title: Recent advances in understanding the anti-diabetic actions of dietary flavonoids.
abstract: Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.
authors.affiliation: Division of Nutrition, College of Health, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Pon Velayutham Anandh
authors.initials: PV
authors.lastname: Babu
authors.forename: Dongmin
authors.initials: D
authors.lastname: Liu
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gilbert
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004032:Diet; D005419:Flavonoids / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism / Q000627:therapeutic use; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism
chemical_list: D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose
keywords: ACC; AMPK; ATP; Acetyl Co-A carboxylase; Adenosine monophosphate-activated protein kinase; Adenosine triphosphate; BBE; BFE; Bayberry fruit extract; Bilberry extract; Carnitine palmitoyltransferase I; DM; Diabetes; Diabetes mellitus; ECG; EGC; EGCG; ER; Endoplasmic reticulum; Epicatechin gallate; Epigallocatechin; Epigallocatechin gallate; FFA; Flavonoids; FoXO1; Forkhead box protein O1; Free fatty acid; G6Pase; GK; GLUT; GSIS; Glucokinase; Glucose transporter; Glucose-6-phosphatase; Glucose-stimulated insulin secretion; HSP; Heat shock proteins; Hyperglycemia; IR; IRS; Insulin receptor; Insulin receptor substrate; Intraperitoneal; Islets; JNK; L-Cpt-1; MAPK; Mitogen activated protein kinase; NF-κB; NOD; Non-obese diabetic mice; Nuclear factor-κB; PDX-1; PEPCK; PGC-1α; PKC; PPAR; Pancreatic duodenal homeobox-1; Pancreatic β-cells; Peroxisome proliferator-activated receptor gamma coactivator-1-α; Phosphoenolpyruvate carboxykinase; Polyphenols; Protein kinase C; RBP4; RIN cells; ROS; Rat insulinoma cells; Reactive oxygen species; Retinol binding protein-4; STZ; Streptozotocin; T1D; T2D; TNFα; TZD; Thiazolidinedione; Tumor necrosis factor α; Type 1 diabetes mellitus; Type 2 diabetes mellitus; WAT; White adipose tissue; c-jun amino terminal kinase; cAMP; cyclic adenosine mono phosphate; i.p.; peroxisome proliferator activated receptor
references.citation: Biofactors. 2009 Jul-Aug;35(4):373-9
references.pmid: 19353690
references.citation: Phytother Res. 2010 Jun;24 Suppl 2:S133-8
references.pmid: 20309949
references.citation: Phytomedicine. 2006 Nov;13(9-10):612-23
references.pmid: 16979328
references.citation: Atherosclerosis. 2002 Aug;163(2):339-47
references.pmid: 12052481
references.citation: J Biol Chem. 2005 Jun 10;280(23):22297-307
references.pmid: 15817464
references.citation: Br J Nutr. 2008 Jun;99(6):1208-16
references.pmid: 18053305
references.citation: Int J Biochem Cell Biol. 2006;38(7):1134-45
references.pmid: 16427799
references.citation: Annu Rev Food Sci Technol. 2010;1:163-87
references.pmid: 22129334
references.citation: Biochem Soc Trans. 1994 May;22(2):209S
references.pmid: 7525376
references.citation: Int J Oncol. 2007 Jan;30(1):233-45
references.pmid: 17143534
references.citation: Nat Prod Rep. 2007 Apr;24(2):417-64
references.pmid: 17390003
references.citation: Clin Nutr. 2003 Dec;22(6):561-8
references.pmid: 14613759
references.citation: Pharmacol Res. 2005 Feb;51(2):117-23
references.pmid: 15629256
references.citation: Biosci Biotechnol Biochem. 2002 Mar;66(3):689-92
references.pmid: 12005074
references.citation: Am J Clin Nutr. 2004 May;79(5):727-47
references.pmid: 15113710
references.citation: PLoS One. 2010 Aug 25;5(8):e12399
references.pmid: 20811644
references.citation: J Nutr Biochem. 2010 Oct;21(10):941-7
references.pmid: 19954946
references.citation: J Agric Food Chem. 2006 Jan 11;54(1):243-8
references.pmid: 16390206
