title: The role of FOXO1 in β-cell failure and type 2 diabetes mellitus.
abstract: Over the past two decades, insulin resistance has been considered essential to the aetiology of type 2 diabetes mellitus (T2DM). However, insulin resistance does not lead to T2DM unless it is accompanied by pancreatic β-cell dysfunction, because healthy β cells can compensate for insulin resistance by increasing in number and functional output. Furthermore, β-cell mass is decreased in patients with diabetes mellitus, suggesting a primary role for β-cell dysfunction in the pathogenesis of T2DM. The dysfunction of β cells can develop through various mechanisms, including oxidative, endoplasmic reticulum or hypoxic stress, as well as via induction of cytokines; these processes lead to apoptosis, uncontrolled autophagy and failure to proliferate. Transdifferentiation between β cells and α cells occurs under certain pathological conditions, and emerging evidence suggests that β-cell dedifferentiation or transdifferentiation might account for the reduction in β-cell mass observed in patients with severe T2DM. FOXO1, a key transcription factor in insulin signalling, is implicated in these mechanisms. This Review discusses advances in our understanding of the contribution of FOXO1 signalling to the development of β-cell failure in T2DM.
authors: Metabolic Signal Research Centre, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15, Showa-machi, Maebashi, Gunma 371-8512, Japan. kitamura@gunma-u.ac.jp.
authors: Tadahiro
authors: T
authors: Kitamura
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors
references: Diabetes. 2004 Jun;53(6):1509-16
references: 15161755
references: J Clin Endocrinol Metab. 2008 Oct;93(10):4065-74
references: 18664535
references: Nat Med. 2011 Jul 31;17(8):961-7
references: 21804540
references: Cell. 2004 Apr 16;117(2):225-37
references: 15084260
references: J Clin Invest. 2007 Sep;117(9):2477-85
references: 17717603
references: Nat Genet. 2008 Sep;40(9):1092-7
references: 18711367
references: Nature. 2010 Apr 22;464(7292):1149-54
references: 20364121
references: Nat Med. 2005 Feb;11(2):175-82
references: 15685168
references: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7
references: 15220471
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: Diabetes. 2003 Jul;52(7):1701-8
references: 12829636
references: Nature. 1997 Mar 27;386(6623):399-402
references: 9121556
references: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:20-6
references: 21029296
references: Nat Genet. 2006 May;38(5):583-8
references: 16642022
references: Nat Genet. 2012 Mar 11;44(4):406-12, S1
references: 22406641
references: Nature. 1999 Aug 26;400(6747):877-81
references: 10476967
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2975-80
references: 14978268
references: J Mol Med (Berl). 1999 Sep;77(9):656-65
references: 10569203
references: Diabetologia. 2004 Feb;47(2):157-69
references: 14722650
references: J Biol Chem. 2006 Oct 6;281(40):30299-304
references: 16901900
references: Development. 1996 May;122(5):1409-16
references: 8625829
references: Cardiovasc Diabetol. 2005 Apr 29;4:5
references: 15862133
references: Mol Med. 1995 Nov;1(7):806-20
references: 8612203
references: Diabetes. 2002 Aug;51(8):2546-51
references: 12145169
references: Cell Metab. 2005 Sep;2(3):153-63
references: 16154098
references: J Clin Invest. 2004 Oct;114(7):917-27
references: 15467830
references: Cell. 2004 May 14;117(4):421-6
references: 15137936
references: Lancet. 2013 Jun 1;381(9881):1905-15
references: 23562090
