KEGG   PATHWAY: oas04931
Entry
oas04931                    Pathway                                
Name
Insulin resistance - Ovis aries (sheep)
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
oas04931  Insulin resistance
oas04931

Organism
Ovis aries (sheep) [GN:oas]
Gene
114110121  INS; insulin [KO:K04526]
101121915  RPS6KA6; ribosomal protein S6 kinase alpha-6 isoform X8 [KO:K04373] [EC:2.7.11.1]
101114530  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
101110124  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
101111428  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X2 [KO:K04373] [EC:2.7.11.1]
101119264  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
101123197  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
101106284  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
101113779  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
101123512  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
101102871  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
101110321  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
101122699  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
443431  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
101102293  IRS1; insulin receptor substrate 1 [KO:K16172]
101118209  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
101114308  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X3 [KO:K07293] [EC:3.1.3.48]
101107037  tyrosine-protein phosphatase non-receptor type 11-like isoform X4 [KO:K07293] [EC:3.1.3.48]
101111588  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X2 [KO:K05695] [EC:3.1.3.48]
101109759  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101110015  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101117348  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101123247  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101111546  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101121455  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
101118462  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101119242  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100294652  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100271659  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101107371  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101109574  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
101118410  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
443406  IL6; interleukin-6 precursor [KO:K05405]
100294659  STAT3; signal transducer and activator of transcription 3 isoform X10 [KO:K04692]
100294595  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100169938  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
101118685  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
101108772  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
443540  TNF; tumor necrosis factor [KO:K03156]
100135698  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
101116201  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120826  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120665  MAPK10; mitogen-activated protein kinase 10 isoform X2 [KO:K04440] [EC:2.7.11.24]
780484  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
780520  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
101108228  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]
101102191  RELA; transcription factor p65 [KO:K04735]
443077  NOS3; nitric oxide synthase 3 isoform X1 [KO:K13242] [EC:1.14.13.39]
101122295  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
101123311  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
101118797  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
100127210  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101103425  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101113114  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
101107899  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100142674  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
101103143  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X3 [KO:K07200]
101104483  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X5 [KO:K07200]
101114816  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
443193  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
101119440  AGT; angiotensinogen [KO:K09821]
101120396  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
101114609  SLC27A1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
101108576  SLC27A2; long-chain fatty acid transport protein 2 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
101101860  SLC27A3; long-chain fatty acid transport protein 3 isoform X1 [KO:K08772] [EC:6.2.1.-]
101120689  SLC27A5; long-chain fatty acid transport protein 5 isoform X2 [KO:K08748] [EC:6.2.1.7]
101104743  SLC27A6; long-chain fatty acid transport protein 6 [KO:K08749]
101102230  platelet glycoprotein 4-like isoform X1 [KO:K06259]
101114861  platelet glycoprotein 4-like isoform X4 [KO:K06259]
101115115  platelet glycoprotein 4 isoform X1 [KO:K06259]
101113426  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
101107639  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
101105403  PTPA; serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605]
100329218  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
106991367  IRS2; insulin receptor substrate 2 [KO:K07187]
101122616  TRIB3; tribbles homolog 3 isoform X2 [KO:K19518]
554320  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
554325  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
442998  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
101107877  FOXO1; forkhead box protein O1 [KO:K07201]
100037690  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
101120669  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
101113421  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
100037689  G6PC1; glucose-6-phosphatase catalytic subunit 1 isoform X1 [KO:K01084] [EC:3.1.3.9]
101121493  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
443205  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
101116762  NR1H3; oxysterols receptor LXR-alpha isoform X2 [KO:K08536]
101111571  NR1H2; oxysterols receptor LXR-beta isoform X2 [KO:K08535]
101121771  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta isoform X1 [KO:K17962]
101102914  MLX; max-like protein X isoform X2 [KO:K09113]
101115503  MLXIPL; carbohydrate-responsive element-binding protein isoform X2 [KO:K09113]
101102760  MLXIP; MLX-interacting protein [KO:K09113]
443434  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
101110314  PRKCE; protein kinase C epsilon type isoform X2 [KO:K18050] [EC:2.7.11.13]
443270  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
443457  PPARA; peroxisome proliferator-activated receptor alpha isoform X2 [KO:K07294]
101117211  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
101119351  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X2 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
101113978  OGA; protein O-GlcNAcase isoform X1 [KO:K15719] [EC:3.2.1.169 2.3.1.48]
101106996  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X2 [KO:K09667] [EC:2.4.1.255]
443461  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
101116643  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X2 [KO:K00820] [EC:2.6.1.16]
101120570  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
101102117  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
443118  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101107485  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X2 [KO:K09048]
101114243  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101108743  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101113586  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
101113882  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101112976  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
oas00010  Glycolysis / Gluconeogenesis
oas00061  Fatty acid biosynthesis
oas00514  Other types of O-glycan biosynthesis
oas00520  Amino sugar and nucleotide sugar metabolism
oas04150  mTOR signaling pathway
oas04151  PI3K-Akt signaling pathway
oas04668  TNF signaling pathway
oas04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

DBGET integrated database retrieval system