references.citation: Nature. 2003 Sep 11;425(6954):191-6
references.pmid: 12939617
references.citation: J Biol Chem. 1990 Jan 25;265(3):1465-9
references.pmid: 2153135
references.citation: Diabetologia. 2007 Apr;50(4):752-63
references.pmid: 17268797
references.citation: Clin Nutr. 2004 Oct;23(5):1025-34
references.pmid: 15380892
references.citation: Br J Pharmacol. 1995 Feb;114(4):872-80
references.pmid: 7773549
references.citation: Free Radic Biol Med. 2012 Jan 15;52(2):314-27
references.pmid: 22085656
references.citation: J Agric Food Chem. 2002 Apr 24;50(9):2519-23
references.pmid: 11958615
references.citation: Pancreas. 2011 Apr;40(3):396-402
references.pmid: 21206328
references.citation: Biol Pharm Bull. 2012;35(1):121-6
references.pmid: 22223348
references.citation: Eur J Pharmacol. 2009 Aug 15;616(1-3):321-7
references.pmid: 19540219
references.citation: Int J Mol Sci. 2010 Mar 31;11(4):1365-402
references.pmid: 20480025
references.citation: J Nutr. 2010 Oct;140(10):1764-8
references.pmid: 20724487
references.citation: Physiol Rev. 2009 Jul;89(3):1025-78
references.pmid: 19584320
references.citation: J Nutr Biochem. 2013 Apr;24(4):638-46
references.pmid: 22819546
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1739-44
references.pmid: 18223156
references.citation: Mol Cells. 2009 Sep;28(3):167-74
references.pmid: 19756396
references.citation: J Lipid Res. 2001 May;42(5):725-34
references.pmid: 11352979
references.citation: J Clin Invest. 1995 Apr;95(4):1512-8
references.pmid: 7706456
references.citation: Biochem J. 2002 May 15;364(Pt 1):219-26
references.pmid: 11988095
references.citation: Diabetes Care. 2007 Jul;30(7):1871-3
references.pmid: 17468359
references.citation: J Lipid Res. 2002 Sep;43(9):1544-54
references.pmid: 12235187
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: J Med Food. 2005 Fall;8(3):281-90
references.pmid: 16176136
references.citation: J Nutr. 2004 Oct;134(10):2499-503
references.pmid: 15465737
references.citation: Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3392-8
references.pmid: 9437184
references.citation: Nature. 2009 Apr 23;458(7241):1056-60
references.pmid: 19262508
references.citation: Menopause. 1999 Spring;6(1):7-13
references.pmid: 10100174
references.citation: J Med Food. 2012 Mar;15(3):288-98
references.pmid: 22181073
references.citation: J Diabetes Complications. 2012 Nov-Dec;26(6):483-90
references.pmid: 22809898
references.citation: Am J Clin Nutr. 2005 Jan;81(1 Suppl):317S-325S
references.pmid: 15640497
references.citation: Asia Pac J Clin Nutr. 2007;16(2):200-8
references.pmid: 17468073
references.citation: Diabetes. 2012 Jun;61(6):1338-45
references.pmid: 22618769
references.citation: Diabetes. 2001 Jan;50(1):131-8
references.pmid: 11147778
references.citation: J Nutr Biochem. 2012 Apr;23(4):349-60
references.pmid: 21543211
references.citation: J Biol Chem. 1997 Dec 12;272(50):31475-81
references.pmid: 9395482
references.citation: Antioxid Redox Signal. 2010 Sep 15;13(6):807-19
references.pmid: 20367277
references.citation: Cell. 1998 Mar 20;92(6):829-39
references.pmid: 9529258
references.citation: Diabetes. 2006 Apr;55(4):1043-50
references.pmid: 16567527
references.citation: Diabetes. 2005 Aug;54(8):2294-304
references.pmid: 16046294
references.citation: Appl Physiol Nutr Metab. 2012 Jun;37(3):480-8
references.pmid: 22509809
references.citation: J Agric Food Chem. 2012 Feb 1;60(4):1059-66
references.pmid: 22191431
references.citation: Cell Metab. 2007 Sep;6(3):208-16
references.pmid: 17767907
references.citation: Eur J Pharmacol. 2011 Oct 15;668(3):492-6
references.pmid: 21816145
references.citation: Diabetes. 2001 May;50(5):1076-82
