KEGG   PATHWAY: mmu04931
Entry
mmu04931                    Pathway                                
Name
Insulin resistance - Mus musculus (house mouse)
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
mmu04931  Insulin resistance
mmu04931

Organism
Mus musculus (house mouse) [GN:mmu]
Gene
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
110651  Rps6ka3; ribosomal protein S6 kinase polypeptide 3 [KO:K04373] [EC:2.7.11.1]
20111  Rps6ka1; ribosomal protein S6 kinase polypeptide 1 [KO:K04373] [EC:2.7.11.1]
20112  Rps6ka2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04373] [EC:2.7.11.1]
67071  Rps6ka6; ribosomal protein S6 kinase polypeptide 6 [KO:K04373] [EC:2.7.11.1]
19045  Ppp1ca; protein phosphatase 1 catalytic subunit alpha [KO:K06269] [EC:3.1.3.16]
19046  Ppp1cb; protein phosphatase 1 catalytic subunit beta [KO:K06269] [EC:3.1.3.16]
19047  Ppp1cc; protein phosphatase 1 catalytic subunit gamma [KO:K06269] [EC:3.1.3.16]
434233  Ppp1ccb; protein phosphatase 1 catalytic subunit gamma B [KO:K06269] [EC:3.1.3.16]
140491  Ppp1r3a; protein phosphatase 1, regulatory subunit 3A [KO:K07189]
53412  Ppp1r3c; protein phosphatase 1, regulatory subunit 3C [KO:K07189]
244416  Ppp1r3b; protein phosphatase 1, regulatory subunit 3B [KO:K07189]
228966  Ppp1r3d; protein phosphatase 1, regulatory subunit 3D [KO:K07189]
105651  Ppp1r3e; protein phosphatase 1, regulatory subunit 3E [KO:K07189]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16367  Irs1; insulin receptor substrate 1 [KO:K16172]
19246  Ptpn1; protein tyrosine phosphatase, non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
19247  Ptpn11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
19268  Ptprf; protein tyrosine phosphatase receptor type F [KO:K05695] [EC:3.1.3.48]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
56717  Mtor; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
58988  Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
72508  Rps6kb1; ribosomal protein S6 kinase, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
16193  Il6; interleukin 6 [KO:K05405]
20848  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
12702  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
56637  Gsk3b; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
14936  Gys1; glycogen synthase 1, muscle [KO:K00693] [EC:2.4.1.11]
232493  Gys2; glycogen synthase 2 [KO:K00693] [EC:2.4.1.11]
21926  Tnf; tumor necrosis factor [KO:K03156]
21937  Tnfrsf1a; tumor necrosis factor receptor superfamily, member 1a [KO:K03158]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
16150  Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:2.7.11.10]
18035  Nfkbia; nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha [KO:K04734]
18033  Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]
19697  Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
18127  Nos3; nitric oxide synthase 3, endothelial cell [KO:K13242] [EC:1.14.13.39]
18762  Prkcz; protein kinase C, zeta [KO:K18952] [EC:2.7.11.13]
210789  Tbc1d4; TBC1 domain family, member 4 [KO:K17902]
20528  Slc2a4; solute carrier family 2 (facilitated glucose transporter), member 4 [KO:K07191]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.31]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.31]
19079  Prkab1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
108097  Prkab2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
19082  Prkag1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
241113  Prkag3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
108099  Prkag2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
100705  Acacb; acetyl-Coenzyme A carboxylase beta [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
12895  Cpt1b; carnitine palmitoyltransferase 1b, muscle [KO:K19523] [EC:2.3.1.21]
11606  Agt; angiotensinogen [KO:K09821]
26457  Slc27a1; solute carrier family 27 (fatty acid transporter), member 1 [KO:K08745] [EC:6.2.1.-]
