Recent compelling data show that reactive oxygen species (ROS) not only are a harmful by-product of aerobic metabolism, but also are used as signaling molecules to regulate various cellular processes. In mammalian cells, ROS are produced transiently in response to many extracellular stimuli, including insulin, and specific inhibition of the ROS suppresses insulin-dependent signaling. Initially, this finding rationalized the concept of ROS acting as insulin mimetics. However, it is becoming evident that ROS are also causal to diabetes, a metabolic disorder characterized by insufficiency of secretion of, or receptor insensitivity to, endogenous insulin. This notion underlines a dual role for ROS in insulin signaling as both deleterious and beneficiary. Moreover, it strongly suggests that a delicate redox balance is required for insulin signaling to remain “healthy” for an organism. Antioxid. Redox Signal. 15, 219–232.
Get full access to this article
View all access options for this article.
References
1.
AltomareDA, TestaJR. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 24:7455–7464. 2005.
ArsenijevicD, OnumaH, PecqueurC, RaimbaultS, ManningBS, MirouxB, CouplanE, Alves-GuerraMC, GoubernM, SurwitR, BouillaudF, RichardD, CollinsS, RicquierD. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet, 26:435–439. 2000.
5.
Asante-AppiahE, KennedyBP. Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am J Physiol Endocrinol Metab, 284:E663–E670. 2003.
6.
AvruchJ. Insulin signal transduction through protein kinase cascades. Mol Cell Biochem, 182:31–48. 1998.
7.
Bloch-DamtiA, BashanN. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal, 7:1553–1567. 2005.
8.
BokochGM, DieboldB, KimJS, GianniD. Emerging evidence for the importance of phosphorylation in the regulation of NADPH oxidases. Antioxid Redox Signal, 11:2429–2441. 2009.
9.
Boura-HalfonS, ZickY. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab, 296:E581–E591. 2009.
10.
BrownleeM. Biochemistry and molecular cell biology of diabetic complications. Nature, 414:813–820. 2001.
11.
CarnesecchiS, CarpentierJL, FotiM, SzantoI. Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3. Exp Cell Res, 312:3413–3424. 2006.
12.
ChenK, KirberMT, XiaoH, YangY, KeaneyJF.Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol, 181:1129–1139. 2008.
13.
ChenT, KablaouiN, LittleJ, TimofeevskiS, TschantzWR, ChenP, FengJ, CharltonM, StantonR, BauerP. Identification of small-molecule inhibitors of the JIP-JNK interaction. Biochem J, 420:283–294. 2009.
14.
ChengZ, GuoS, CoppsK, DongX, KolliparaR, RodgersJT, DepinhoRA, PuigserverP, WhiteMF. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med, 15:1307–1311. 2009.
ChiarugiP. PTPs versus PTKs: the redox side of the coin. Free Radic Res, 39:353–364. 2005.
17.
CsordasG, HajnoczkyG. SR/ER-mitochondrial local communication: calcium and ROS. Biochim Biophys Acta, 1787:1352–1362. 2009.
18.
CullinanSB, DiehlJA. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol, 38:317–332. 2006.
19.
CunninghamJT, RodgersJT, ArlowDH, VazquezF, MoothaVK, PuigserverP. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature, 450:736–740. 2007.
20.
DamesSA, MuletJM, Rathgeb-SzaboK, HallMN, GrzesiekS. The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redox-dependent structural and cellular stability. J Biol Chem, 280:20558–20564. 2005.
21.
DansenTB, SmitsLM, van TriestMH, de KeizerPL, van LeenenD, KoerkampMG, SzypowskaA, MeppelinkA, BrenkmanAB, YodoiJ, HolstegeFC, BurgeringBM. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol, 5:664–672. 2009.
22.
de KeizerPLJ, BurgeringBMT, DansenTB. Forkhead box O as a sensor, mediator, and regulator of redox signaling. Antioxid Redox Signal, 14:1093–1106. 2011.
23.
DelepineM, NicolinoM, BarrettT, GolamaullyM, LathropGM, JulierC. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet, 25:406–409. 2000.
24.
ElcheblyM, PayetteP, MichaliszynE, CromlishW, CollinsS, LoyAL, NormandinD, ChengA, Himms-HagenJ, ChanCC, RamachandranC, GresserMJ, TremblayML, KennedyBP. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 283:1544–1548. 1999.
25.
EssersMA, WeijzenS, de Vries-SmitsAM, SaarloosI, de RuiterND, BosJL, BurgeringBM. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J, 23:4802–4812. 2004.
26.
FourquetS, HuangME, D'AutreauxB, ToledanoMB. The dual functions of thiol-based peroxidases in H2O2 scavenging and signaling. Antioxid Redox Signal, 10:1565–1576. 2008.
27.
FurukawaS, FujitaT, ShimabukuroM, IwakiM, YamadaY, NakajimaY, NakayamaO, MakishimaM, MatsudaM, ShimomuraI. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest, 114:1752–1761. 2004.
28.
