KEGG   PATHWAY: mthb04931
Entry
mthb04931                   Pathway                                
Name
Insulin resistance - Macaca thibetana thibetana (Pere David's macaque)
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
mthb04931  Insulin resistance
mthb04931

Organism
Macaca thibetana thibetana (Pere David's macaque) [GN:mthb]
Gene
126935873  insulin isoform X1 [KO:K04526]
126957229  ribosomal protein S6 kinase alpha-1 isoform X1 [KO:K04373] [EC:2.7.11.1]
126945242  ribosomal protein S6 kinase alpha-3 isoform X1 [KO:K04373] [EC:2.7.11.1]
126946218  ribosomal protein S6 kinase alpha-6 isoform X1 [KO:K04373] [EC:2.7.11.1]
126953765  ribosomal protein S6 kinase alpha-2 isoform X1 [KO:K04373] [EC:2.7.11.1]
126931492  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
126933834  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
126935389  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
126961465  protein phosphatase 1 regulatory subunit 3B [KO:K07189]
126962131  protein phosphatase 1 regulatory subunit 3C [KO:K07189]
126949810  protein phosphatase 1 regulatory subunit 3A [KO:K07189]
126958244  protein phosphatase 1 regulatory subunit 3E [KO:K07189]
126929353  protein phosphatase 1 regulatory subunit 3D [KO:K07189]
126942469  insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
126932885  insulin receptor substrate 1 [KO:K16172]
126964386  tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
126931454  tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
126958744  receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
126947557  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
126952893  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
126948170  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
126961422  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
126956531  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
126942202  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
126943096  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
126959416  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126942032  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126952739  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
126939388  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
126935360  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
126944386  protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
126950025  interleukin-6 isoform X1 [KO:K05405]
126938424  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
126939248  suppressor of cytokine signaling 3 [KO:K04696]
126949239  glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
126930517  glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
126943552  glycogen [starch] synthase, muscle isoform X1 [KO:K00693] [EC:2.4.1.11]
126953141  tumor necrosis factor isoform X1 [KO:K03156]
126930443  tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
126954697  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
126963142  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
126956917  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
126960750  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
126959170  NF-kappa-B inhibitor alpha [KO:K04734]
126955390  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
126935358  transcription factor p65 isoform X1 [KO:K04735]
126951570  nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
126951757  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
126940500  TBC1 domain family member 4 isoform X1 [KO:K17902]
126939701  solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
126956450  5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
126932625  5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
126930676  5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
126932421  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
126930179  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
126932994  5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
126951597  5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
126931421  acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
126929429  carnitine O-palmitoyltransferase 1, muscle isoform isoform X1 [KO:K19523] [EC:2.3.1.21]
126942065  angiotensinogen isoform X1 [KO:K09821]
126936938  long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
126942214  long-chain fatty acid transport protein 1 isoform X1 [KO:K08745] [EC:6.2.1.-]
126958693  long-chain fatty acid transport protein 2 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
126933464  long-chain fatty acid transport protein 3 isoform X1 [KO:K08772] [EC:6.2.1.-]
126941889  long-chain fatty acid transport protein 5 [KO:K08748] [EC:6.2.1.7]
126957644  long-chain fatty acid transport protein 6 isoform X1 [KO:K08749]
126951242  platelet glycoprotein 4 [KO:K06259]
126962914  protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
126948783  protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
126937038  serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605]
126938791  sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
126940155  insulin receptor substrate 2 [KO:K07187]
126964248  tribbles homolog 3 isoform X1 [KO:K19518]
126958501  glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
126929290  glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
126935557  glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
126940335  forkhead box protein O1 [KO:K07201]
126964013  phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
126958803  phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
126932332  glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
126938517  glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
126938691  glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
126948355  solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
126936383  oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
126943111  oxysterols receptor LXR-beta isoform X1 [KO:K08535]
126956583  peroxisome proliferator-activated receptor gamma coactivator 1-beta isoform X1 [KO:K17962]
126930605  MLX-interacting protein isoform X1 [KO:K09113]
126938527  max-like protein X isoform X1 [KO:K09113]
126950339  carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
126935951  carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
126933879  protein kinase C epsilon type isoform X1 [KO:K18050] [EC:2.7.11.13]
126954797  peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
126963592  peroxisome proliferator-activated receptor alpha isoform X1 [KO:K07294]
126944637  3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
126944712  LOW QUALITY PROTEIN: 3-phosphoinositide-dependent protein kinase 1-like [KO:K06276] [EC:2.7.11.1]
126963336  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]
126962741  protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
126946211  UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667] [EC:2.4.1.255]
126959708  solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
126956904  glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
126934018  glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820] [EC:2.6.1.16]
126933482  CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333]
126933094  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
126942639  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
126938066  cyclic AMP-responsive element-binding protein 3 [KO:K09048]
126951142  cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
126934237  cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
126935751  cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
126950050  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
mthb00010  Glycolysis / Gluconeogenesis
mthb00061  Fatty acid biosynthesis
mthb00514  Other types of O-glycan biosynthesis
mthb00520  Amino sugar and nucleotide sugar metabolism
mthb04150  mTOR signaling pathway
mthb04151  PI3K-Akt signaling pathway
mthb04668  TNF signaling pathway
mthb04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

DBGET integrated database retrieval system