KEGG   PATHWAY: cbai04931
Entry
cbai04931                   Pathway                                
Name
Insulin resistance - Camelus bactrianus (Bactrian camel)
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
cbai04931  Insulin resistance
cbai04931

Organism
Camelus bactrianus (Bactrian camel) [GN:cbai]
Gene
105068636  RPS6KA3; ribosomal protein S6 kinase alpha-3 [KO:K04373] [EC:2.7.11.1]
105063460  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
105064748  RPS6KA6; ribosomal protein S6 kinase alpha-6 isoform X1 [KO:K04373] [EC:2.7.11.1]
105065398  RPS6KA2; ribosomal protein S6 kinase alpha-2 [KO:K04373] [EC:2.7.11.1]
105080605  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105063807  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
105070330  PPP1CA; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105081834  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
105073777  LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D-like [KO:K07189]
105063159  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
105071793  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
105067635  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
105078270  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
105064075  IRS1; insulin receptor substrate 1 [KO:K16172]
105071851  PTPN1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
105080590  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
105071204  tyrosine-protein phosphatase non-receptor type 6-like [KO:K07293] [EC:3.1.3.48]
105072712  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
105063312  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105071167  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
105066839  PIK3CB; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
105082679  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105064416  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
105065663  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
105079975  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105083596  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105062855  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105070974  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105070333  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
105065845  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105073669  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105079801  IL6; interleukin-6 [KO:K05405]
105080116  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
105065593  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
105081598  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
105062281  GYS2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
105062760  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
105074074  TNF; tumor necrosis factor [KO:K03156]
105071112  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
105075609  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105077723  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105062001  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105071245  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
105079152  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
105067913  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105070689  RELA; transcription factor p65 [KO:K04735]
105067010  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
105071048  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
105083640  TBC1 domain family member 4 isoform X1 [KO:K17902]
105077487  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
105070805  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
105071667  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
105080553  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105079157  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
105076196  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
105064024  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
105067027  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
105075668  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105070820  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
105075087  AGT; angiotensinogen [KO:K09821]
105082677  SLC27A1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
105065983  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
105077014  SLC27A2; very long-chain acyl-CoA synthetase [KO:K08746] [EC:6.2.1.- 6.2.1.3]
105068256  SLC27A3; LOW QUALITY PROTEIN: long-chain fatty acid transport protein 3 [KO:K08772] [EC:6.2.1.-]
105074455  SLC27A5; bile acyl-CoA synthetase [KO:K08748] [EC:6.2.1.7]
105082243  SLC27A6; long-chain fatty acid transport protein 6 [KO:K08749]
105062382  platelet glycoprotein 4-like [KO:K06259]
105062383  platelet glycoprotein 4 [KO:K06259]
105074303  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
105080156  PRKCD; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
105066013  PPP2R4; serine/threonine-protein phosphatase 2A activator [KO:K17605]
105082523  SREBF1; LOW QUALITY PROTEIN: sterol regulatory element-binding protein 1 [KO:K07197]
105073642  TRIB3; tribbles homolog 3 [KO:K19518]
105083188  PYGB; LOW QUALITY PROTEIN: glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
105078429  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
105070647  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
105066187  FOXO1; forkhead box protein O1 [KO:K07201]
105068796  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
105071815  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
105080088  G6PC; LOW QUALITY PROTEIN: glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
105081978  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
105072558  G6PC3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
105063293  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
105076451  NR1H3; oxysterols receptor LXR-alpha [KO:K08536]
105062661  NR1H2; oxysterols receptor LXR-beta [KO:K08535]
105069882  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
105080107  MLX; max-like protein X isoform X1 [KO:K09113]
105080638  MLXIP; MLX-interacting protein [KO:K09113]
105082862  MLXIPL; carbohydrate-responsive element-binding protein [KO:K09113]
105070362  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform isoform X1 [KO:K08765] [EC:2.3.1.21]
105079021  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
105075295  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
105073019  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
105064838  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105081861  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]
105081720  MGEA5; protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
105083681  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
105072730  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
105075801  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
105061999  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 isoform X1 [KO:K00820] [EC:2.6.1.16]
105068252  CRTC2; CREB-regulated transcription coactivator 2 [KO:K16333]
105072963  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105076770  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
105078379  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105068196  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
105063046  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105067333  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
105082021  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
cbai00010  Glycolysis / Gluconeogenesis
cbai00061  Fatty acid biosynthesis
cbai00514  Other types of O-glycan biosynthesis
cbai00520  Amino sugar and nucleotide sugar metabolism
cbai04150  mTOR signaling pathway
cbai04151  PI3K-Akt signaling pathway
cbai04668  TNF signaling pathway
cbai04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

DBGET integrated database retrieval system