references: Mol Cell Biol. 2009 Aug;29(16):4417-30
references: 19506018
references: Science. 1995 Mar 10;267(5203):1449-56
references: 7533326
references: Science. 2006 Oct 13;314(5797):294-7
references: 17038621
references: PLoS One. 2011;6(9):e25566
references: 21984932
references: Cell. 1999 Mar 19;96(6):857-68
references: 10102273
references: J Clin Invest. 2007 Jan;117(1):246-57
references: 17200721
references: Development. 1998 Jun;125(12):2213-21
references: 9584121
references: Diabetes. 2005 Mar;54(3):727-35
references: 15734849
references: Anal Chem. 1999 Sep 1;71(17):3642-9
references: 10489519
references: Endocr J. 2007 Aug;54(4):507-15
references: 17510498
references: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4952-7
references: 16547133
references: J Clin Invest. 2004 Sep;114(6):828-36
references: 15372107
references: Diabetes. 2001 Mar;50(3):521-33
references: 11246871
references: Metabolism. 2002 Oct;51(10):1340-7
references: 12370856
references: Cell. 1999 Feb 5;96(3):329-39
references: 10025399
references: J Clin Invest. 2006 Sep;116(9):2464-72
references: 16906224
references: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:1-3
references: 21029293
references: Genes Dev. 2007 Nov 15;21(22):2861-73
references: 18006683
references: Genes Dev. 2003 Oct 15;17(20):2591-603
references: 14561778
references: Nature. 2000 Apr 13;404(6779):782-7
references: 10783894
references: Cell. 2012 Jun 8;149(6):1314-26
references: 22682251
references: Nat Med. 2001 Oct;7(10):1133-7
references: 11590437
references: J Clin Invest. 2010 Jan;120(1):115-26
references: 19955657
references: Diabetologia. 2009 Jun;52(6):1083-6
references: 19367387
references: J Biol Chem. 2006 Jan 13;281(2):1091-8
references: 16282329
references: J Clin Invest. 2007 Apr;117(4):961-70
references: 17404619
references: J Pharm Sci. 2012 May;101(5):1647-58
references: 22271340
references: Diabetologia. 2007 Dec;50(12):2486-94
references: 17906960
references: Annu Rev Biochem. 2012;81:767-93
references: 22443930
references: Am J Physiol Cell Physiol. 2010 Jul;299(1):C1-6
references: 20457840
references: Diabetes. 2006 Nov;55(11):2965-73
references: 17065332
references: Cell Metab. 2008 Oct;8(4):325-32
references: 18840363
references: Diabetes. 2003 Oct;52(10):2461-74
references: 14514628
references: Nat Cell Biol. 2010 Jul;12(7):665-75
references: 20543840
references: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1607-11
references: 10677506
references: J Clin Invest. 2012 Jul;122(7):2578-89
references: 22653058
references: Nature. 1998 Feb 26;391(6670):900-4
references: 9495343
references: Dev Cell. 2003 Jan;4(1):119-29
references: 12530968
references: Nature. 2001 Dec 13;414(6865):792-8
references: 11742411
references: J Cell Biol. 2003 Aug 18;162(4):535-41
references: 12925703
references: Diabetes. 1999 Apr;48(4):738-44
references: 10102689
references: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14152-7
references: 20660764
references: Nature. 2002 Sep 19;419(6904):316-21
references: 12239572
references: Diabetes. 2003 Sep;52(9):2304-14
references: 12941770
references: Endocr Rev. 2007 May;28(3):253-83
references: 17409288
references: J Biol Chem. 1999 Jun 4;274(23):15982-5
references: 10347145
references: J Clin Invest. 2005 Sep;115(9):2382-92
references: 16100571
references: Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E603-13
references: 22215655
references: Dev Biol. 2004 Feb 1;266(1):178-89
references: 14729487
references: Diabetes Obes Metab. 2008 Nov;10 Suppl 4:32-42
