We previously proposed that LYR motif containing 1 (LYRM1)-induced mitochondrial reactive oxygen species (ROS) production contributes to obesity-related insulin resistance. Metformin inhibits ROS production and promotes mitochondrial biogenesis in specific tissues. We assessed the effects of metformin on insulin resistance in LYRM1-over-expressing 3T3-L1 adipocytes. Metformin enhanced basal and insulin-stimulated glucose uptake and GLUT4 translocation, reduced IRS-1 and Akt phosphorylation and ROS levels, and affected the expression of regulators of mitochondrial biogenesis in LYRM1-over-expressing adipocytes. Metformin may ameliorate LYRM1-induced insulin resistance and mitochondrial dysfunction in part via a direct antioxidant effect and in part by activating the adenosine monophosphate-activated protein kinase (AMPK)-PGC1/NRFs pathway.
LuHKoshkinVAllisterEMGyulkhandanyanAVWheelerMB. Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes2010; 59: 448–59.
3.
KimJAWeiYSowersJR. Role of mitochondrial dysfunction in insulin resistance. Circ Res2008; 102: 401–14.
4.
WangXGuCHeWYeXChenHZhangXHaiC. Glucose oxidase induces insulin resistance via influencing multiple targets in vitro and in vivo: the central role of oxidative stress. Biochimie2012; 94: 1705–17.
5.
BashanNKovsanJKachkoIOvadiaHRudichA. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev2009; 89: 27–71.
6.
HoustisNRosenEDLanderES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature2006; 440: 944–8.
7.
QinZYZhangMGuoXRWangYMZhuGZNiYHZhaoYPQiuJKouCZQinRCaoXG. α-Lipoic acid ameliorates impaired glucose uptake in LYRM1 overexpressing 3T3-L1 adipocytes through the IRS-1/Akt signaling pathway. J Bioenerg Biomembr2012; 44: 579–86.
8.
RiceSPellattLJBryanSJWhiteheadSAMasonHD. Action of metformin on the insulin-signaling pathway and on glucose transport in human granulosa cells. J Clin Endocrinol Metab2011; 96: E427–35.
9.
GrisouardJTimperKRadimerskiTMFreyDMPeterliRKolaBKorbonitsMHerrmannPKrahenbuhlSZulewskiHKellerUMullerBChrist-CrainM. Mechanisms of metformin action on glucose transport and metabolism in human adipocytes. Biochem Pharmacol2010; 80: 1736–45.
10.
KukidomeDNishikawaTSonodaKImotoKFujisawaKYanoMMotoshimaHTaguchiTMatsumuraTArakiE. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes2006; 55: 120–7.
11.
QiuJNiYHGongHXFeiLPanXQGuoMChenRHGuoXR. Identification of differentially expressed genes in omental adipose tissues of obese patients by suppression subtractive hybridization. Biochem Biophys Res Commun2007; 352: 469–78.
12.
CaoXGKouCZZhaoYPGaoCLZhuCZhangCMJiCBQinDNZhangMGuoXR. Overexpression of LYRM1 induces mitochondrial impairment in 3T3-L1 adipocytes. Mol Genet Metab2010; 101: 395–9.
13.
BaileyCJTurnerRC. Metformin. N Engl J Med1996; 334: 574–9.
14.
HundalRSKrssakMDufourSLaurentDLebonVChandramouliVInzucchiSESchumannWCPetersenKFLandauBRShulmanGI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes2000; 49: 2063–9.
15.
FujisawaKNishikawaTKukidomeDImotoKYamashiroTMotoshimaHMatsumuraTArakiE. TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis. Biochem Biophys Res Commun2009; 379: 43–8.
16.
QiuJGaoCLZhangMChenRHChiXLiuFZhangCMJiCBChenXHZhaoYPLiXNTongMLNiYHGuoXR. LYRM1, a novel gene promotes proliferation and inhibits apoptosis of preadipocytes. Eur J Endocrinol2009; 160: 177–84.
17.
MaxwellDPWangYMcIntoshL. The alternative oxidase lowers mitochondrial reactive oxygen production in plant cells. Proc Natl Acad Sci U S A1999; 96: 8271–6.
18.