references.pmid: 11334411
references.citation: Cell Mol Life Sci. 2008 Nov;65(23):3737-55
references.pmid: 18810325
references.citation: Biofactors. 2000;12(1-4):17-28
references.pmid: 11216482
references.citation: Diabetes Care. 2005 Jan;28(1):154-63
references.pmid: 15616251
references.citation: Diabetes. 2008 Apr;57(4):967-79
references.pmid: 18162507
references.citation: Nature. 2005 Jul 21;436(7049):356-62
references.pmid: 16034410
references.citation: Life Sci. 2003 Jul 4;73(7):933-46
references.pmid: 12798418
references.citation: Diabetes Metab Res Rev. 2008 Jan-Feb;24(1):74-81
references.pmid: 17932873
references.citation: Dev Cell. 2003 Jan;4(1):119-29
references.pmid: 12530968
references.citation: Curr Top Med Chem. 2010;10(4):397-410
references.pmid: 20180761
references.citation: Pancreas. 2007 Nov;35(4):e1-9
references.pmid: 18090225
references.citation: Nature. 1998 Feb 26;391(6670):900-4
references.pmid: 9495343
references.citation: Nutr Res Pract. 2012 Jun;6(3):201-7
references.pmid: 22808343
references.citation: Diabetes. 1997 Jan;46(1):3-10
references.pmid: 8971073
references.citation: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2524-31
references.pmid: 9409223
references.citation: Mol Nutr Food Res. 2009 Nov;53(11):1419-29
references.pmid: 19785000
references.citation: Proc Soc Exp Biol Med. 1998 Mar;217(3):365-8
references.pmid: 9492349
references.citation: Nat Prod Rep. 2009 Aug;26(8):1001-43
references.pmid: 19636448
references.citation: Nutr Metab (Lond). 2012 Feb 14;9:11
references.pmid: 22333133
references.citation: Mol Cell Endocrinol. 2007 Nov 15;278(1-2):18-28
references.pmid: 17881116
references.citation: J Agric Food Chem. 2009 Dec 23;57(24):11463-8
references.pmid: 19938837
references.citation: Life Sci. 2004 Feb 13;74(13):1621-34
references.pmid: 14738906
references.citation: Food Funct. 2013 Feb;4(2):200-12
references.pmid: 23160185
references.citation: Diabetologia. 2005 Jul;48(7):1339-49
references.pmid: 15902400
references.citation: Diabetes Care. 2012 Feb;35(2):226-32
references.pmid: 22250063
references.citation: Yakugaku Zasshi. 1981 Jan;101(1):86-90
references.pmid: 6454778
references.citation: J Pharm Pharmacol. 2007 Nov;59(11):1543-8
references.pmid: 17976266
references.citation: J Clin Invest. 2006 Mar;116(3):598-606
references.pmid: 16511592
references.citation: Science. 1993 Mar 5;259(5100):1409-10
references.pmid: 8451637
references.citation: Endocrinology. 1994 Apr;134(4):1975-8
references.pmid: 8137766
references.citation: Br J Nutr. 2011 Apr;105(8):1218-25
references.pmid: 21144096
references.citation: J Nutr. 2010 Mar;140(3):527-33
references.pmid: 20089785
references.citation: J Appl Physiol (1985). 1999 Nov;87(5):1990-5
references.pmid: 10562646
references.citation: Int J Clin Pract. 2009 Feb;63(2):321-32
references.pmid: 19196370
references.citation: J Biol Chem. 2000 Apr 14;275(15):10761-6
references.pmid: 10753867
references.citation: J Nutr. 2003 Oct;133(10):3248S-3254S
references.pmid: 14519822
references.citation: Diabetes. 2001 Apr;50(4):810-6
references.pmid: 11289046
references.citation: Nat Genet. 2002 Oct;32(2):245-53
references.pmid: 12219087
references.citation: J Nutr. 2007 May;137(5):1244-52
references.pmid: 17449588
references.citation: Diabetes. 2011 Sep;60(9):2234-44
references.pmid: 21788573
references.citation: J Agric Food Chem. 2005 Jan 12;53(1):28-31
references.pmid: 15631504
references.citation: FEBS Lett. 2008 Jan 9;582(1):81-9
references.pmid: 18022388
references.citation: Cell Metab. 2009 May;9(5):407-16
references.pmid: 19416711
references.citation: J Clin Pharmacol. 2011 Jun;51(6):796-804
