoid naringenin stimulates the intercellular colonization of wheat roots by azorhizobium caulinodans. Plant Cell Environ. 1998, 21, 373-383.
175. Harborne, J.B. The comparative biochemistry of phytoalexin induction in plants. Biochem. Syst. Ecol. 1999, 27, 335-367.
176. Havsteen, B.H. The biochemistry and medical significance of the flavonoids. Pharm. Ther. 2002, 96, 67-202.
177. Rusznyak, S.; Szent-Gyorgyi, A. Vitamin P: Flavonols as vitamins. Nature 1936, 138, 27.
178. Harborne, J.B.; Mabry, T.J.; Mabry, H. The Flavonoids; Academic Press: New York, NY, USA, 1975.
179. Kuhnau, J. The flavonoids. A class of semi-essential food components: Their role in human nutrition. World Rev. Nutr. Diet. 1976, 24, 117-191.
180. Scalbert, A.; Johnson, I.T.; Saltmarsh, M. Polyphenols: Antioxidants and beyond. Am. J. Clin. Nutr. 2005, 81, 215s-217s.
181. Tapas, A.R.; Sakarkar, D.M.; Kakde, R.B. Flavonoids as nutraceuticals: A review. Trop. J. Pharm. Res. 2008, 7, 1089-1099.
182. Espin, J.C.; Garcia-Conesa, M.T.; Tomas-Barberan, F.A. Nutraceuticals: Facts and fiction. Phytochemistry 2007, 68, 2986-3008.
183. Dillard, C.J.; German, J.B. Phytochemicals: Nutraceuticals and human health. J. Sci. Food. Agric. 2000, 80, 1744-1756.
184. Williams, C.A.; Grayer, R.J. Anthocyanins and other flavonoids. Nat. Prod. Rep. 2004, 21, 539-573.
185. Beecher, G.R. Overview of dietary flavonoids: Nomenclature, occurrence and intake. J. Nutr. 2003, 133, 3248S-3254S.
186. Dixon, R.A.; Pasinetti, G.M. Flavonoids and isoflavonoids: From plant biology to agriculture and neuroscience. Plant Physiol. 2010, 154, 453-457.
187. Debeaujon, I.; Peeters, A.J.; Leon-Kloosterziel, K.M.; Koornneef, M. The transparent testa12 gene of arabidopsis encodes a multidrug secondary transporter-like protein required for flavonoid sequestration in vacuoles of the seed coat endothelium. Plant Cell 2001, 13, 853-871.
188. Hertog, M.G.L.; Hollman, P.C.H.; Katan, M.B. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the netherlands. J. Agric. Food Chem. 1992, 40, 2379-2383.
189. Ewald, C.; Fjelkner-Modig, S.; Johansson, K.; Sjoholm, I.; Akesson, B. Effect of processing on major flavonoids in processed onions, green beans, and peas. Food Chem. 1999, 64, 231-235.
190. Pennington, J.A.T. Food composition databases for bioactive food components. J. Food. Compos. Anal. 2002, 15, 419-434.
191. Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. USDA Database for the Flavonoid Content of Selected Foods, Release 3.1; U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory: Beltsville, MD, USA, 2013.
192. Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. USDA Database for the Isoflavone Content of Selected Foods, Release 2.0; U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory: Beltsville, MD, USA, 2008.
193. Chun, O.K.; Chung, S.J.; Song, W.O. Estimated dietary flavonoid intake and major food sources of U.S. Adults. J. Nutr. 2007, 137, 1244-1252.
194. Bai, W.; Wang, C.; Ren, C. Intakes of total and individual flavonoids by us adults. Int. J. Food Sci. Nutr. 2014, 65, 9-20.
195. Bhagwat, S.; Haytowitz, D.B.; Wasswa-Kintu, S.I.; Holden, J.M. Usda develops a database for flavonoids to assess dietary intakes. Proc. Food Sci. 2013, 2, 81-86.
196. Walle, T.; Browning, A.M.; Steed, L.L.; Reed, S.G.; Walle, U.K. Flavonoid glucosides are hydrolyzed and thus activated in the oral cavity in humans. J. Nutr. 2005, 135, 48-52.
197. Piskula, M.K. Factors affecting flavonoids absorption. Biofactors 2000, 12, 175-180.
198. Walle, T.; Otake, Y.; Walle, U.K.; Wilson, F.A. Quercetin glucosides are completely hydrolyzed in ileostomy patients before absorption. J. Nutr. 2000, 130, 2658-2661.
199. Day, A.J.; DuPont, M.S.; Ridley, S.; Rhodes, M.; Rhodes, M.J.C.; Morgan, M.R.A.; Williamson, G. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity. FEBS Lett. 1998, 436, 71-75.
200. Nemeth, K.; Plumb, G.W.; Berrin, J.G.; Juge, N.; Jacob, R.; Naim, H.Y.; Williamson, G.; Swallow, D.M.; Kroon, P.A. Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur. J. Nutr. 2003, 42, 29-42.
201. Spencer, J.P.E.; Chowrimootoo, G.; Choudhury, R.; Debnam, E.S.; Srai, S.K.; Rice-Evans, C. The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett. 1999, 458, 224-230.
202. Spencer, J.P.E.; Schroeter, H.; Rechner, A.R.; Rice-Evans, C. Bioavailability of flavan-3-ols and procyanidins: Gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid. Redox Signal. 2001, 3, 1023-1039.
203. Piskula, M.K.; Terao, J. Accumulation of (-)-epicatechin metabolites in rat plasma after oral administration and distribution of conjugation enzymes in rat tissues. J. Nutr. 1998, 128, 1172-1178.