CeddiaRBSomwarRMaidaAFangXBikopoulosGSweeneyG. Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia2005; 48: 132–9.
KouCCaoXQinDJiCZhuJZhangCZhuCGaoCChenRGuoXZhangM. Over-expression of LYRM1 inhibits glucose transport in rat skeletal muscles via attenuated phosphorylation of PI3K (p85) and Akt. Mol Cell Biochem2011; 348: 149–54.
21.
BonnardCDurandAPeyrolSChanseaumeEChauvinMAMorioBVidalHRieussetJ. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest2008; 118: 789–800.
22.
ScarpullaRC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta2011; 1813: 1269–78.
23.
ArduiniAServiddioGEscobarJTormosAMBellantiFVinaJMonsalveMSastreJ. Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions. Am J Physiol Gastrointest Liver Physiol2011; 301: G119–27.
24.
PattiMECorveraS. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev2010; 31: 364–95.
25.
KaneDAAndersonEJPriceJWIIIWoodliefTLLinCTBikmanBTCortrightRNNeuferPD. Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med2010; 49: 1082–7.
26.
MoralesAIDetailleDPrietoMPuenteABrionesEArevaloMLeverveXLopez-NovoaJMEl-MirMY. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int2010; 77: 861–9.
27.
SuwaMEgashiraTNakanoHSasakiHKumagaiS. Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol2006; 101: 1685–92.
28.
CiaraldiTPKongAPChuNVKimDDBaxiSLoviscachMPlodkowskiRReitzRCaulfieldMMudaliarSHenryRR. Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects. Diabetes2002; 51: 30–6.
29.
MagnoniLJVraskouYPalstraAPPlanasJV. AMP-activated protein kinase plays an important evolutionary conserved role in the regulation of glucose metabolism in fish skeletal muscle cells. PLoS One2012; 7: e31219–e31219.
30.
BentonCRNickersonJGLallyJHanXXHollowayGPGlatzJFLuikenJJGrahamTEHeikkilaJJBonenA. Modest PGC-1alpha overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria. J Biol Chem2008; 283: 4228–40.
31.
IkeuchiMMatsusakaHKangDMatsushimaSIdeTKubotaTFujiwaraTHamasakiNTakeshitaASunagawaKTsutsuiH. Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation2005; 112: 683–90.
32.
LiangHBalasBTantiwongPDubeJGoodpasterBHO’DohertyRMDeFronzoRARichardsonAMusiNWardWF. Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity. Am J Physiol Endocrinol Metab2009; 296: E945–54.
33.
ChoiCSBefroyDECodellaRKimSReznickRMHwangYJLiuZXLeeHYDistefanoASamuelVTZhangDClineGWHandschinCLinJPetersenKFSpiegelmanBMShulmanGI. Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci U S A2008; 105: 19926–31.
34.
MiuraSKaiYOnoMEzakiO. Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1alpha down-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem2003; 278: 31385–90.
35.
YangWLuJWengJJiaWJiLXiaoJShanZLiuJTianHJiQZhuDGeJLinLChenLGuoXZhaoZLiQZhouZShanGHeJChina NationalDMetabolic Disorders StudyG. Prevalence of diabetes among men and women in China. N Engl J Med2010; 362: 1090–101.
36.
GiovannoneBScaldaferriMLFedericiMPorzioOLauroDFuscoASbracciaPBorboniPLauroRSestiG. Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential. Diabetes Metab Res Rev2000; 16: 434–41.
37.
ShibataMHakunoFYamanakaDOkajimaHFukushimaTHasegawaTOgataTToyoshimaYChidaKKimuraKSakodaHTakenakaAAsanoTTakahashiS. Paraquat-induced oxidative stress represses phosphatidylinositol 3-kinase activities leading to impaired glucose uptake in 3T3-L1 adipocytes. J Biol Chem2010; 285: 20915–25.
38.
KumarNDeyCS. Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells. Br J Pharmacol2002; 137: 329–36.
39.
YuanLZieglerRHamannA. Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated Hep G2 cells. Acta Pharmacol Sin2003; 24: 55–60.
40.
Bloch-DamtiAPotashnikRGualPLe Marchand-BrustelYTantiJFRudichABashanN. Differential effects of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stress. Diabetologia2006; 49: 2463–73.
