KEGG   PATHWAY: mleu04931
Entry
mleu04931                   Pathway                                
Name
Insulin resistance - Mandrillus leucophaeus (drill)
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
mleu04931  Insulin resistance
mleu04931

Organism
Mandrillus leucophaeus (drill) [GN:mleu]
Gene
105545324  INS; insulin isoform X1 [KO:K04526]
105540900  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
105553567  RPS6KA2; ribosomal protein S6 kinase alpha-2 [KO:K04373] [EC:2.7.11.1]
105534481  RPS6KA6; ribosomal protein S6 kinase alpha-6 [KO:K04373] [EC:2.7.11.1]
105550773  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X1 [KO:K04373] [EC:2.7.11.1]
105552307  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
105533954  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
105544467  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
105532567  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
105548349  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
105529849  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
105537145  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
105541159  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
105543176  IRS1; insulin receptor substrate 1 [KO:K16172]
105548953  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
105552315  PTPN11; tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
105555062  PTPRF; receptor-type tyrosine-protein phosphatase F [KO:K05695] [EC:3.1.3.48]
105539923  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105552763  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
105549588  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
105547376  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105543389  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105531763  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105540494  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105541755  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105542359  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105551388  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105539063  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
105544470  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
105545146  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
105534984  IL6; interleukin-6 isoform X1 [KO:K05405]
105552958  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
105544615  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
105531538  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
105539163  GYS1; glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
105554159  TNF; tumor necrosis factor [KO:K03156]
105541778  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
105547365  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
105554734  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105537274  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105554929  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
105550156  NFKBIA; NF-kappa-B inhibitor alpha isoform X1 [KO:K04734]
105548314  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105528449  RELA; transcription factor p65 isoform X1 [KO:K04735]
105542707  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
105544659  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
105533533  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
105549897  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
105534954  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
105529209  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
105527920  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105550295  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
105528047  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
105542686  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
105544908  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
105534647  acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
105543613  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
105528652  AGT; angiotensinogen isoform X1 [KO:K09821]
105547507  SLC27A1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
105545101  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
105550760  SLC27A2; very long-chain acyl-CoA synthetase isoform X1 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
105554046  SLC27A3; LOW QUALITY PROTEIN: long-chain fatty acid transport protein 3 [KO:K08772] [EC:6.2.1.-]
105531198  SLC27A5; bile acyl-CoA synthetase isoform X1 [KO:K08748] [EC:6.2.1.7]
105540522  SLC27A6; long-chain fatty acid transport protein 6 [KO:K08749]
105543914  CD36; platelet glycoprotein 4 isoform X1 [KO:K06259]
105535716  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
105543983  PRKCD; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
105532862  PPP2R4; serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605]
105536007  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
105539525  TRIB3; tribbles homolog 3 [KO:K19518]
105553616  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
105548723  PYGB; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
105549112  PYGM; glycogen phosphorylase, muscle form isoform X1 [KO:K00688] [EC:2.4.1.1]
105546932  FOXO1; forkhead box protein O1 [KO:K07201]
105532712  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
105538322  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
105545290  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
105552932  G6PC; glucose-6-phosphatase [KO:K01084] [EC:3.1.3.9]
105543793  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
105552594  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
105554814  NR1H3; LOW QUALITY PROTEIN: oxysterols receptor LXR-alpha [KO:K08536]
105528959  NR1H2; oxysterols receptor LXR-beta isoform X1 [KO:K08535]
105543441  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
105552951  MLX; max-like protein X isoform X1 [KO:K09113]
105527966  MLXIP; MLX-interacting protein [KO:K09113]
105536875  MLXIPL; carbohydrate-responsive element-binding protein [KO:K09113]
105544526  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
105528827  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
105547650  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
105542493  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
105541556  PDPK1; LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
105546962  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]
105537773  MGEA5; protein O-GlcNAcase isoform X1 [KO:K15719] [EC:3.2.1.169 2.3.1.48]
105548169  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
105555046  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
105543201  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
105537273  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
105554056  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
105549382  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105539715  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
105554054  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
105554841  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
105530028  CREB3L3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105550535  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105533710  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
mleu00010  Glycolysis / Gluconeogenesis
mleu00061  Fatty acid biosynthesis
mleu00514  Other types of O-glycan biosynthesis
mleu00520  Amino sugar and nucleotide sugar metabolism
mleu04150  mTOR signaling pathway
mleu04151  PI3K-Akt signaling pathway
mleu04668  TNF signaling pathway
mleu04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

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