KEGG   PATHWAY: oga04931
Entry
oga04931                    Pathway                                
Name
Insulin resistance - Otolemur garnettii (small-eared galago)
Description
Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.
Class
Human Diseases; Endocrine and metabolic disease
Pathway map
oga04931  Insulin resistance
oga04931

Organism
Otolemur garnettii (small-eared galago) [GN:oga]
Gene
100958310  INS; insulin isoform X1 [KO:K04526]
100950673  RPS6KA6; LOW QUALITY PROTEIN: ribosomal protein S6 kinase alpha-6 [KO:K04373] [EC:2.7.11.1]
100945202  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X3 [KO:K04373] [EC:2.7.11.1]
100963421  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X5 [KO:K04373] [EC:2.7.11.1]
100946311  RPS6KA2; ribosomal protein S6 kinase alpha-2 [KO:K04373] [EC:2.7.11.1]
100941909  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100960152  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100945379  serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269] [EC:3.1.3.16]
100955191  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100940860  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
100949665  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
100966727  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100944077  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
100962237  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
100958778  IRS1; insulin receptor substrate 1 [KO:K16172]
100952815  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
100955860  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X2 [KO:K07293] [EC:3.1.3.48]
100958136  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X4 [KO:K05695] [EC:3.1.3.48]
100947138  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100953367  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100954109  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100956838  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100952580  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
100949858  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100959825  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100955276  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100945977  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100957753  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100945805  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100940650  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X5 [KO:K04688] [EC:2.7.11.1]
100943579  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100949231  IL6; LOW QUALITY PROTEIN: interleukin-6 [KO:K05405]
100958469  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
100960974  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100952751  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
100956758  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
100949141  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100963613  TNF; tumor necrosis factor [KO:K03156]
100955892  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
100957169  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100967053  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100960275  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100946157  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100947991  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100951061  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100957990  RELA; transcription factor p65 isoform X3 [KO:K04735]
100956703  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
100965310  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100966356  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
100945996  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100948837  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
100947892  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100943975  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100963213  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100941359  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100944531  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
100947945  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100959432  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100959176  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
100944302  AGT; angiotensinogen [KO:K09821]
100953173  SLC27A1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
100961079  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
100966005  SLC27A2; very long-chain acyl-CoA synthetase [KO:K08746] [EC:6.2.1.- 6.2.1.3]
100964746  SLC27A3; long-chain fatty acid transport protein 3 [KO:K08772] [EC:6.2.1.-]
100943998  SLC27A5; bile acyl-CoA synthetase isoform X2 [KO:K08748] [EC:6.2.1.7]
100962821  SLC27A6; long-chain fatty acid transport protein 6 [KO:K08749]
100962623  platelet glycoprotein 4 [KO:K06259]
100953094  platelet glycoprotein 4-like [KO:K06259]
100963918  PRKCQ; protein kinase C theta type isoform X2 [KO:K18052] [EC:2.7.11.13]
100951664  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
100966274  PTPA; serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605]
100955236  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
100951299  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
100956452  TRIB3; tribbles homolog 3 [KO:K19518]
100943479  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100949519  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
100966783  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100960421  FOXO1; forkhead box protein O1 [KO:K07201]
100941836  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100963401  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100941852  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100950588  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100966484  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
100955667  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X2 [KO:K07593]
100963453  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
100941828  NR1H2; oxysterols receptor LXR-beta isoform X1 [KO:K08535]
100942024  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
100962289  MLXIP; MLX-interacting protein [KO:K09113]
100944316  MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
100955620  MLX; max-like protein X isoform X3 [KO:K09113]
100961040  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
100943756  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
100965953  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X4 [KO:K07202]
100943292  PPARA; peroxisome proliferator-activated receptor alpha isoform X2 [KO:K07294]
100950210  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
100959283  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
100955878  protein O-GlcNAcase-like isoform X1 [KO:K15719] [EC:3.2.1.169 2.3.1.48]
100966970  MGEA5; protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
100951420  ZNF79; zinc finger protein 79 isoform X1 [KO:K09667] [EC:2.4.1.255]
100946588  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
100959166  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
100957668  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
100955987  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 [KO:K00820] [EC:2.6.1.16]
100955731  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
100964324  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870]
100966324  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100951671  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100941510  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100955062  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100952085  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100952718  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
Compound
C00022  Pyruvate
C00024  Acetyl-CoA
C00031  D-Glucose
C00043  UDP-N-acetyl-alpha-D-glucosamine
C00083  Malonyl-CoA
C00085  D-Fructose 6-phosphate
C00092  D-Glucose 6-phosphate
C00095  D-Fructose
C00162  Fatty acid
C00165  Diacylglycerol
C00195  N-Acylsphingosine
C00352  D-Glucosamine 6-phosphate
C00369  Starch
C00422  Triacylglycerol
C00533  Nitric oxide
C02571  O-Acetylcarnitine
C02843  Long-chain acyl-CoA
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06156  alpha-D-Glucosamine 1-phosphate
G00369   
Reference
PMID:22360800
  Authors
Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT, Lambertucci RH, Cury-Boaventura MF, Silveira LR, Curi R, Hirabara SM
  Title
Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function.