204. Manach, C.; Morand, C.; Texier, O.; Favier, M.L.; Agullo, G.; Demigne, C.; Regerat, F.; Remesy, C. Quercetin metabolites in plasma of rats fed diets containing rutin or quercetin. J. Nutr. 1995, 125, 1911-1922.
205. Landete, J.M. Updated knowledge about polyphenols: Functions, bioavailability, metabolism, and health. Crit. Rev. Food Sci. Nutr. 2012, 52, 936-948.
206. Crespy, V.; Morand, C.; Manach, C.; Besson, C.; Demigne, C.; Remesy, C. Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am. J. Physiol. 1999, 277, G120-G126.
207. Kim, D.H.; Jung, E.A.; Sohng, I.S.; Han, J.A.; Kim, T.H.; Han, M.J. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch. Pharm. Res. 1998, 21, 17-23.
208. Meselhy, M.R.; Nakamura, N.; Hattori, M. Biotransformation of (-)-epicatechin 3-o-gallate by human intestinal bacteria. Chem. Pharm. Bull. 1997, 45, 888-893.
209. Scalbert, A.;Williamson, G. Dietary intake and bioavailability of polyphenols. J. Nutr. 2000, 130, 2073S-2085S.
210. Vukics, V.; Guttman, A. Structural characterization of flavonoid glycosides by multi-stage mass spectrometry. Mass Spectrom. Rev. 2010, 29, 1-16.
211. Hollman, P.C.; Katan, M.B. Dietary flavonoids: Intake, health effects and bioavailability. Food Chem. Toxicol. 1999, 37, 937-942.
212. Okushio, K.; Matsumoto, N.; Kohri, T.; Suzuki, M.; Nanjo, F.; Hara, Y. Absorption of tea catechins into rat portal vein. Biol. Pharm. Bull. 1996, 19, 326-329.
213. Crespy, V.; Morand, C.; Besson, C.; Manach, C.; Demigne, C.; Remesy, C. Quercetin, but not its glycosides, is absorbed from the rat stomach. J. Agric. Food Chem. 2002, 50, 618-621.
214. Arts, I.C.W.; Sesink, A.L.A.; Faassen-Peters, M.; Hollman, P.C.H. The type of sugar moiety is a major determinant of the small intestinal uptake and subsequent biliary excretion of dietary quercetin glycosides. Br. J. Nutr. 2004, 91, 841-847.
215. Graefe, E.U.; Wittig, J.; Mueller, S.; Riethling, A.K.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.; Derendorf, H.; Veit, M. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin. Pharmacol. 2001, 41, 492-499.
216. Hollman, P.C.; de Vries, J.H.; van Leeuwen, S.D.; Mengelers, M.J.; Katan, M.B. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am. J. Clin. Nutr. 1995, 62, 1276-1282.
217. Olthof, M.R.; Hollman, P.C.; Vree, T.B.; Katan, M.B. Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans. J. Nutr. 2000, 130, 1200-1203.
218. Cao, G.; Sofic, E.; Prior, R.L. Antioxidant and prooxidant behavior of flavonoids: Structure-activity relationships. Free Radic. Biol. Med. 1997, 22, 749-760.
219. Garcia-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M.A.; Martinez, J.A. Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease. Inflamm. Res. 2009, 58, 537-552.
220. Chahar, M.K.; Sharma, N.; Dobhal, M.P.; Joshi, Y.C. Flavonoids: A versatile source of anticancer drugs. Pharmacogn. Rev. 2011, 5, 1-12.
221. Chang, Y.C.; Nair, M.G. Metabolism of daidzein and genistein by intestinal bacteria. J. Nat. Prod. 1995, 58, 1892-1896.
222. Manach, C.; Morand, C.; Crespy, V.; Demigne, C.; Texier, O.; Regerat, F.; Remesy, C. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett. 1998, 426, 331-336.
223. Bell, J.R.; Donovan, J.L.; Wong, R.; Waterhouse, A.L.; German, J.B.; Walzem, R.L.; Kasim-Karakas, S.E. (+)-catechin in human plasma after ingestion of a single serving of reconstituted red wine. Am. J. Clin. Nutr. 2000, 71, 103-108.
224. Hollman, P.C.H. Absorption, bioavailability, and metabolism of flavonoids. Arch. Physiol. Biochem. 2004, 42, 74-83.
225. Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Remesy, C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 2005, 81, 230s-242s.
226. Paganga, G.; Rice-Evans, C.A. The identification of flavonoids as glycosides in human plasma. FEBS Lett. 1997, 401, 78-82.
227. Cao, J.; Zhang, Y.; Chen,W.; Zhao, X. The relationship between fasting plasma concentrations of selected flavonoids and their ordinary dietary intake. Br. J. Nutr. 2010, 103, 249-255.
228. Young, J.F.; Nielsen, S.E.; Haraldsdottir, J.; Daneshvar, B.; Lauridsen, S.T.; Knuthsen, P.; Crozier, A.; Sandstrom, B.; Dragsted, L.O. Effect of fruit juice intake on urinary quercetin excretion and biomarkers of antioxidative status. Am. J. Clin. Nutr. 1999, 69, 87-94.
229. Rechner, A.R.; Kuhnle, G.; Bremner, P.; Hubbard, G.P.; Moore, K.P.; Rice-Evans, C.A. The metabolic fate of dietary polyphenols in humans. Free Radic. Biol. Med. 2002, 33, 220-235.
230. Erlund, I.; Kosonen, T.; Alfthan, G.; Maenpaa, J.; Perttunen, K.; Kenraali, J.; Parantainen, J.; Aro, A. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur. J. Clin. Pharmacol. 2000, 56, 545-553.
231. Erlund, I.; Freese, R.; Marniemi, J.; Hakala, P.; Alfthan, G. Bioavailability of quercetin from berries and the diet. Nutr. Cancer 2006, 54, 13-17.
