KEGG   PATHWAY: rno04931
Entry
rno04931                    Pathway                                
Name
Insulin resistance - Rattus norvegicus (rat)
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
rno04931  Insulin resistance
rno04931

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
81771  Rps6ka1; ribosomal protein S6 kinase alpha-1 [KO:K04373] [EC:2.7.11.1]
117269  Rps6ka2; ribosomal protein S6 kinase alpha-2 [KO:K04373] [EC:2.7.11.1]
501560  Rps6ka3; ribosomal protein S6 kinase alpha-3 [KO:K04373] [EC:2.7.11.1]
317203  Rps6ka6; ribosomal protein S6 kinase alpha-6 [KO:K04373] [EC:2.7.11.1]
24668  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
24669  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
25594  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
192280  Ppp1r3b; protein phosphatase 1 regulatory subunit 3B [KO:K07189]
309513  Ppp1r3c; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
500036  Ppp1r3a; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
689995  Ppp1r3d; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
691447  Ppp1r3e; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:2.7.10.1]
25467  Irs1; insulin receptor substrate 1 [KO:K16172]
24697  Ptpn1; tyrosine-protein phosphatase non-receptor type 1 [KO:K05696] [EC:3.1.3.48]
25622  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform 2 [KO:K07293] [EC:3.1.3.48]
360406  Ptprf; receptor-type tyrosine-protein phosphatase F precursor [KO:K05695] [EC:3.1.3.48]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
83840  Rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
361696  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24498  Il6; interleukin-6 precursor [KO:K05405]
25125  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
89829  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
84027  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
25623  Gys2; glycogen [starch] synthase, liver [KO:K00693] [EC:2.4.1.11]
690987  Gys1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
24835  Tnf; tumor necrosis factor [KO:K03156]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
25493  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
24600  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
25522  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
306117  Tbc1d4; similar to TBC1 domain family member 4 [KO:K17902]
25139  Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
65248  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
78975  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
83803  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
64562  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
25520  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
301518  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
116719  Acacb; acetyl-CoA carboxylase 2 precursor [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
25756  Cpt1b; carnitine O-palmitoyltransferase 1, muscle isoform [KO:K19523] [EC:2.3.1.21]
24179  Agt; angiotensinogen precursor [KO:K09821]
94172  Slc27a1; long-chain fatty acid transport protein 1 [KO:K08745] [EC:6.2.1.-]
311839  Slc27a4; long-chain fatty acid transport protein 4 [KO:K08745] [EC:6.2.1.-]
65192  Slc27a2; long-chain fatty acid transport protein 2 [KO:K08746] [EC:6.2.1.- 6.2.1.3]
295219  Slc27a3; long-chain fatty acid transport protein 3 precursor [KO:K08772] [EC:6.2.1.-]
79111  Slc27a5; long-chain fatty acid transport protein 5 [KO:K08748] [EC:6.2.1.7]
291582  Slc27a6; long-chain fatty acid transport protein 6 [KO:K08749]
29184  Cd36; platelet glycoprotein 4 [KO:K06259]
499985  Cd36l1; CD36 molecule like 1 [KO:K06259]
120093085  Cd36-ps1; platelet glycoprotein 4-like [KO:K06259]
134486712  platelet glycoprotein 4-like [KO:K06259]
85420  Prkcq; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
170538  Prkcd; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
362102  Ptpa; serine/threonine-protein phosphatase 2A activator [KO:K17605]
78968  Srebf1; sterol regulatory element-binding protein 1 isoform 1 precursor [KO:K07197]
29376  Irs2; insulin receptor substrate 2 [KO:K07187]
246273  Trib3; tribbles homolog 3 [KO:K19518]
64035  Pygl; glycogen phosphorylase, liver form [KO:K00688] [EC:2.4.1.1]
25739  Pygb; glycogen phosphorylase, brain form [KO:K00688] [EC:2.4.1.1]
24701  Pygm; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
84482  Foxo1; forkhead box protein O1 [KO:K07201]
362282  Pck1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] [KO:K01596] [EC:4.1.1.32]
361042  Pck2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial [KO:K01596] [EC:4.1.1.32]
25634  G6pc1; glucose-6-phosphatase catalytic subunit 1 [KO:K01084] [EC:3.1.3.9]
303565  G6pc3; glucose-6-phosphatase 3 [KO:K01084] [EC:3.1.3.9]
25351  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
58852  Nr1h3; oxysterols receptor LXR-alpha [KO:K08536]
58851  Nr1h2; oxysterols receptor LXR-beta isoform b [KO:K08535]
291567  Ppargc1b; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962]
360631  Mlx; max-like protein X [KO:K09113]
304479  Mlxip; MLX interacting protein [KO:K09113]
171078  Mlxipl; carbohydrate-responsive element-binding protein isoform 2 [KO:K09113]
25757  Cpt1a; carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
29340  Prkce; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
83516  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
25747  Ppara; peroxisome proliferator-activated receptor alpha [KO:K07294]
81745  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
50557  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]
154968  Oga; protein O-GlcNAcase [KO:K15719] [EC:3.2.1.169 2.3.1.48]
26295  Ogt; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform 1 [KO:K09667] [EC:2.4.1.255]
24778  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
360518  Gfpt2; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 2 [KO:K00820] [EC:2.6.1.16]
297417  Gfpt1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 [KO:K00820] [EC:2.6.1.16]
310615  Crtc2; CREB-regulated transcription coactivator 2 [KO:K16333]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
500131  Creb5; cyclic AMP-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
rno00010  Glycolysis / Gluconeogenesis
rno00061  Fatty acid biosynthesis
rno00514  Other types of O-glycan biosynthesis
rno00520  Amino sugar and nucleotide sugar metabolism
rno04150  mTOR signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04668  TNF signaling pathway
rno04910  Insulin signaling pathway
KO pathway
ko04931   
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