KEGG   PATHWAY: ko04931
ko04931                     Pathway                                

Insulin resistance
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.
Human Diseases; Endocrine and metabolic disease
Pathway map
ko04931  Insulin resistance

K04526  insulin
K04373  ribosomal protein S6 kinase alpha-1/2/3/6 [EC:]
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:]
K07189  protein phosphatase 1 regulatory subunit 3A/B/C/D/E
K04527  insulin receptor [EC:]
K16172  insulin receptor substrate 1
K05696  tyrosine-protein phosphatase non-receptor type 1 [EC:]
K07293  tyrosine-protein phosphatase non-receptor type 11 [EC:]
K05695  receptor-type tyrosine-protein phosphatase F [EC:]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K07203  serine/threonine-protein kinase mTOR [EC:]
K04688  ribosomal protein S6 kinase beta [EC:]
K19662  classical protein kinase C beta type [EC:]
K05405  interleukin 6
K04692  signal transducer and activator of transcription 3
K04696  suppressor of cytokine signaling 3
K03083  glycogen synthase kinase 3 beta [EC:]
K00693  glycogen synthase [EC:]
K03156  tumor necrosis factor superfamily, member 2
K03158  tumor necrosis factor receptor superfamily member 1A
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:]
K04734  NF-kappa-B inhibitor alpha
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K13242  nitric-oxide synthase, endothelial [EC:]
K18952  atypical protein kinase C zeta type [EC:]
K17902  TBC1 domain family member 4
K07191  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
K14497  protein phosphatase 2C [EC:]
K07198  5'-AMP-activated protein kinase, catalytic alpha subunit [EC:]
K07199  5'-AMP-activated protein kinase, regulatory beta subunit
K07200  5'-AMP-activated protein kinase, regulatory gamma subunit
K01946  acetyl-CoA carboxylase / biotin carboxylase 2 [EC:]
K19523  carnitine O-palmitoyltransferase 1, muscle isoform [EC:]
K09821  angiotensinogen
K08745  solute carrier family 27 (fatty acid transporter), member 1/4 [EC:6.2.1.-]
K08746  solute carrier family 27 (fatty acid transporter), member 2 [EC:6.2.1.-]
K08772  solute carrier family 27 (fatty acid transporter), member 3 [EC:6.2.1.-]
K08748  solute carrier family 27 (fatty acid transporter), member 5 [EC:]
K08749  solute carrier family 27 (fatty acid transporter), member 6
K06259  CD36 antigen
K18052  novel protein kinase C theta type [EC:]
K06068  novel protein kinase C delta type [EC:]
K17605  serine/threonine-protein phosphatase 2A activator
K07197  sterol regulatory element-binding transcription factor 1
K07187  insulin receptor substrate 2
K19518  tribbles homolog 3
K00688  glycogen phosphorylase [EC:]
K07201  forkhead box protein O1
K01596  phosphoenolpyruvate carboxykinase (GTP) [EC:]
K01084  glucose-6-phosphatase [EC:]
K07593  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2
K08536  liver X receptor alpha
K08535  liver X receptor beta
K17962  peroxisome proliferator-activated receptor gamma coactivator 1-beta
K09113  MAX-like protein X
K08765  carnitine O-palmitoyltransferase 1, liver isoform [EC:]
K11533  fatty acid synthase, bacteria type [EC:2.3.1.-]
K18050  novel protein kinase C epsilon type [EC:]
K07202  alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K07294  peroxisome proliferator-activated receptor alpha
K06276  3-phosphoinositide dependent protein kinase-1 [EC:]
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:]
K15719  protein O-GlcNAcase / histone acetyltransferase [EC:]
K09667  protein O-GlcNAc transferase [EC:]
K07299  MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
K00820  glutamine---fructose-6-phosphate transaminase (isomerizing) [EC:]
K16333  CREB-regulated transcription coactivator 2
K05870  cyclic AMP-responsive element-binding protein 1
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
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
Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT, Lambertucci RH, Cury-Boaventura MF, Silveira LR, Curi R, Hirabara SM
Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function.
Lipids Health Dis 11:30 (2012)
Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H
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.
Diabetes 52:1319-25 (2003)
Choi K, Kim YB
Molecular mechanism of insulin resistance in obesity and type 2 diabetes.
Korean J Intern Med 25:119-29 (2010)
Ahmad F, Goldstein BJ
Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus.
Metabolism 44:1175-84 (1995)
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
A family with severe insulin resistance and diabetes due to a mutation in AKT2.
Science 304:1325-8 (2004)
Snel M, Jonker JT, Schoones J, Lamb H, de Roos A, Pijl H, Smit JW, Meinders AE, Jazet IM
Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.
Int J Endocrinol 2012:983814 (2012)
Morino K, Petersen KF, Shulman GI
Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction.
Diabetes 55 Suppl 2:S9-S15 (2006)
Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK
Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation.
Diabetes 54:2939-45 (2005)
Kim JA, Wei Y, Sowers JR
Role of mitochondrial dysfunction in insulin resistance.
Circ Res 102:401-14 (2008)
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
Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.
Cell Metab 4:465-74 (2006)
Ruderman NB, Saha AK, Vavvas D, Witters LA
Malonyl-CoA, fuel sensing, and insulin resistance.
Am J Physiol 276:E1-E18 (1999)
Saha AK, Kurowski TG, Colca JR, Ruderman NB
Lipid abnormalities in tissues of the KKAy mouse: effects of pioglitazone on malonyl-CoA and diacylglycerol.
Am J Physiol 267:E95-101 (1994)
Blachnio-Zabielska AU, Koutsari C, Tchkonia T, Jensen MD
Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance.
Obesity (Silver Spring) 20:2341-7 (2012)
Larter CZ, Farrell GC
Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
J Hepatol 44:253-61 (2006)
Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, Evans RM, Olefsky J, Montminy M
PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.
Nat Med 10:530-4 (2004)
Slawson C, Copeland RJ, Hart GW
O-GlcNAc signaling: a metabolic link between diabetes and cancer?
Trends Biochem Sci 35:547-55 (2010)
Ruan HB, Singh JP, Li MD, Wu J, Yang X
Cracking the O-GlcNAc code in metabolism.
Trends Endocrinol Metab 24:301-9 (2013)
Muoio DM, Newgard CB
Obesity-related derangements in metabolic regulation.
Annu Rev Biochem 75:367-401 (2006)
Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL
Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.
Diabetes 49:1353-8 (2000)
ko00010  Glycolysis / Gluconeogenesis
ko00061  Fatty acid biosynthesis
ko00514  Other types of O-glycan biosynthesis
ko00520  Amino sugar and nucleotide sugar metabolism
ko04150  mTOR signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04668  TNF signaling pathway
ko04910  Insulin signaling pathway
ko05230  Central carbon metabolism in cancer

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