KEGG   PATHWAY: hsa04931
Entry
hsa04931                    Pathway                                
Name
Insulin resistance - Homo sapiens (human)
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
hsa04931  Insulin resistance
hsa04931

Network
nt06325  Hormone/cytokine signaling
  Element
N01708  INS-AKT signaling pathway
Drug
D04050  Ertiprotafib (USAN/INN)
D06647  Sodelglitazar (USAN)
D11034  Insulin glargine and lixisenatide
D11567  Insulin degludec and liraglutide
Organism
Homo sapiens (human) [GN:hsa]
Gene
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
10062  NR1H3; nuclear receptor subfamily 1 group H member 3 [KO:K08536]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
10724  OGA; O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
10891  PPARGC1A; PPARG coactivator 1 alpha [KO:K07202]
10998  SLC27A5; solute carrier family 27 member 5 [KO:K08748] [EC:6.2.1.7]
10999  SLC27A4; solute carrier family 27 member 4 [KO:K08745] [EC:6.2.1.-]
11000  SLC27A3; solute carrier family 27 member 3 [KO:K08772] [EC:6.2.1.-]
11001  SLC27A2; solute carrier family 27 member 2 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
110117499  P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649]
133522  PPARGC1B; PPARG coactivator 1 beta [KO:K17962]
1374  CPT1A; carnitine palmitoyltransferase 1A [KO:K08765] [EC:2.3.1.21]
1375  CPT1B; carnitine palmitoyltransferase 1B [KO:K19523] [EC:2.3.1.21]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
183  AGT; angiotensinogen [KO:K09821]
200186  CRTC2; CREB regulated transcription coactivator 2 [KO:K16333]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
22877  MLXIP; MLX interacting protein [KO:K09113]
2308  FOXO1; forkhead box O1 [KO:K07201]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
2538  G6PC1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
2673  GFPT1; glutamine--fructose-6-phosphate transaminase 1 [KO:K00820] [EC:2.6.1.16]
27330  RPS6KA6; ribosomal protein S6 kinase A6 [KO:K04373] [EC:2.7.11.1]
28965  SLC27A6; solute carrier family 27 member 6 [KO:K08749]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
2997  GYS1; glycogen synthase 1 [KO:K00693] [EC:2.4.1.11]
2998  GYS2; glycogen synthase 2 [KO:K00693] [EC:2.4.1.11]
32  ACACB; acetyl-CoA carboxylase beta [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
3569  IL6; interleukin 6 [KO:K05405]
3630  INS; insulin [KO:K04526]
3643  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3667  IRS1; insulin receptor substrate 1 [KO:K16172]
376497  SLC27A1; solute carrier family 27 member 1 [KO:K08745] [EC:6.2.1.-]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4846  NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
5105  PCK1; phosphoenolpyruvate carboxykinase 1 [KO:K01596] [EC:4.1.1.32]
5106  PCK2; phosphoenolpyruvate carboxykinase 2, mitochondrial [KO:K01596] [EC:4.1.1.32]
51085  MLXIPL; MLX interacting protein like [KO:K09113]
51422  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
53632  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
5465  PPARA; peroxisome proliferator activated receptor alpha [KO:K07294]
5499  PPP1CA; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
5500  PPP1CB; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
5501  PPP1CC; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
5506  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
5507  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
5509  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
5524  PTPA; protein phosphatase 2 phosphatase activator [KO:K17605]
5562  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]
5563  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]
5564  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
5565  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
5571  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5580  PRKCD; protein kinase C delta [KO:K06068] [EC:2.7.11.13]
5581  PRKCE; protein kinase C epsilon [KO:K18050] [EC:2.7.11.13]
5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
5590  PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5728  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
5770  PTPN1; protein tyrosine phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
57761  TRIB3; tribbles pseudokinase 3 [KO:K19518]
5781  PTPN11; protein tyrosine phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
57818  G6PC2; glucose-6-phosphatase catalytic subunit 2 [KO:K01084] [EC:3.1.3.9]
5792  PTPRF; protein tyrosine phosphatase receptor type F [KO:K05695] [EC:3.1.3.48]
5834  PYGB; glycogen phosphorylase B [KO:K00688] [EC:2.4.1.1]
5836  PYGL; glycogen phosphorylase L [KO:K00688] [EC:2.4.1.1]
5837  PYGM; glycogen phosphorylase, muscle associated [KO:K00688] [EC:2.4.1.1]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
6195  RPS6KA1; ribosomal protein S6 kinase A1 [KO:K04373] [EC:2.7.11.1]
6196  RPS6KA2; ribosomal protein S6 kinase A2 [KO:K04373] [EC:2.7.11.1]
6197  RPS6KA3; ribosomal protein S6 kinase A3 [KO:K04373] [EC:2.7.11.1]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
6513  SLC2A1; solute carrier family 2 member 1 [KO:K07299]
6514  SLC2A2; solute carrier family 2 member 2 [KO:K07593]
6517  SLC2A4; solute carrier family 2 member 4 [KO:K07191]
6720  SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
6945  MLX; MAX dimerization protein MLX [KO:K09113]
7124  TNF; tumor necrosis factor [KO:K03156]
7132  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
7376  NR1H2; nuclear receptor subfamily 1 group H member 2 [KO:K08535]
79660  PPP1R3B; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
8473  OGT; O-linked N-acetylglucosamine (GlcNAc) transferase [KO:K09667] [EC:2.4.1.255]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
8660  IRS2; insulin receptor substrate 2 [KO:K07187]
9021  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
90673  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
92579  G6PC3; glucose-6-phosphatase catalytic subunit 3 [KO:K01084] [EC:3.1.3.9]
948  CD36; CD36 molecule (CD36 blood group) [KO:K06259]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
9882  TBC1D4; TBC1 domain family member 4 [KO:K17902]
9945  GFPT2; glutamine-fructose-6-phosphate transaminase 2 [KO:K00820] [EC:2.6.1.16]
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
hsa00010  Glycolysis / Gluconeogenesis
hsa00061  Fatty acid biosynthesis
hsa00514  Other types of O-glycan biosynthesis
hsa00520  Amino sugar and nucleotide sugar metabolism
hsa04150  mTOR signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04668  TNF signaling pathway
hsa04910  Insulin signaling pathway
KO pathway
ko04931   

DBGET integrated database retrieval system