  Journal
Lipids Health Dis 11:30 (2012)
DOI:10.1186/1476-511X-11-30
Reference
PMID:12765939
  Authors
Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H
  Title
Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes.
  Journal
Diabetes 52:1319-25 (2003)
DOI:10.2337/diabetes.52.6.1319
Reference
PMID:20526383
  Authors
Choi K, Kim YB
  Title
Molecular mechanism of insulin resistance in obesity and type 2 diabetes.
  Journal
Korean J Intern Med 25:119-29 (2010)
DOI:10.3904/kjim.2010.25.2.119
Reference
PMID:7666792
  Authors
Ahmad F, Goldstein BJ
  Title
Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus.
  Journal
Metabolism 44:1175-84 (1995)
DOI:10.1016/0026-0495(95)90012-8
Reference
PMID:15166380
  Authors
George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S, Barroso I
  Title
A family with severe insulin resistance and diabetes due to a mutation in AKT2.
  Journal
Science 304:1325-8 (2004)
DOI:10.1126/science.1096706
Reference
PMID:22675355
  Authors
Snel M, Jonker JT, Schoones J, Lamb H, de Roos A, Pijl H, Smit JW, Meinders AE, Jazet IM
  Title
Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.
  Journal
Int J Endocrinol 2012:983814 (2012)
DOI:10.1155/2012/983814
Reference
PMID:17130651
  Authors
Morino K, Petersen KF, Shulman GI
  Title
Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction.
  Journal
Diabetes 55 Suppl 2:S9-S15 (2006)
DOI:10.2337/db06-S002
Reference
PMID:16186396
  Authors
Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK
  Title
Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation.
  Journal
Diabetes 54:2939-45 (2005)
DOI:10.2337/diabetes.54.10.2939
Reference
PMID:18309108
  Authors
Kim JA, Wei Y, Sowers JR
  Title
Role of mitochondrial dysfunction in insulin resistance.
  Journal
Circ Res 102:401-14 (2008)
DOI:10.1161/CIRCRESAHA.107.165472
Reference
PMID:17141630
  Authors
Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, Andrikopoulos S, Proietto J, Gorgun CZ, Carling D, Hotamisligil GS, Febbraio MA, Kay TW, Kemp BE
  Title
Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.
  Journal
Cell Metab 4:465-74 (2006)
DOI:10.1016/j.cmet.2006.11.005
Reference
PMID:9886945
  Authors
Ruderman NB, Saha AK, Vavvas D, Witters LA
  Title
Malonyl-CoA, fuel sensing, and insulin resistance.
  Journal
Am J Physiol 276:E1-E18 (1999)
DOI:10.1152/ajpendo.1999.276.1.E1
Reference
PMID:8048519
  Authors
Saha AK, Kurowski TG, Colca JR, Ruderman NB
  Title
Lipid abnormalities in tissues of the KKAy mouse: effects of pioglitazone on malonyl-CoA and diacylglycerol.
  Journal
Am J Physiol 267:E95-101 (1994)
DOI:10.1152/ajpendo.1994.267.1.E95
Reference
PMID:22677645
  Authors
Blachnio-Zabielska AU, Koutsari C, Tchkonia T, Jensen MD
  Title
Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance.
  Journal
Obesity (Silver Spring) 20:2341-7 (2012)
DOI:10.1038/oby.2012.126
Reference
PMID:16364488
  Authors
Larter CZ, Farrell GC
  Title
Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
  Journal
J Hepatol 44:253-61 (2006)
DOI:10.1016/j.jhep.2005.11.030
Reference
PMID:15107844
  Authors
Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, Evans RM, Olefsky J, Montminy M
  Title
PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.
  Journal
Nat Med 10:530-4 (2004)
DOI:10.1038/nm1044
Reference
PMID:20466550
  Authors
Slawson C, Copeland RJ, Hart GW
  Title
O-GlcNAc signaling: a metabolic link between diabetes and cancer?
  Journal
Trends Biochem Sci 35:547-55 (2010)
DOI:10.1016/j.tibs.2010.04.005
Reference
PMID:23647930
  Authors
Ruan HB, Singh JP, Li MD, Wu J, Yang X
  Title
Cracking the O-GlcNAc code in metabolism.
  Journal
Trends Endocrinol Metab 24:301-9 (2013)
DOI:10.1016/j.tem.2013.02.002
Reference
PMID:16756496
  Authors
Muoio DM, Newgard CB
  Title
Obesity-related derangements in metabolic regulation.
  Journal
Annu Rev Biochem 75:367-401 (2006)
DOI:10.1146/annurev.biochem.75.103004.142512
Reference
PMID:10923637
  Authors
Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL
  Title
Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.
  Journal
Diabetes 49:1353-8 (2000)
DOI:10.2337/diabetes.49.8.1353
Related
pathway
oga00010  Glycolysis / Gluconeogenesis
oga00061  Fatty acid biosynthesis
oga00514  Other types of O-glycan biosynthesis
oga00520  Amino sugar and nucleotide sugar metabolism
oga04150  mTOR signaling pathway
oga04151  PI3K-Akt signaling pathway
oga04668  TNF signaling pathway
oga04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

DBGET integrated database retrieval system