references: 18834431
references: Nat Genet. 1999 Sep;23(1):32-40
references: 10471495
references: Diabetes Obes Metab. 2011 Oct;13 Suppl 1:47-52
references: 21824256
references: Nat Cell Biol. 2006 Oct;8(10):1124-32
references: 16998475
references: N Engl J Med. 2007 Apr 12;356(15):1517-26
references: 17429083
references: Nat Genet. 2006 May;38(5):589-93
references: 16642023
references: Diabetes. 2003 Mar;52(3):581-7
references: 12606496
references: Diabetes. 2005 Nov;54(11):3238-44
references: 16249450
references: Cell. 2012 Sep 14;150(6):1223-34
references: 22980982
references: Nat Genet. 2006 Mar;38(3):320-3
references: 16415884
references: Nat Genet. 2002 Oct;32(2):245-53
references: 12219087
references: J Biol Chem. 1999 Mar 12;274(11):7238-44
references: 10066785
references: Diabetes. 2001 Feb;50 Suppl 1:S84-8
references: 11272209
references: Diabetes Obes Metab. 2012 Oct;14 Suppl 3:57-67
references: 22928565
references: Genes Dev. 2008 Nov 15;22(22):3135-46
references: 19056893
references: Nat Clin Pract Endocrinol Metab. 2007 Nov;3(11):758-68
references: 17955017
references: Endocr Rev. 2008 May;29(3):303-16
references: 18314421
references: Diabetes. 2001 Aug;50(8):1683-90
references: 11473025
references: Diabetologia. 2010 Jun;53(6):1046-56
references: 20182863
references: PLoS One. 2012;7(1):e29807
references: 22235342
references: PLoS One. 2012;7(2):e32249
references: 22384192
references: Free Radic Biol Med. 1996;20(3):463-6
references: 8720919
references: Biochim Biophys Acta. 2011 Nov;1813(11):1954-60
references: 21396404
references: Nature. 2006 Sep 28;443(7110):453-7
references: 16957737
references: Nat Med. 2006 May;12(5):534-40
references: 16604086
references: Genes Dev. 2000 Jun 1;14(11):1343-52
references: 10837027
references: Diabetes. 2002 Apr;51(4):977-87
references: 11916915
references: Science. 2002 Mar 29;295(5564):2450-2
references: 11884717
references: Cell. 2009 Aug 7;138(3):449-62
references: 19665969
references: Mol Cell. 2001 Jun;7(6):1165-76
references: 11430820
references: Science. 2004 Dec 24;306(5705):2261-4
references: 15564314
references: Dev Cell. 2011 Apr 19;20(4):419-29
references: 21497756
references: Cancer Cell. 2002 Jul;2(1):81-91
references: 12150827
references: Diabetes. 2000 Nov;49(11):1880-9
references: 11078455
references: Cell. 2004 Feb 20;116(4):551-63
references: 14980222
references: J Clin Invest. 2006 Mar;116(3):775-82
references: 16485043
references: Mol Cell Biol. 2004 Apr;24(8):3505-13
references: 15060169
references: Biochim Biophys Acta. 2007 Aug;1768(8):2002-9
references: 17349968
references: J Clin Invest. 2013 Mar;123(3):1275-84
references: 23434589
references: Diabetes. 2007 Sep;56(9):2356-70
references: 17579207
references: J Hum Genet. 2008;53(2):174-180
references: 18097733
references: Proc Natl Acad Sci U S A. 1987 Dec;84(23):8628-32
references: 3317417
references: Mol Cell Biol. 2006 Dec;26(24):9220-31
references: 17030611
references: Genes Dev. 2007 Apr 1;21(7):756-69
references: 17403778
references: Endocr Rev. 1998 Aug;19(4):477-90
references: 9715376
references: Circulation. 2005 Apr 12;111(14):1826-32
references: 15809373
references: Mol Cell. 2008 Oct 24;32(2):221-31
references: 18951090
references: Diabetes. 2003 Feb;52(2):409-16
references: 12540615
references: Genes Dev. 1999 Nov 15;13(22):2905-27
references: 10579998
references: Diabetes. 2008 Apr;57(4):846-59
references: 18174526
references: J Clin Invest. 2002 Dec;110(12):1839-47
references: 12488434
references: Diabetes. 2003 Jan;52(1):102-10
references: 12502499