KEGG   PATHWAY: cfa04931
Entry
cfa04931                    Pathway                                
Name
Insulin resistance - Canis lupus familiaris (dog)
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
cfa04931  Insulin resistance
cfa04931

Organism
Canis lupus familiaris (dog) [GN:cfa]
Gene
100683481  [KO:K07293] [EC:3.1.3.48]
100685468  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
100855793  SLC27A3; solute carrier family 27 member 3 [KO:K08772] [EC:6.2.1.-]
100856339  [KO:K02649]
100856379  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
403475  SREBF1; sterol regulatory element-binding protein 1 [KO:K07197]
403492  G6PC1; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
403557  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
403558  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
403560  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
403583  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
403609  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
403634  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X5 [KO:K03158]
403654  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
403673  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
403737  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
403738  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
403783  AGT; angiotensinogen [KO:K09821]
403784  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
403832  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]
403922  TNF; tumor necrosis factor [KO:K03156]
403985  IL6; interleukin-6 precursor [KO:K05405]
442859  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
442949  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
442964  AKT3; RAC-gamma serine/threonine-protein kinase isoform X8 [KO:K04456] [EC:2.7.11.1]
449021  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
474624  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
474652  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
474653  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
474666  SLC27A6; long-chain fatty acid transport protein 6 isoform X2 [KO:K08749]
475266  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X5 [KO:K09047]
475389  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X25 [KO:K05695] [EC:3.1.3.48]
475546  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
475931  CD36; platelet glycoprotein 4 [KO:K06259]
477003  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
477085  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
477263  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X12 [KO:K05696] [EC:3.1.3.48]
477295  FOXO1; forkhead box protein O1 [KO:K07201]
477464  MLXIP; MLX-interacting protein isoform X5 [KO:K09113]
477488  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
477746  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
477766  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
477802  OGA; protein O-GlcNAcase isoform X2 [KO:K15719] [EC:3.2.1.169 2.3.1.48]
478013  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
478232  MTOR; serine/threonine-protein kinase mTOR isoform X5 [KO:K07203] [EC:2.7.11.1]
478298  SLC27A2; very long-chain acyl-CoA synthetase [KO:K08746] [EC:6.2.1.- 6.2.1.3]
478464  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
478575  GSK3B; glycogen synthase kinase-3 beta isoform X13 [KO:K03083] [EC:2.7.11.26]
479127  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
479351  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
479577  PRKCZ; protein kinase C zeta type isoform X5 [KO:K18952] [EC:2.7.11.13]
479875  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X3 [KO:K06276] [EC:2.7.11.1]
480255  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
480291  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
480580  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X3 [KO:K04688] [EC:2.7.11.1]
480955  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X2 [KO:K09667] [EC:2.4.1.255]
481184  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform isoform X1 [KO:K19523] [EC:2.3.1.21]
482411  PPP1R3A; protein phosphatase 1 regulatory subunit 3A isoform X5 [KO:K07189]
482437  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
482839  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
482881  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
483625  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
483636  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
483665  INS; insulin precursor [KO:K04526]
483729  RELA; transcription factor p65 isoform X2 [KO:K04735]
484835  SLC27A1; long-chain fatty acid transport protein 1 isoform X2 [KO:K08745] [EC:6.2.1.-]
484990  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
485046  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
485494  TBC1D4; TBC1 domain family member 4 isoform X15 [KO:K17902]
485548  IRS2; insulin receptor substrate 2 isoform X8 [KO:K07187]
485819  TRIB3; tribbles homolog 3 [KO:K19518]
485953  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
486148  IRS1; insulin receptor substrate 1 [KO:K16172]
486295  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
486559  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
487235  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
487353  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X2 [KO:K04373] [EC:2.7.11.1]
488084  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
488165  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X2 [KO:K07593]
488389  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
488526  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
489190  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta isoform X1 [KO:K17962]
489571  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
489644  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
489807  MLXIPL; carbohydrate-responsive element-binding protein isoform X27 [KO:K09113]
489968  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
490610  PPP1R3E; protein phosphatase 1 regulatory subunit 3E isoform X1 [KO:K07189]
490878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
490942  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
490967  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
491303  PTPA; serine/threonine-protein phosphatase 2A activator isoform X2 [KO:K17605]
491317  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
491369  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
491989  RPS6KA6; ribosomal protein S6 kinase alpha-6 isoform X1 [KO:K04373] [EC:2.7.11.1]
494005  PRKCD; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
607668  MLX; max-like protein X isoform X3 [KO:K09113]
607922  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
608675  SLC27A5; bile acyl-CoA synthetase [KO:K08748] [EC:6.2.1.7]
609934  PRKCE; protein kinase C epsilon type isoform X3 [KO:K18050] [EC:2.7.11.13]
609956  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
610057  NR1H2; oxysterols receptor LXR-beta [KO:K08535]
610499  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
611078  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
611934  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X2 [KO:K09048]
611993  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
612303  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
612305  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
612448  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
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
cfa00010  Glycolysis / Gluconeogenesis
cfa00061  Fatty acid biosynthesis
cfa00514  Other types of O-glycan biosynthesis
cfa00520  Amino sugar and nucleotide sugar metabolism
cfa04150  mTOR signaling pathway
cfa04151  PI3K-Akt signaling pathway
cfa04668  TNF signaling pathway
cfa04910  Insulin signaling pathway
KO pathway
ko04931   

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