KEGG   PATHWAY: biu04931
Entry
biu04931                    Pathway                                
Name
Insulin resistance - Bos indicus (zebu cattle)
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
biu04931  Insulin resistance
biu04931

Organism
Bos indicus (zebu cattle) [GN:biu]
Gene
109554336  INS; insulin isoform X1 [KO:K04526]
109573377  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
109564113  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
109555127  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X1 [KO:K04373] [EC:2.7.11.1]
109554414  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
109571193  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
109566263  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
109567662  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
109553499  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
109564802  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
109557421  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X1 [KO:K07189]
109553067  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
109571355  IRS1; insulin receptor substrate 1 [KO:K16172]
109567547  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
109570927  PTPN11; tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
109570168  tyrosine-protein phosphatase non-receptor type 11-like [KO:K07293] [EC:3.1.3.48]
109556400  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
109559805  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109570415  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109557823  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
109574805  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
109561418  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109556345  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109572496  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109570286  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109570401  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109554358  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
109573726  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
109578560  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
109558077  IL6; interleukin-6 [KO:K05405]
109573817  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
109574319  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
109571966  glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
109572216  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
109559597  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
109577428  TNF; tumor necrosis factor [KO:K03156]
109559729  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
109561331  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
109560650  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553773  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109553353  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
109575581  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
109560296  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
109554392  RELA; transcription factor p65 [KO:K04735]
109557793  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
109570580  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
109566880  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
109574066  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
109574812  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
109556244  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
109574695  5'-AMP-activated protein kinase catalytic subunit alpha-1-like [KO:K07198] [EC:2.7.11.31]
109555847  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
109571380  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
109570727  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
109557811  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
109559147  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
109571092  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
109553744  AGT; angiotensinogen [KO:K09821]
109561433  SLC27A1; long-chain fatty acid transport protein 1 isoform X1 [KO:K08745] [EC:6.2.1.-]
109566506  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
109566513  long-chain fatty acid transport protein 4-like [KO:K08745] [EC:6.2.1.-]
109565139  SLC27A2; very long-chain acyl-CoA synthetase [KO:K08746] [EC:6.2.1.- 6.2.1.3]
109554519  SLC27A3; long-chain fatty acid transport protein 3 [KO:K08772] [EC:6.2.1.-]
109571897  SLC27A5; bile acyl-CoA synthetase [KO:K08748] [EC:6.2.1.7]
109561836  SLC27A6; long-chain fatty acid transport protein 6 isoform X1 [KO:K08749]
109557879  LOW QUALITY PROTEIN: platelet glycoprotein 4-like [KO:K06259]
109557335  platelet glycoprotein 4-like [KO:K06259]
109567889  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
109576388  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
109566535  PTPA; serine/threonine-protein phosphatase 2A activator [KO:K17605]
109573629  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
109567100  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
109567336  TRIB3; tribbles homolog 3 [KO:K19518]
109567623  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
109554068  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
109554069  glycogen phosphorylase, muscle form-like [KO:K00688] [EC:2.4.1.1]
109565026  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
109566997  FOXO1; forkhead box protein O1 [KO:K07201]
109564787  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
109567303  PCK1; LOW QUALITY PROTEIN: phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
109573874  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
109576447  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
109574284  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
109558192  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
109569543  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
109571907  NR1H2; oxysterols receptor LXR-beta [KO:K08535]
109562191  PPARGC1B; LOW QUALITY PROTEIN: peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
109574083  MLX; max-like protein X isoform X1 [KO:K09113]
109578640  MLXIPL; carbohydrate-responsive element-binding protein [KO:K09113]
109571097  MLXIP; MLX-interacting protein isoform X1 [KO:K09113]
109579152  max-like protein X isoform X1 [KO:K09113]
109554147  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
109566044  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
109560366  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
109559910  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
109578066  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
109552991  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]
109578999  MGEA5; LOW QUALITY PROTEIN: protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
109555132  UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit [KO:K09667] [EC:2.4.1.255]
109556419  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 isoform X1 [KO:K07299]
109561329  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
109566236  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
109554474  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
109570093  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
109554418  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
109557676  CREB3L2; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
109563018  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
109569868  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
109561750  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
109557489  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
biu00010  Glycolysis / Gluconeogenesis
biu00061  Fatty acid biosynthesis
biu00514  Other types of O-glycan biosynthesis
biu00520  Amino sugar and nucleotide sugar metabolism
biu04150  mTOR signaling pathway
biu04151  PI3K-Akt signaling pathway
biu04668  TNF signaling pathway
biu04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

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