232. Zhang, Y.; Song, T.T.; Cunnick, J.E.; Murphy, P.A.; Hendrich, S. Daidzein and genistein glucuronides in vitro are weakly estrogenic and activate human natural killer cells at nutritionally relevant concentrations. J. Nutr. 1999, 129, 399-405.
233. Selma, M.V.; Espin, J.C.; Tomas-Barberan, F.A. Interaction between phenolics and gut microbiota: Role in human health. J. Agric. Food Chem. 2009, 57, 6485-6501.
234. Sampson, L.; Rimm, E.; Hollman, P.C.; de Vries, J.H.; Katan, M.B. Flavonol and flavone intakes in us health professionals. J. Am. Diet. Assoc. 2002, 102, 1414-1420.
235. Galati, G.; O’Brien, P.J. Potential toxicity of flavonoids and other dietary phenolics: Significance for their chemopreventive and anticancer properties. Free Radic. Biol. Med. 2004, 37, 287-303.
236. Pamukcu, A.M.; Yalciner, S.; Hatcher, J.F.; Bryan, G.T. Quercetin, a rat intestinal and bladder carcinogen present in bracken fern (pteridium aquilinum). Cancer Res. 1980, 40, 3468-3472.
237. Sahu, S.C.; Gray, G.C. Interactions of flavonoids, trace metals, and oxygen: Nuclear DNA damage and lipid peroxidation induced by myricetin. Cancer Lett. 1993, 70, 73-79.
238. Sahu, S.C.; Gray, G.C. Kaempferol-induced nuclear DNA damage and lipid peroxidation. Cancer Lett. 1994, 85, 159-164.
239. Dickinson, A.; Boyon, N.; Shao, A. Physicians and nurses use and recommend dietary supplements: Report of a survey. Nutr. J. 2009, 8.
240. Brantsaeter, A.L.; Haugen, M.; Hagve, T.A.; Aksnes, L.; Rasmussen, S.E.; Julshamn, K.; Alexander, J.; Meltzer, H.M. Self-reported dietary supplement use is confirmed by biological markers in the norwegian mother and child cohort study (moba). Ann. Nutr. Metab. 2007, 51, 146-154.
241. Halliwell, B. Dietary polyphenols: Good, bad, or indifferent for your health? Cardiovasc. Res. 2007, 73, 341-347.
242. Popp, R.; Schimmer, O. Induction of sister-chromatid exchanges (SCE), polyploidy, and micronuclei by plant flavonoids in human lymphocyte cultures. A comparative study of 19 flavonoids. Mutat. Res. 1991, 246, 205-213.
243. Tiwari, A.K.; Rao, J.M. Diabetes mellitus and multiple therapeutic approaches of phytochemicals: Present status and future prospects. Curr. Sci. India 2002, 83, 30-38.
244. Kaneto, H.; Katakami, N.; Matsuhisa, M.; Matsuoka, T.A. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediat. Inflamm. 2010, 2010, 453892.
245. Rolin, B.; Larsen, M.O.; Gotfredsen, C.F.; Deacon, C.F.; Carr, R.D.; Wilken, M.; Knudsen, L.B. The long-acting glp-1 derivative nn2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am. J. Physiol. Endocrinol. Metab. 2002, 283, E745-E752.
246. Kotchen, T.A. Attenuation of hypertension by insulin-sensitizing agents. Hypertension 1996, 28, 219-223.
247. Derosa, G.; D’Angelo, A.; Ragonesi, P.D.; Ciccarelli, L.; Piccinni, M.N.; Pricolo, F.; Salvadeo, S.A.; Montagna, L.; Gravina, A.; Ferrari, I.; et al. Metformin-pioglitazone and metformin-rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome. J. Clin. Pharm. Ther. 2006, 31, 375-383.
248. White, M.F. Insulin signaling in health and disease. Science 2003, 302, 1710-1711.
249. Houstis, N.; Rosen, E.D.; Lander, E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006, 440, 944-948.
250. Evans, J.L.; Goldfine, I.D.; Maddux, B.A.; Grodsky, G.M. Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocr. Rev. 2002, 23, 599-622.
251. Kravchenko, L.V.; Morozov, S.V.; Tutel’yan, V.A. Effects of flavonoids on the resistance of microsomes to lipid peroxidation in vitro and ex vivo. Bull. Exp. Biol. Med. 2003, 136, 572-575.
252. Valenzuela, A.; Lagos, C.; Schmidt, K.; Videla, L.A. Silymarin protection against hepatic lipid-peroxidation induced by acute ethanol intoxication in the rat. Biochem. Pharmacol. 1985, 34, 2209-2212.
253. Yao, X.; Zhu, L.; Chen, Y.; Tian, J.;Wang, Y. In vivo and in vitro antioxidant activity and alpha-glucosidase, alpha-amylase inhibitory effects of flavonoids from cichorium glandulosum seeds. Food Chem. 2013, 139, 59-66.
254. Yi, L.; Chen, C.Y.; Jin, X.; Zhang, T.; Zhou, Y.; Zhang, Q.Y.; Zhu, J.D.; Mi, M.T. Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids. Biochimie 2012, 94, 2035-2044.
255. Lin, C.M.; Chen, C.T.; Lee, H.H.; Lin, J.K. Prevention of cellular ros damage by isovitexin and related flavonoids. Planta Medica 2002, 68, 365-367.
256. Lotito, S.B.; Frei, B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon? Free Radic. Biol. Med. 2006, 41, 1727-1746.
257. Brunetti, C.; Di Ferdinando, M.; Fini, A.; Pollastri, S.; Tattini, M. Flavonoids as antioxidants and developmental regulators: Relative significance in plants and humans. Int. J. Mol. Sci. 2013, 14, 3540-3555.
