KEGG   PATHWAY: pale04931
Entry
pale04931                   Pathway                                
Name
Insulin resistance - Pteropus alecto (black flying fox)
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
pale04931  Insulin resistance
pale04931

Organism
Pteropus alecto (black flying fox) [GN:pale]
Gene
102881117  insulin [KO:K04526]
102881119  RPS6KA3; ribosomal protein S6 kinase alpha-3 isoform X1 [KO:K04373] [EC:2.7.11.1]
102880166  RPS6KA2; ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
102882958  RPS6KA6; ribosomal protein S6 kinase alpha-6 [KO:K04373] [EC:2.7.11.1]
102890775  RPS6KA1; ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
102892254  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
102881448  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
102887827  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
102897087  PPP1R3C; protein phosphatase 1 regulatory subunit 3C isoform X1 [KO:K07189]
102891010  PPP1R3D; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D [KO:K07189]
102891839  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
102890505  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
102882220  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
102879346  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
102891583  IRS1; insulin receptor substrate 1 [KO:K16172]
102896636  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
102889219  PTPN11; LOW QUALITY PROTEIN: tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
102887205  tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
102882304  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X2 [KO:K05695] [EC:3.1.3.48]
102889227  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102880320  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102889576  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102879163  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102891637  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X3 [KO:K02649]
102879453  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102885144  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102879337  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102898305  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102885092  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102891214  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
102889369  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102880663  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102895746  IL6; interleukin-6 [KO:K05405]
102884374  STAT3; LOW QUALITY PROTEIN: signal transducer and activator of transcription 3 [KO:K04692]
102887834  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102882441  GSK3B; glycogen synthase kinase-3 beta isoform X4 [KO:K03083] [EC:2.7.11.26]
102890809  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
102884634  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
102887632  TNF; tumor necrosis factor [KO:K03156]
102885752  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
102885064  MAPK10; mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
102890689  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102892777  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102893261  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
102891056  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
102880692  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102878395  RELA; transcription factor p65 [KO:K04735]
102879945  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
102892135  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
102898844  TBC1D4; TBC1 domain family member 4 isoform X1 [KO:K17902]
102881931  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 isoform X1 [KO:K07191]
102884524  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102886520  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102886980  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
102887949  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102898038  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
102882613  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X3 [KO:K07200]
102887347  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200]
102887451  ACACB; acetyl-CoA carboxylase 2 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102879520  CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform isoform X2 [KO:K19523] [EC:2.3.1.21]
102892951  AGT; angiotensinogen [KO:K09821]
102886595  SLC27A4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
102896644  SLC27A1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
102886687  SLC27A2; very long-chain acyl-CoA synthetase isoform X1 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
102890200  SLC27A5; bile acyl-CoA synthetase [KO:K08748] [EC:6.2.1.7]
102882149  SLC27A6; LOW QUALITY PROTEIN: long-chain fatty acid transport protein 6 [KO:K08749]
102885145  CD36; platelet glycoprotein 4 [KO:K06259]
102892408  PRKCQ; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
102888600  PRKCD; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
102892781  PTPA; serine/threonine-protein phosphatase 2A activator [KO:K17605]
102882131  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
102898575  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
102884619  TRIB3; tribbles homolog 3 [KO:K19518]
102887527  PYGL; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
102897270  PYGM; glycogen phosphorylase, muscle form isoform X2 [KO:K00688] [EC:2.4.1.1]
102878850  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
102892244  FOXO1; forkhead box protein O1 [KO:K07201]
102888528  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
102897596  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
102887492  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
102896886  G6PC2; glucose-6-phosphatase 2 isoform X1 [KO:K01084] [EC:3.1.3.9]
102898137  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
102883555  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
102879732  NR1H3; oxysterols receptor LXR-alpha [KO:K08536]
102896653  NR1H2; LOW QUALITY PROTEIN: oxysterols receptor LXR-beta [KO:K08535]
102885807  PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta isoform X1 [KO:K17962]
102877888  MLXIP; MLX-interacting protein [KO:K09113]
102892282  MLXIPL; LOW QUALITY PROTEIN: carbohydrate-responsive element-binding protein [KO:K09113]
102881428  MLX; max-like protein X isoform X1 [KO:K09113]
102886073  CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
102894641  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
102879270  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
102878006  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
102896950  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
102881949  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102892734  OGA; protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
102890872  OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
102885620  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
102888488  GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 [KO:K00820] [EC:2.6.1.16]
102890448  GFPT2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
102879203  CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
102888198  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102878515  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
102894633  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
102882888  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
102886510  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
102879289  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
102884583  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
pale00010  Glycolysis / Gluconeogenesis
pale00061  Fatty acid biosynthesis
pale00514  Other types of O-glycan biosynthesis
pale00520  Amino sugar and nucleotide sugar metabolism
pale04150  mTOR signaling pathway
pale04151  PI3K-Akt signaling pathway
pale04668  TNF signaling pathway
pale04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

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