KEGG   PATHWAY: oaa04931
Entry
oaa04931                    Pathway                                
Name
Insulin resistance - Ornithorhynchus anatinus (platypus)
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
oaa04931  Insulin resistance
oaa04931

Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
114810063  INS; insulin [KO:K04526]
100088568  RPS6KA6; ribosomal protein S6 kinase alpha-6 isoform X2 [KO:K04373] [EC:2.7.11.1]
100083378  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X1 [KO:K04373] [EC:2.7.11.1]
100077380  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
100081928  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
100074395  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X3 [KO:K06269] [EC:3.1.3.16]
100078635  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100092226  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
100079515  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
100080024  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
100075652  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
100091257  protein phosphatase 1 regulatory subunit 3C-like [KO:K07189]
103166670  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
114816130  PPP1R3E; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3E [KO:K07189]
100079104  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
103170729  IRS1; insulin receptor substrate 1 [KO:K16172]
100077166  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X3 [KO:K05696] [EC:3.1.3.48]
100089978  PTPN11; LOW QUALITY PROTEIN: tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
100086381  tyrosine-protein phosphatase non-receptor type 11-like [KO:K07293] [EC:3.1.3.48]
100078392  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
100086270  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100073788  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100074273  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100080187  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100082075  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
103167126  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100083320  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100081473  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100090267  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100079751  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100087780  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100078852  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100074181  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100083298  IL6; interleukin-6 [KO:K05405]
100087932  STAT3; signal transducer and activator of transcription 3 isoform X2 [KO:K04692]
100090302  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100092089  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100074446  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
107547250  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
100085643  TNF; tumor necrosis factor [KO:K03156]
100085735  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
100073424  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100076033  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
100082590  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100078925  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100090081  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100083819  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100074633  RELA; transcription factor p65 isoform X1 [KO:K04735]
100091599  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
100089779  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100077864  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
100091317  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100075352  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100088284  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
100083731  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
100093063  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100082459  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X3 [KO:K07200]
100080957  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
100082856  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100076923  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100073995  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
100092976  AGT; angiotensinogen [KO:K09821]
100088247  SLC27A1; long-chain fatty acid transport protein 1 isoform X1 [KO:K08745] [EC:6.2.1.-]
103169806  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
100075331  SLC27A2; very long-chain acyl-CoA synthetase [KO:K08746] [EC:6.2.1.- 6.2.1.3]
107547662  SLC27A3; solute carrier family 27 member 3 [KO:K08772] [EC:6.2.1.-]
100090562  SLC27A5; bile acyl-CoA synthetase [KO:K08748] [EC:6.2.1.7]
100073807  CD36; platelet glycoprotein 4 [KO:K06259]
100085025  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
100088214  PRKCD; protein kinase C delta type isoform X3 [KO:K06068] [EC:2.7.11.13]
100077508  PTPA; serine/threonine-protein phosphatase 2A activator [KO:K17605]
100079611  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
114805830  IRS2; insulin receptor substrate 2 [KO:K07187]
100084785  PYGL; LOW QUALITY PROTEIN: glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
100084973  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
100085834  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
100082288  FOXO1; forkhead box protein O1 [KO:K07201]
100073969  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
100088404  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
100083297  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
100088723  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100092475  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
100086793  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
100088231  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
114814595  NR1H2; oxysterols receptor LXR-beta isoform X1 [KO:K08535]
100075366  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
100085135  MLX; max-like protein X isoform X1 [KO:K09113]
100074728  MLX-interacting protein [KO:K09113]
114817878  MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
100081561  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
103168168  PRKCE; protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
100081496  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
100076848  PPARA; peroxisome proliferator-activated receptor alpha isoform X1 [KO:K07294]
100089083  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
100074365  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]
100086916  OGA; protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
103169766  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
100074548  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 isoform X1 [KO:K07299]
100073861  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
100073443  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
114808055  CRTC2; CREB-regulated transcription coactivator 2 [KO:K16333]
100093310  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100078176  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100092528  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100076562  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103165821  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100080655  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [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
oaa00010  Glycolysis / Gluconeogenesis
oaa00061  Fatty acid biosynthesis
oaa00514  Other types of O-glycan biosynthesis
oaa00520  Amino sugar and nucleotide sugar metabolism
oaa04150  mTOR signaling pathway
oaa04151  PI3K-Akt signaling pathway
oaa04668  TNF signaling pathway
oaa04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

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