258. Papas, A.M. Determinants of antioxidant status in humans. Lipids 1996, 31, S77-S82.
259. Gray, G.M. Carbohydrate digestion and absorption. Role of the small intestine. N. Engl. J. Med. 1975, 292, 1225-1230.
260. Luna, B.; Feinglos, M.N. Oral agents in the management of type 2 diabetes mellitus. Am. Fam. Phys. 2001, 63, 1747-1756.
261. Cheng, A.Y.; Fantus, I.G. Oral antihyperglycemic therapy for type 2 diabetes mellitus. Can. Med. Assoc. J. 2005, 172, 213-226.
262. Li, Y.Q.; Zhou, F.C.; Gao, F.; Bian, J.S.; Shan, F. Comparative evaluation of quercetin, isoquercetin and rutin as inhibitors of alpha-glucosidase. J. Agric. Food. Chem. 2009, 57, 11463-11468.
263. Zhang, X.; Liu, Z.; Bi, X.; Liu, J.; Li,W.; Zhao, Y. Flavonoids and its derivatives from callistephus chinensis flowers and their inhibitory activities against alpha-glucosidase. EXCLI J. 2013, 12, 956-966.
264. Pereira, D.F.; Cazarolli, L.H.; Lavado, C.; Mengatto, V.; Figueiredo, M.S.R.B.; Guedes, A.; Pizzolatti, M.G.; Silva, F.R.M.B. Effects of flavonoids on alpha-glucosidase activity: Potential targets for glucose homeostasis. Nutrition 2011, 27, 1161-1167.
265. Cermak, R.; Landgraf, S.; Wolffram, S. Quercetin glucosides inhibit glucose uptake into brush-border-membrane vesicles of porcine jejunum. Br. J. Nutr. 2004, 91, 849-855.
266. Song, J.; Kwon, O.; Chen, S.L.; Daruwala, R.; Eck, P.; Park, J.B.; Levine, M. Flavonoid inhibition of sodium-dependent vitamin c transporter 1 (SVCT1) and glucose transporter isoform 2 (GLUT2), intestinal transporters for vitamin c and glucose. J. Biol. Chem. 2002, 277, 15252-15260.
267. Goto, T.; Horita, M.; Nagai, H.; Nagatomo, A.; Nishida, N.; Matsuura, Y.; Nagaoka, S. Tiliroside, a glycosidic flavonoid, inhibits carbohydrate digestion and glucose absorption in the gastrointestinal tract. Mol. Nutr. Food Res. 2012, 56, 435-445.
268. de la Garza, A.L.; Etxeberria, U.; Lostao, M.P.; San Roman, B.; Barrenetxe, J.; Martinez, J.A.; Milagro, F.I. Helichrysum and grapefruit extracts inhibit carbohydrate digestion and absorption, improving postprandial glucose levels and hyperinsulinemia in rats. J. Agric. Food Chem. 2013, 61, 12012-12019.
269. Kim, J.S.; Kwon, C.S.; Son, K.H. Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. Biosci. Biotechnol. Biochem. 2000, 64, 2458-2461.
270. Matsui, T.; Kobayashi, M.; Hayashida, S.; Matsumoto, K. Luteolin, a flavone, does not suppress postprandial glucose absorption through an inhibition of alpha-glucosidase action. Biosci. Biotechnol. Biochem. 2002, 66, 689-692.
271. Kobayashi, Y.; Suzuki, M.; Satsu, H.; Arai, S.; Hara, Y.; Suzuki, K.; Miyamoto, Y.; Shimizu, M. Green tea polyphenols inhibit the sodium-dependent glucose transporter of intestinal epithelial cells by a competitive mechanism. J. Agric. Food Chem. 2000, 48, 5618-5623.
272. Shimizu, M.; Kobayashi, Y.; Suzuki, M.; Satsu, H.; Miyamoto, Y. Regulation of intestinal glucose transport by tea catechins. Biofactors 2000, 13, 61-65.
273. Johnston, K.L.; Clifford, M.N.; Morgan, L.M. Possible role for apple juice phenolic, compounds in the acute modification of glucose tolerance and gastrointestinal hormone secretion in humans. J. Sci. Food Agric. 2002, 82, 1800-1805.
274. Holt, S.; Jong, V.D.; Faramus, E.; Lang, T.; Brand Miller, J. A bioflavonoid in sugar cane can reduce the postprandial glycaemic response to a high-gi starchy food. Asia Pac. J. Clin. Nutr. 2003, 12, S66.
275. Grussu, D.; Stewart, D.; McDougall, G.J. Berry polyphenols inhibit alpha-amylase in vitro: Identifying active components in rowanberry and raspberry. J. Agric. Food Chem. 2011, 59, 2324-2331.
276. Alzaid, F.; Cheung, H.M.; Preedy, V.R.; Sharp, P.A. Regulation of glucose transporter expression in human intestinal caco-2 cells following exposure to an anthocyanin-rich berry extract. PLoS ONE 2013, 8, e78932.
277. Zhang, A.J.; Rimando, A.M.; Fish,W.; Mentreddy, S.R.; Mathews, S.T. Serviceberry [amelanchier alnifolia (nutt.) nutt. Ex. M. Roem (rosaceae)] leaf extract inhibits mammalian alpha-glucosidase activity and suppresses postprandial glycemic response in a mouse model of diet-induced obesity and hyperglycemia. J. Ethnopharmacol. 2012, 143, 481-487.
278. Torronen, R.; Sarkkinen, E.; Tapola, N.; Hautaniemi, E.; Kilpi, K.; Niskanen, L. Berries modify the postprandial plasma glucose response to sucrose in healthy subjects. Br. J. Nutr. 2010, 103, 1094-1097.