GalicS, Klingler-HoffmannM, Fodero-TavolettiMT, PuryerMA, MengTC, TonksNK, TiganisT. Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Mol Cell Biol, 23:2096–2108. 2003.
29.
GemsD, PartridgeL. Stress-response hormesis and aging: “that which does not kill us makes us stronger.”Cell Metab, 7:200–203. 2008.
30.
GeorgeS, RochfordJJ, WolfrumC, GraySL, SchinnerS, WilsonJC, SoosMA, MurgatroydPR, WilliamsRM, AceriniCL, DungerDB, BarfordD, UmplebyAM, WarehamNJ, DaviesHA, SchaferAJ, StoffelM, O'RahillyS, BarrosoI. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science, 304:1325–1328. 2004.
31.
GertzM, FischerF, WoltersD, SteegbornC. Activation of the lifespan regulator p66Shc through reversible disulfide bond formation. Proc Natl Acad Sci U S A, 105:5705–5709. 2008.
32.
GiorgiC, AgnolettoC, BaldiniC, BononiA, BonoraM, MarchiS, MissiroliS, PatergnaniS, PolettiF, RimessiA, ZavanB, PintonP. Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid Redox Signal, 13:1051–1085. 2010.
33.
GiorgioM, TrineiM, MigliaccioE, PelicciPG. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?Nat Rev Mol Cell Biol, 8:722–728. 2007.
34.
GoldsteinBJ, MahadevK, WuX, ZhuL, MotoshimaH. Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antioxid Redox Signal, 7:1021–1031. 2005.
35.
GrossDN, van den HeuvelAP, BirnbaumMJ. The role of FoxO in the regulation of metabolism. Oncogene, 27:2320–2336. 2008.
36.
GuilhermeA, VirbasiusJV, PuriV, CzechMP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol, 9:367–377. 2008.
37.
HirosumiJ, TuncmanG, ChangL, GorgunCZ, UysalKT, MaedaK, KarinM, HotamisligilGS. A central role for JNK in obesity and insulin resistance. Nature, 420:333–336. 2002.
38.
HoehnKL, SalmonAB, Hohnen-BehrensC, TurnerN, HoyAJ, MaghzalGJ, StockerR, Van RemmenH, KraegenEW, CooneyGJ, RichardsonAR, JamesDE. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A, 106:17787–17792. 2009.
39.
HotamisligilGS. Inflammation and metabolic disorders. Nature, 444:860–867. 2006.
40.
HoustisN, RosenED, LanderES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature, 440:944–948. 2006.
41.
HuangW, BansodeR, MehtaM, MehtaKD. Loss of protein kinase Cbeta function protects mice against diet-induced obesity and development of hepatic steatosis and insulin resistance. Hepatology, 49:1525–1536. 2009.
42.
ImotoK, KukidomeD, NishikawaT, MatsuhisaT, SonodaK, FujisawaK, YanoM, MotoshimaH, TaguchiT, TsuruzoeK, MatsumuraT, IchijoH, ArakiE. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. Diabetes, 55:1197–1204. 2006.
43.
KatsoR, OkkenhaugK, AhmadiK, WhiteS, TimmsJ, WaterfieldMD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 17:615–675. 2001.
44.
KennerKA, AnyanwuE, OlefskyJM, KusariJ. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem, 271:19810–19816. 1996.
45.
KushnerJA, CiemerychMA, SicinskaE, WartschowLM, TetaM, LongSY, SicinskiP, WhiteMF. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol, 25:3752–3762. 2005.
46.
KwonJ, LeeSR, YangKS, AhnY, KimYJ, StadtmanER, RheeSG. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A, 101:16419–16424. 2004.
47.
LeeSR, KwonKS, KimSR, RheeSG. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem, 273:15366–15372. 1998.
48.
LeeSS, KennedyS, TolonenAC, RuvkunG. DAF-16 target genes that control C. elegans life-span and metabolism. Science, 300:644–647. 2003.
49.
LeslieNR, BennettD, LindsayYE, StewartH, GrayA, DownesCP. Redox regulation of PI3-kinase signaling via inactivation of PTEN. EMBO J, 22:5501–5510. 2003.
50.
LetoTL, MorandS, HurtD, UeyamaT. Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal, 11:2607–2619. 2009.
MaassenJA, BurgeringBM, MedemaRH, OsteropAP, van der ZonGC, MollerW, BosJL. The role of ras proteins in insulin signal transduction. Horm Metab Res, 24:214–218. 1992.
53.
MahadevK, MotoshimaH, WuX, RuddyJM, ArnoldRS, ChengG, LambethJD, GoldsteinBJ. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol, 24:1844–1854. 2004.
54.
MahadevK, ZilberingA, ZhuL, GoldsteinBJ. Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J Biol Chem, 276:21938–21942. 2001.
55.
MalhotraJD, KaufmanRJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?Antioxid Redox Signal, 9:2277–2293. 2007.
56.
MengTC, BuckleyDA, GalicS, TiganisT, TonksNK. Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J Biol Chem, 279:37716–37725. 2004.
57.
MengTC, FukadaT, TonksNK. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell, 9:387–399. 2002.