references.pmid: 20705952
references.citation: Eur J Clin Invest. 1994 Aug;24 Suppl 3:19-24
references.pmid: 8001622
references.citation: FASEB J. 2003 Sep;17(12):1658-65
references.pmid: 12958172
references.citation: Am J Clin Nutr. 2012 Apr;95(4):925-33
references.pmid: 22357723
references.citation: J Nutr Biochem. 2005 Nov;16(11):693-9
references.pmid: 16081264
references.citation: Phytomedicine. 2009 May;16(5):406-15
references.pmid: 19303751
references.citation: Biochem J. 2011 Apr 15;435(2):463-74
references.pmid: 21323644
references.citation: J Nutr. 2007 Mar;137(3 Suppl 1):718S-737S
references.pmid: 17311968
references.citation: Life Sci. 2002 Aug 9;71(12):1405-15
references.pmid: 12127161
references.citation: J Nutr. 1998 Apr;128(4):728-32
references.pmid: 9521635
references.citation: Mol Nutr Food Res. 2009 Jul;53(7):859-68
references.pmid: 19496084
references.citation: Life Sci. 2008 May 23;82(21-22):1102-10
references.pmid: 18440560
references.citation: J Nutr. 1989 Dec;119(12):2023-9
references.pmid: 2695605
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2003 Jul;135C(3):357-64
references.pmid: 12927910
references.citation: J Nutr. 2012 Apr;142(4):724-30
references.pmid: 22399524
references.citation: Diabetes Care. 1992 Jun;15(6):792-805
references.pmid: 1600838
references.citation: Diabetes Obes Metab. 2007 Nov;9 Suppl 2:140-6
references.pmid: 17919188
references.citation: Diabetologia. 2011 Feb;54(2):390-402
references.pmid: 21046358
references.citation: Br J Nutr. 2011 Dec;106(11):1713-23
references.pmid: 21736771
references.citation: Mol Pharmacol. 2005 Oct;68(4):1018-30
references.pmid: 16037419
references.citation: FASEB J. 2005 Jul;19(9):1146-8
references.pmid: 15878932
references.citation: Mol Nutr Food Res. 2010 Jul;54(7):991-1003
references.pmid: 20087853
references.citation: Eur J Pharmacol. 2011 Nov 16;670(1):311-6
references.pmid: 21925162
references.citation: J Nutr Biochem. 2012 Jul;23(7):716-24
references.pmid: 21820301
references.citation: J Agric Food Chem. 2009 Oct 28;57(20):9817-27
references.pmid: 19803520
references.citation: Eur J Pharmacol. 2011 Nov 16;670(1):325-32
references.pmid: 21914439
references.citation: Diabetes. 2006 Aug;55(8):2180-91
references.pmid: 16873680
references.citation: J Nutr. 2003 Jul;133(7):2125-30
references.pmid: 12840166
references.citation: J Nutr. 1996 Jan;126(1):43-50
references.pmid: 8558324
references.citation: Diabetes. 2008 May;57(5):1176-85
references.pmid: 18420492
references.citation: J Mol Endocrinol. 1999 Feb;22(1):19-28
references.pmid: 9924176
references.citation: Food Chem. 2012 Mar 15;131(2):387-396
references.pmid: 26279603
references.citation: Am J Cardiol. 2000 Jun 1;85(11):1297-301
references.pmid: 10831943
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22
references.pmid: 17609368
references.citation: Cancer Sci. 2004 Aug;95(8):644-50
references.pmid: 15298726
references.citation: J Nutr. 2003 May;133(5):1238-43
references.pmid: 12730403
references.citation: J Agric Food Chem. 2001 Dec;49(12):5848-51
references.pmid: 11743773
references.citation: Curr Med Chem. 2011;18(2):291-300
references.pmid: 21110799
references.citation: Endocr Res. 1993 Dec;19(4):273-85
references.pmid: 7508378
references.citation: Int J Mol Med. 2013 Jan;31(1):265-71
references.pmid: 23138875
references.citation: Br J Pharmacol. 2010 Oct;161(4):799-814
references.pmid: 20860660
references.citation: Int J Obes (Lond). 2008 Sep;32 Suppl 4:S55-9
references.pmid: 18719600
references.citation: Endocrinology. 2010 Jul;151(7):3026-37
references.pmid: 20484465
references.citation: Br J Nutr. 2010 Apr;103(8):1094-7
references.pmid: 19930765