ENTRY ko04931 Pathway NAME Insulin resistance 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 ko04931 Insulin resistance ORTHOLOGY K00688 PYG, glgP; glycogen phosphorylase [EC:2.4.1.1] K00693 GYS; glycogen synthase [EC:2.4.1.11] K00820 glmS, GFPT; glutamine---fructose-6-phosphate transaminase (isomerizing) [EC:2.6.1.16] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K01084 G6PC; glucose-6-phosphatase [EC:3.1.3.9] K01110 PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67] K01596 E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32] K01946 ACACB; acetyl-CoA carboxylase / biotin carboxylase 2 [EC:6.4.1.2 6.3.4.14 2.1.3.15] K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K03083 GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26] K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2 K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A K04373 RPS6KA; ribosomal protein S6 kinase alpha-1/2/3/6 [EC:2.7.11.1] K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04526 INS; insulin K04527 INSR, CD220; insulin receptor [EC:2.7.10.1] K04688 RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1] K04692 STAT3; signal transducer and activator of transcription 3 K04696 SOCS3, CIS3; suppressor of cytokine signaling 3 K04734 NFKBIA; NF-kappa-B inhibitor alpha K04735 RELA; transcription factor p65 K05405 IL6; interleukin 6 K05695 PTPRF, LAR; receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48] K05696 PTPN1, PTP1B; tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48] K05870 CREB1; cyclic AMP-responsive element-binding protein 1 K06068 PRKCD; novel protein kinase C delta type [EC:2.7.11.13] K06259 CD36; CD36 antigen K06269 PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16] K06276 PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1] K07187 IRS2; insulin receptor substrate 2 K07189 PPP1R3; protein phosphatase 1 regulatory subunit 3A/B/C/D/E K07191 SLC2A4, GLUT4; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4 K07197 SREBP1, SREBF1; sterol regulatory element-binding transcription factor 1 K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit K07201 FOXO1; forkhead box protein O1 K07202 PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07293 PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48] K07294 NR1C1, PPARA; peroxisome proliferator-activated receptor alpha K07299 SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 K07593 SLC2A2, GLUT2; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2 K08535 NR1H2, LXRB; liver X receptor beta K08536 NR1H3, LXRA; liver X receptor alpha K08745 SLC27A1_4, FATP1_4; solute carrier family 27 (fatty acid transporter), member 1/4 [EC:6.2.1.-] K08746 SLC27A2, FACVL1, FATP2; solute carrier family 27 (fatty acid transporter), member 2 [EC:6.2.1.- 6.2.1.3] K08748 SLC27A5, FATP5; solute carrier family 27 (fatty acid transporter), member 5 [EC:6.2.1.7] K08749 SLC27A6, FATP6; solute carrier family 27 (fatty acid transporter), member 6 K08765 CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [EC:2.3.1.21] K08772 SLC27A3, FATP3; solute carrier family 27 (fatty acid transporter), member 3 [EC:6.2.1.-] K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5 K09048 CREB3; cyclic AMP-responsive element-binding protein 3 K09113 MLX; MAX-like protein X K09667 OGT; protein O-GlcNAc transferase [EC:2.4.1.255] K09821 AGT, SERPINA8; angiotensinogen K11533 fas; fatty acid synthase, bacteria type [EC:2.3.1.-] K13242 NOS3; nitric-oxide synthase, endothelial [EC:1.14.13.39] K14497 PP2C; protein phosphatase 2C [EC:3.1.3.16] K15719 NCOAT, MGEA5; protein O-GlcNAcase / histone acetyltransferase [EC:3.2.1.169 2.3.1.48] K16172 IRS1; insulin receptor substrate 1 K16333 CRTC2, TORC2; CREB-regulated transcription coactivator 2 K17605 PPP2R4, PTPA; serine/threonine-protein phosphatase 2A activator K17902 TBC1D4, AS160; TBC1 domain family member 4 K17962 PPARGC1B, PGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta K18050 PRKCE; novel protein kinase C epsilon type [EC:2.7.11.13] K18052 PRKCQ; novel protein kinase C theta type [EC:2.7.11.13] K18952 PRKCZ; atypical protein kinase C zeta type [EC:2.7.11.13] K19518 TRIB3; tribbles homolog 3 K19523 CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21] K19662 PRKCB; classical protein kinase C beta type [EC:2.7.11.13] 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. 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