279. Torronen, R.; McDougall, G.J.; Dobson, G.; Stewart, D.; Hellstrom, J.; Mattila, P.; Pihlava, J.M.; Koskela, A.; Karjalainen, R. Fortification of blackcurrant juice with crowberry: Impact on polyphenol composition, urinary phenolic metabolites, and postprandial glycemic response in healthy subjects. J. Funct. Foods 2012, 4, 746-756.
280. Clegg, M.E.; Pratt, M.; Meade, C.M.; Henry, C.J.K. The addition of raspberries and blueberries to a starch-based food does not alter the glycaemic response. Br. J. Nutr. 2011, 106, 335-338.
281. Wilson, T.; Singh, A.P.; Vorsa, N.; Goettl, C.D.; Kittleson, K.M.; Roe, C.M.; Kastello, G.M.; Ragsdale, F.R. Human glycemic response and phenolic content of unsweetened cranberry juice. J. Med. Food 2008, 11, 46-54.
282. Wilson, T.; Luebke, J.L.; Morcomb, E.F.; Carrell, E.J.; Leveranz, M.C.; Kobs, L.; Schmidt, T.P.; Limburg, P.J.; Vorsa, N.; Singh, A.P. Glycemic responses to sweetened dried and raw cranberries in humans with type 2 diabetes. J. Food Sci. 2010, 75, H218-H223.
283. Lo Piparo, E.; Scheib, H.; Frei, N.; Williamson, G.; Grigorov, M.; Chou, C.J. Flavonoids for controlling starch digestion: Structural requirements for inhibiting human alpha-amylase. J. Med. Chem. 2008, 51, 3555-3561.
284. Yang, J.P.; He, H.; Lu, Y.H. Four flavonoid compounds from phyllostachys edulis leaf extract retard the digestion of starch and its working mechanisms. J. Agric. Food Chem. 2014, 62, 7760-7770.
285. Zhao, F.Q.; Keating, A.F. Functional properties and genomics of glucose transporters. Curr. Genom. 2007, 8, 113-128.
286. Uldry, M.; Thorens, B. The SLC2 family of facilitated hexose and polyol transporters. Pflug. Arch. Eur. J. Physiol. 2004, 447, 480-489.
287. Zaid, H.; Antonescu, C.N.; Randhawa, V.K.; Klip, A. Insulin action on glucose transporters through molecular switches, tracks and tethers. Biochem. J. 2008, 413, 201-215.
288. Dugani, C.B.; Randhawa, V.K.; Cheng, A.W.P.; Patel, N.; Klip, A. Selective regulation of the perinuclear distribution of glucose transporter 4 (GLUT4) by insulin signals in muscle cells. Eur. J. Cell Biol. 2008, 87, 337-351.
289. Liu, W.; Hsin, C.; Tang, F. A molecular mathematical model of glucose mobilization and uptake. Math. Biosci. 2009, 221, 121-129.
290. Yamaguchi, S.; Katahira, H.; Ozawa, S.; Nakamichi, Y.; Tanaka, T.; Shimoyama, T.; Takahashi, K.; Yoshimoto, K.; Imaizumi, M.O.; Nagamatsu, S.; et al. Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 2005, 289, E643-E649.
291. Musi, N.; Hayashi, T.; Fujii, N.; Hirshman, M.F.; Witters, L.A.; Goodyear, L.J. Amp-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2001, 280, E677-E684.
292. Pinent, M.; Blay, M.; Blade, M.C.; Salvado, M.J.; Arola, L.; Ardevol, A. Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insulinomimetic activity in insulin-sensitive cell lines. Endocrinology 2004, 145, 4985-4990.
293. Montagut, G.; Onnockx, S.; Vaque, M.; Blade, C.; Blay, M.; Fernandez-Larrea, J.; Pujadas, G.; Salvado, M.J.; Arola, L.; Pirson, I.; et al. Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. J. Nutr. Biochem. 2010, 21, 476-481.
294. Montagut, G.; Blade, C.; Blay, M.; Fernandez-Larrea, J.; Pujadas, G.; Salvado, M.J.; Arola, L.; Pinent, M.; Ardevol, A. Effects of a grapeseed procyanidin extract (GSPE) on insulin resistance. J. Nutr. Biochem. 2010, 21, 961-967.
295. Cao, H.; Hininger-Favier, I.; Kelly, M.A.; Benaraba, R.; Dawson, H.D.; Coves, S.; Roussel, A.M.; Anderson, R.A. Green tea polyphenol extract regulates the expression of genes involved in glucose uptake and insulin signaling in rats fed a high fructose diet. J. Agric. Food Chem. 2007, 55, 6372-6378.
296. Zhang, Z.F.; Li, Q.; Liang, J.; Dai, X.Q.; Ding, Y.; Wang, J.B.; Li, Y. Epigallocatechin-3-O-gallate (EGCG) protects the insulin sensitivity in rat l6 muscle cells exposed to dexamethasone condition. Phytomed. Int. J. Phytother. Phytopharmacol. 2010, 17, 14-18.
297. Lee, M.S.; Kim, C.H.; Hoang, D.M.; Kim, H.Y.; Sohn, C.B.; Kim, M.R.; Ahn, J.S. Genistein-derivatives from tetracera scandens stimulate glucose-uptake in l6 myotubes. Biol. Pharm. Bull. 2009, 32, 504-508.
298. Zhang, W.Y.; Lee, J.J.; Kim, Y.; Kim, I.S.; Han, J.H.; Lee, S.G.; Ahn, M.J.; Jung, S.H.; Myung, C.S. Effect of eriodictyol on glucose uptake and insulin resistance in vitro. J. Agric. Food. Chem. 2012, 60, 7652-7658.