MurataH, IharaY, NakamuraH, YodoiJ, SumikawaK, KondoT. Glutaredoxin exerts an antiapoptotic effect by regulating the redox state of Akt. J Biol Chem, 278:50226–50233. 2003.
60.
NadeauPJ, CharetteSJ, ToledanoMB, LandryJ. Disulfide bond-mediated multimerization of Ask1 and its reduction by thioredoxin-1 regulate H(2)O(2)-induced c-Jun NH(2)-terminal kinase activation and apoptosis. Mol Biol Cell, 18:3903–3913. 2007.
61.
OhSW, MukhopadhyayA, SvrzikapaN, JiangF, DavisRJ, TissenbaumHA. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A, 102:4494–4499. 2005.
OzcanU, YilmazE, OzcanL, FuruhashiM, VaillancourtE, SmithRO, GorgunCZ, HotamisligilGS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science, 313:1137–1140. 2006.
RavichandranKS. Signaling via Shc family adapter proteins. Oncogene, 20:6322–6330. 2001.
66.
RoloAP, PalmeiraCM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol, 212:167–178. 2006.
67.
SabioG, DavisRJ. cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. Trends Biochem Sci, 35:490–496. 2007.
68.
SalminenA, KaarnirantaK. ER stress and hormetic regulation of the aging process. Ageing Res Rev, 9:211–217.
69.
SantosCX, TanakaLY, WosniakJ, LaurindoFR. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal, 11:2409–2427. 2009.
70.
SarsourEH, KumarMG, ChaudhuriL, KalenAL, GoswamiPC. Redox control of the cell cycle in health and disease. Antioxid Redox Signal, 11:2985–3011. 2009.
71.
SchulzTJ, ZarseK, VoigtA, UrbanN, BirringerM, RistowM. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab, 6:280–293. 2007.
72.
SeelyBL, StaubsPA, ReichartDR, BerhanuP, MilarskiKL, SaltielAR, KusariJ, OlefskyJM. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes, 45:1379–1385. 1996.
73.
ShawRJ. Raptor swoops in on metabolism. Cell Metab, 8:343–344. 2008.
74.
SolinasG, NauglerW, GalimiF, LeeMS, KarinM. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A, 103:16454–16459. 2006.
75.
SongB, ScheunerD, RonD, PennathurS, KaufmanRJ. CHOP deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest, 118:3378–3389. 2008.
76.
StebbinsJL, DeSK, MachleidtT, BecattiniB, VazquezJ, KuntzenC, ChenLH, CellittiJF, Riel-MehanM, EmdadiA, SolinasG, KarinM, PellecchiaM. Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proc Natl Acad Sci U S A, 105:16809–16813. 2008.
StorzP. Forkhead homeobox type O transcription factors in the responses to oxidative stress. Antioxid Redox Signal, 14:593–605. 2011.
79.
TaniguchiCM, EmanuelliB, KahnCR. Critical nodes in signaling pathways: insights into insulin action. Nat Rev Mol Cell Biol, 7:85–96. 2006.
80.
UchidaT, NakamuraT, HashimotoN, MatsudaT, KotaniK, SakaueH, KidoY, HayashiY, NakayamaKI, WhiteMF, KasugaM. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med, 11:175–182. 2005.
81.
Ushio-FukaiM. Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal, 11:1289–1299. 2009.
82.
van den BergMCW, BurgeringBMT. Integrating opposing signals towards forkhead box O. Antioxid Redox Signal, 14:607–621. 2011.
83.
van MontfortRL, CongreveM, TisiD, CarrR, JhotiH. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature, 423:773–777. 2003.
84.
von LohneysenK, NoackD, JesaitisAJ, DinauerMC, KnausUG. Mutational analysis reveals distinct features of the Nox4-p22 phox complex. J Biol Chem, 283:35273–35282. 2008.
85.
WalkerUA. Acquired and inherited lipodystrophies. N Engl J Med, 351:103–104author reply 103–1042004.
WooHA, YimSH, ShinDH, KangD, YuDY, RheeSG. Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell, 140:517–518. 2007.
88.
WoodZA, PooleLB, KarplusPA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science, 300:650–653. 2003.
89.
YuanM, KonstantopoulosN, LeeJ, HansenL, LiZW, KarinM, ShoelsonSE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science, 293:1673–1677. 2001.
90.
ZhangDX, GuttermanDD. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol, 292:H2023–H2031. 2007.
91.
ZhangL, LaiE, TeodoroT, VolchukA. GRP78, but not protein-disulfide isomerase, partially reverses hyperglycemia-induced inhibition of insulin synthesis and secretion in pancreatic {beta}-cells. J Biol Chem, 284:5289–5298. 2009.
92.
ZhangW, FengD, LiY, IidaK, McGrathB, CavenerDR. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab, 4:491–497. 2006.
93.
ZhangZY, LeeSY. PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity. Expert Opin Invest Drugs, 12:223–2233. 2003.
94.
ZmijewskiJW, BanerjeeS, BaeH, FriggeriA, LazarowskiER, AbrahamE. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem, 285:33154–33164. 2009.