26569  Slc27a4; solute carrier family 27 (fatty acid transporter), member 4 [KO:K08745] [EC:6.2.1.-]
26458  Slc27a2; solute carrier family 27 (fatty acid transporter), member 2 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
26568  Slc27a3; solute carrier family 27 (fatty acid transporter), member 3 [KO:K08772] [EC:6.2.1.-]
26459  Slc27a5; solute carrier family 27 (fatty acid transporter), member 5 [KO:K08748] [EC:6.2.1.7]
225579  Slc27a6; solute carrier family 27 (fatty acid transporter), member 6 [KO:K08749]
12491  Cd36; CD36 molecule [KO:K06259]
18761  Prkcq; protein kinase C, theta [KO:K18052] [EC:2.7.11.13]
18753  Prkcd; protein kinase C, delta [KO:K06068] [EC:2.7.11.13]
110854  Ptpa; protein phosphatase 2 protein activator [KO:K17605]
20787  Srebf1; sterol regulatory element binding transcription factor 1 [KO:K07197]
384783  Irs2; insulin receptor substrate 2 [KO:K07187]
228775  Trib3; tribbles pseudokinase 3 [KO:K19518]
19309  Pygm; muscle glycogen phosphorylase [KO:K00688] [EC:2.4.1.1]
110078  Pygb; brain glycogen phosphorylase [KO:K00688] [EC:2.4.1.1]
110095  Pygl; liver glycogen phosphorylase [KO:K00688] [EC:2.4.1.1]
56458  Foxo1; forkhead box O1 [KO:K07201]
18534  Pck1; phosphoenolpyruvate carboxykinase 1, cytosolic [KO:K01596] [EC:4.1.1.32]
74551  Pck2; phosphoenolpyruvate carboxykinase 2 (mitochondrial) [KO:K01596] [EC:4.1.1.32]
14377  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
14378  G6pc2; glucose-6-phosphatase, catalytic, 2 [KO:K01084] [EC:3.1.3.9]
68401  G6pc3; glucose 6 phosphatase, catalytic, 3 [KO:K01084] [EC:3.1.3.9]
20526  Slc2a2; solute carrier family 2 (facilitated glucose transporter), member 2 [KO:K07593]
22259  Nr1h3; nuclear receptor subfamily 1, group H, member 3 [KO:K08536]
22260  Nr1h2; nuclear receptor subfamily 1, group H, member 2 [KO:K08535]
170826  Ppargc1b; peroxisome proliferative activated receptor, gamma, coactivator 1 beta [KO:K17962]
21428  Mlx; MAX-like protein X [KO:K09113]
208104  Mlxip; MLX interacting protein [KO:K09113]
58805  Mlxipl; MLX interacting protein-like [KO:K09113]
12894  Cpt1a; carnitine palmitoyltransferase 1a, liver [KO:K08765] [EC:2.3.1.21]
18754  Prkce; protein kinase C, epsilon [KO:K18050] [EC:2.7.11.13]
19017  Ppargc1a; peroxisome proliferative activated receptor, gamma, coactivator 1 alpha [KO:K07202]
19013  Ppara; peroxisome proliferator activated receptor alpha [KO:K07294]
18607  Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
19211  Pten; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
76055  Oga; O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
108155  Ogt; O-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyl transferase) [KO:K09667] [EC:2.4.1.255]
20525  Slc2a1; solute carrier family 2 (facilitated glucose transporter), member 1 [KO:K07299]
14583  Gfpt1; glutamine fructose-6-phosphate transaminase 1 [KO:K00820] [EC:2.6.1.16]
14584  Gfpt2; glutamine fructose-6-phosphate transaminase 2 [KO:K00820] [EC:2.6.1.16]
74343  Crtc2; CREB regulated transcription coactivator 2 [KO:K16333]
12912  Creb1; cAMP responsive element binding protein 1 [KO:K05870]
12913  Creb3; cAMP responsive element binding protein 3 [KO:K09048]
26427  Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
208647  Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
208677  Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
78284  Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
231991  Creb5; cAMP responsive element binding protein 5 [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
mmu00010  Glycolysis / Gluconeogenesis
mmu00061  Fatty acid biosynthesis
mmu00514  Other types of O-glycan biosynthesis
mmu00520  Amino sugar and nucleotide sugar metabolism
mmu04150  mTOR signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04668  TNF signaling pathway
mmu04910  Insulin signaling pathway
KO pathway
ko04931   
LinkDB

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