299. Zhang, W.Y.; Lee, J.J.; Kim, I.S.; Kim, Y.; Park, J.S.; Myung, C.S. 7-O-methylaromadendrin stimulates glucose uptake and improves insulin resistance in vitro. Biol. Pharm. Bull. 2010, 33, 1494-1499.
300. Fang, X.K.; Gao, J.; Zhu, D.N. Kaempferol and quercetin isolated from euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activity. Life Sci. 2008, 82, 615-622.
301. Miyata, Y.; Tanaka, H.; Shimada, A.; Sato, T.; Ito, A.; Yamanouchi, T.; Kosano, H. Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. Life Sci. 2011, 88, 613-618.
302. Sharma, A.K.; Bharti, S.; Ojha, S.; Bhatia, J.; Kumar, N.; Ray, R.; Kumari, S.; Arya, D.S. Up-regulation of ppar gamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br. J. Nutr. 2011, 106, 1713-1723.
303. Lv, X.W.; Li, J.; Jin, Y.; Zhang, L.; Wang, J.Q. Effects and mechanisms of total flavonoids of litsea coreana on insulin resistance in rats with hyperlipidemia. J. Chin. Med. Mater. 2009, 32, 1568-1571.
304. Lu, Y.X.; Zhang, Q.; Li, J.; Sun, Y.X.;Wang, L.Y.; Cheng,W.M.; Hu, X.Y. Antidiabetic effects of total flavonoids from litsea coreana leve on fat-fed, streptozotocin-induced type 2 diabetic rats. Am. J. Chin. Med. 2010, 38, 713-725.
305. Goto, T.; Teraminami, A.; Lee, J.Y.; Ohyama, K.; Funakoshi, K.; Kim, Y.I.; Hirai, S.; Uemura, T.; Yu, R.; Takahashi, N.; et al. Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice. J. Nutr. Biochem. 2012, 23, 768-776.
306. Stoffers, D.A. The development of beta-cell mass: Recent progress and potential role of glp-1. Horm. Metab. Res. 2004, 36, 811-821.
307. Tourrel, C.; Bailbe, D.; Lacorne, M.; Meile, M.J.; Kergoat, M.; Portha, B. Persistent improvement of type 2 diabetes in the goto-kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 2002, 51, 1443-1452.
308. Sakuraba, H.; Mizukami, H.; Yagihashi, N.; Wada, R.; Hanyu, C.; Yagihashi, S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of japanese type ii diabetic patients. Diabetologia 2002, 45, 85-96.
309. Marchetti, P.; Del Guerra, S.; Marselli, L.; Lupi, R.; Masini, M.; Pollera, M.; Bugliani, M.; Boggi, U.; Vistoli, F.; Mosca, F.; et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J. Clin. Endocrinol. Metab. 2004, 89, 5535-5541.
310. Cozar-Castellano, I.; Fiaschi-Taesch, N.; Bigatel, T.A.; Takane, K.K.; Garcia-Ocana, A.; Vasavada, R.; Stewart, A.F. Molecular control of cell cycle progression in the pancreatic beta-cell. Endocr. Rev. 2006, 27, 356-370.
311. Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52, 102-110.
312. Chang-Chen, K.J.; Mullur, R.; Bernal-Mizrachi, E. Beta-cell failure as a complication of diabetes. Rev. Endocr. Metab. Dis. 2008, 9, 329-343.
313. Lenzen, S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008, 51, 216-226.
314. Vessal, M.; Hemmati, M.; Vasei, M. Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp. Biochem. Physiol. Toxicol. Pharmacol. 2003, 135C, 357-364.
315. Coskun, O.; Kanter, M.; Korkmaz, A.; Oter, S. Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and beta-cell damage in rat pancreas. Pharmacol. Res. 2005, 51, 117-123.
316. Choi, J.S.; Yokozawa, T.; Oura, H. Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of prunus-davidiana stems and its main component prunin. Planta Medica 1991, 57, 208-211.
317. Chakravarthy, B.K.; Gupta, S.; Gode, K.D. Functional beta cell regeneration in the islets of pancreas in alloxan induced diabetic rats by (-)-epicatechin. Life Sci. 1982, 31, 2693-2697.
318. Martin, M.A.; Fernandez-Millan, E.; Ramos, S.; Bravo, L.; Goya, L. Cocoa flavonoid epicatechin protects pancreatic beta cell viability and function against oxidative stress. Mol. Nutr. Food Res. 2014, 58, 447-456.
319. Esmaeili, M.A.; Zohari, F.; Sadeghi, H. Antioxidant and protective effects of major flavonoids from teucrium polium on beta-cell destruction in a model of streptozotocin-induced diabetes. Planta Medica 2009, 75, 1418-1420.
320. Kwon, D.Y.; Daily, J.W., 3rd; Kim, H.J.; Park, S. Antidiabetic effects of fermented soybean products on type 2 diabetes. Nutr. Res. 2010, 30, 1-13.
321. Hanhineva, K.; Torronen, R.; Bondia-Pons, I.; Pekkinen, J.; Kolehmainen, M.; Mykkanen, H.; Poutanen, K. Impact of dietary polyphenols on carbohydrate metabolism. Int. J. Mol. Sci. 2010, 11, 1365-1402.
322. Choi, M.S.; Jung, U.J.; Yeo, J.; Kim, M.J.; Lee, M.K. Genistein and daidzein prevent diabetes onset by elevating insulin level and altering hepatic gluconeogenic and lipogenic enzyme activities in non-obese diabetic (NOD) mice. Diabetes/Metab. Res. Rev. 2008, 24, 74-81.
323. Guo, T.L.; Germolec, D.R.; Zheng, J.F.; Kooistra, L.; Auttachoat, W.; Smith, M.J.; White, K.L.; Elmore, S.A. Genistein protects female nonobese diabetic mice from developing type 1 diabetes when fed a soy- and alfalfa-free diet. Toxicol. Pathol. 2015, 43, 435-448.
324. Fu, Z.; Zhang, W.; Zhen, W.; Lum, H.; Nadler, J.; Bassaganya-Riera, J.; Jia, Z.; Wang, Y.; Misra, H.; Liu, D. Genistein induces pancreatic beta-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice. Endocrinology 2010, 151, 3026-3037.
325. Fu, Z.; Gilbert, E.R.; Pfeiffer, L.; Zhang, Y.; Fu, Y.; Liu, D. Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes. Appl. Physiol. Nutr. Metab. 2012, 37, 480-488.
326. Liu, D.; Zhen, W.; Yang, Z.; Carter, J.D.; Si, H.; Reynolds, K.A. Genistein acutely stimulates insulin secretion in pancreatic beta-cells through a camp-dependent protein kinase pathway. Diabetes 2006, 55, 1043-1050.
327. Gilbert, E.R.; Liu, D. Anti-diabetic functions of soy isoflavone genistein: Mechanisms underlying its effects on pancreatic beta-cell function. Food Funct. 2013, 4, 200-212.
328. Liu, Y.J.; Zhan, J.; Liu, X.L.; Wang, Y.; Ji, J.; He, Q.Q. Dietary flavonoids intake and risk of type 2 diabetes: A meta-analysis of prospective cohort studies. Clin. Nutr. 2014, 33, 59-63.
329. Nettleton, J.A.; Harnack, L.J.; Scrafford, C.G.; Mink, P.J.; Barraj, L.M.; Jacobs, D.R., Jr. Dietary flavonoids and flavonoid-rich foods are not associated with risk of type 2 diabetes in postmenopausal women. J. Nutr. 2006, 136, 3039-3045.
330. Zamora-Ros, R.; Forouhi, N.G.; Sharp, S.J.; Gonzalez, C.A.; Buijsse, B.; Guevara, M.; van der Schouw, Y.T.; Amiano, P.; Boeing, H.; Bredsdorff, L.; et al. Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in european populations. J. Nutr. 2014, 144, 335-343.
331. Knekt, P.; Kumpulainen, J.; Jarvinen, R.; Rissanen, H.; Heliovaara, M.; Reunanen, A.; Hakulinen, T.; Aromaa, A. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 2002, 76, 560-568.
332. Huxley, R.; Lee, C.M.; Barzi, F.; Timmermeister, L.; Czernichow, S.; Perkovic, V.; Grobbee, D.E.; Batty, D.; Woodward, M. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: A systematic review with meta-analysis. Arch. Intern. Med. 2009, 169, 2053-2063.
333. Yang, W.S.; Wang, W.Y.; Fan, W.Y.; Deng, Q.; Wang, X. Tea consumption and risk of type 2 diabetes: A dose-response meta-analysis of cohort studies. Br. J. Nutr. 2014, 111, 1329-1339.
334. Iso, H.; Date, C.; Wakai, K.; Fukui, M.; Tamakoshi, A.; Grp, J.S. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among japanese adults. Ann. Intern. Med. 2006, 144, 554-562.
335. InterAct, C.; vanWoudenbergh, G.J.; Kuijsten, A.; Drogan, D.; van der, A.D.; Romaguera, D.; Ardanaz, E.; Amiano, P.; Barricarte, A.; Beulens, J.W.; et al. Tea consumption and incidence of type 2 diabetes in europe: The epic-interact case-cohort study. PLoS ONE 2012, 7, e36910.
336. Jing, Y.; Han, G.; Hu, Y.; Bi, Y.; Li, L.; Zhu, D. Tea consumption and risk of type 2 diabetes: A meta-analysis of cohort studies. J. Gen. Intern. Med. 2009, 24, 557-562.
337. Panagiotakos,D.B.; Lionis,C.; Zeimbekis,A.;Gelastopoulou,K.; Papairakleous,N.;Das,U.N.; Polychronopoulos, E. Long-term tea intake is associated with reduced prevalence of (type 2) diabetes mellitus among elderly people from mediterranean islands: Medis epidemiological study. Yonsei Med. J. 2009, 50, 31-38.
338. Muraki, I.; Imamura, F.; Manson, J.E.; Hu, F.B.; Willett, W.C.; van Dam, R.M.; Sun, Q. Fruit consumption and risk of type 2 diabetes: Results from three prospective longitudinal cohort studies. BMJ 2013, 347, f5001.
339. Wedick, N.M.; Pan, A.; Cassidy, A.; Rimm, E.B.; Sampson, L.; Rosner, B.; Willett, W.; Hu, F.B.; Sun, Q.; van Dam, R.M. Dietary flavonoid intakes and risk of type 2 diabetes in us men and women. Am. J. Clin. Nutr. 2012, 95, 925-933.
340. Pandey, K.B.; Rizvi, S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2009, 2, 270-278.
341. Fu, Z.; Zhen, W.; Yuskavage, J.; Liu, D. Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice. Br. J. Nutr. 2010, 105, 1218-1225.
342. Seeram, N.P.; Adams, L.S.; Hardy, M.L.; Heber, D. Total cranberry extract versus its phytochemical constituents: Antiproliferative and synergistic effects against human tumor cell lines. J. Agric. Food Chem. 2004, 52, 2512-2517.
343. Yang, J.; Liu, R.H. Synergistic effect of apple extracts and quercetin 3-beta-d-glucoside combination on antiproliferative activity in mcf-7 human breast cancer cells in vitro. J. Agric. Food Chem. 2009, 57, 8581-8586.
344. Huseini, H.F.; Larijani, B.; Heshmat, R.; Fakhrzadeh, H.; Radjabipour, B.; Toliat, T.; Raza, M. The efficacy of silybum marianum (L.) gaertn. (silymarin) in the treatment of type ii diabetes: A randomized, double-blind, placebo-controlled, clinical trial. Phytother. Res. 2006, 20, 1036-1039.
345. Lirussi, F.; Beccarello, A.; Zanette, G.; De Monte, A.; Donadon, V.; Velussi, M.; Crepaldi, G. Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Diabetes Nutr. Metab. 2002, 15, 222-231.
346. Chambers, B.K.; Camire, M.E. Can cranberry supplementation benefit adults with type 2 diabetes? Diabetes Care 2003, 26, 2695-2696.
347. Simeonov, S.B.; Botushanov, N.P.; Karahanian, E.B.; Pavlova, M.B.; Husianitis, H.K.; Troev, D.M. Effects of aronia melanocarpa juice as part of the dietary regimen in patients with diabetes mellitus. Folia Medica 2002, 44, 20-23.
348. Kar, P.; Laight, D.; Rooprai, H.K.; Shaw, K.M.; Cummings, M. Effects of grape seed extract in type 2 diabetic subjects at high cardiovascular risk: A double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet. Med. 2009, 26, 526-531.
349. Zunino, S.J.; Peerson, J.M.; Freytag, T.L.; Breksa, A.P.; Bonnel, E.L.; Woodhouse, L.R.; Storms, D.H. Dietary grape powder increases IL-1beta and IL-6 production by lipopolysaccharide-activated monocytes and reduces plasma concentrations of large ldl and large ldl-cholesterol particles in obese humans. Br. J. Nutr. 2014, 112, 369-380.
350. Qin, Y.; Xia, M.; Ma, J.; Hao, Y.; Liu, J.; Mou, H.; Cao, L.; Ling,W. Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am. J. Clin. Nutr. 2009, 90, 485-492.
351. Zhu, Y.; Ling, W.; Guo, H.; Song, F.; Ye, Q.; Zou, T.; Li, D.; Zhang, Y.; Li, G.; Xiao, Y.; et al. Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: A randomized controlled trial. Nutr. Metab. Cardiovasc. Dis. 2013, 23, 843-849.
352. Fukino, Y.; Shimbo, M.; Aoki, N.; Okubo, T.; Iso, H. Randomized controlled trial for an effect of green tea consumption on insulin resistance and inflammation markers. J. Nutr. Sci. Vitaminol. 2005, 51, 335-342.
353. Ryu, O.H.; Lee, J.; Lee, K.W.; Kim, H.Y.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H.; Choi, D.S.; Choi, K.M. Effects of green tea consumption on inflammation, insulin resistance and pulse wave velocity in type 2 diabetes patients. Diabetes Res. Clin. Pract. 2006, 71, 356-358.
354. Mackenzie, T.; Leary, L.; Brooks,W.B. The effect of an extract of green and black tea on glucose control in adults with type 2 diabetes mellitus: Double-blind randomized study. Metab. Clin. Exp. 2007, 56, 1340-1344.
355. Hsu, C.H.; Liao, Y.L.; Lin, S.C.; Tsai, T.H.; Huang, C.J.; Chou, P. Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial. Altern. Med. Rev. 2011, 16, 157-163.
356. Nagao, T.; Meguro, S.; Hase, T.; Otsuka, K.; Komikado, M.; Tokimitsu, I.; Yamamoto, T.; Yamamoto, K. A catechin-rich beverage improves obesity and blood glucose control in patients with type 2 diabetes. Obesity 2009, 17, 310-317.
357. Takahashi, M.; Miyashita, M.; Suzuki, K.; Bae, S.R.; Kim, H.K.; Wakisaka, T.; Matsui, Y.; Takeshita, M.; Yasunaga, K. Acute ingestion of catechin-rich green tea improves postprandial glucose status and increases serum thioredoxin concentrations in postmenopausal women. Br. J. Nutr. 2014, 112, 1542-1550.
358. Larsen, N.; Vogensen, F.K.; van den Berg, F.W.; Nielsen, D.S.; Andreasen, A.S.; Pedersen, B.K.; Al-Soud,W.A.; Sørensen, S.J.; Hansen, L.H.; Jakobsen, M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 2010, 5, e9085.
359. Zhang, X.; Shen, D.; Fang, Z.; Jie, Z.; Qiu, X.; Zhang, C.; Chen, Y.; Ji, L. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS ONE 2013, 8, e71108.
360. Qin, J.; Li, Y.; Cai, Z.; Li, S.; Zhu, J.; Zhang, F.; Liang, S.; Zhang, W.; Guan, Y.; Shen, D. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012, 490, 55-60.
361. Egshatyan, L.; Kashtanova, D.; Popenko, A.; Tkacheva, O.; Tyakht, A.; Alexeev, D.; Karamnova, N.; Kostryukova, E.; Babenko, V.; Vakhitova, M. Gut microbiota and diet in patients with different glucose tolerance. Endocr. Connect. 2016, 5, 1-9.
362. Cani, P.D.; Possemiers, S.; Van de Wiele, T.; Guiot, Y.; Everard, A.; Rottier, O.; Geurts, L.; Naslain, D.; Neyrinck, A.; Lambert, D.M. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009, 58, 1091-1103.
363. Cani, P.D.; Neyrinck, A.; Fava, F.; Knauf, C.; Burcelin, R.; Tuohy, K.; Gibson, G.; Delzenne, N. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007, 50, 2374-2383.
364. Yan, J.; Zhang, G.; Pan, J.; Wang, Y. α-glucosidase inhibition by luteolin: Kinetics, interaction and molecular docking. Int. J. Biol. Macromol. 2014, 64, 213-223.
365. Braune, A.; Blaut, M. Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microb. 2016, 7, 216-234.