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 K04526 insulin K04373 ribosomal protein S6 kinase alpha-1/2/3/6 [EC:2.7.11.1] K06269 serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16] K07189 protein phosphatase 1 regulatory subunit 3A/B/C/D/E K04527 insulin receptor [EC:2.7.10.1] K16172 insulin receptor substrate 1 K05696 tyrosine-protein phosphatase non-receptor type 1 [EC:3.1.3.48] K07293 tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48] K05695 receptor-type tyrosine-protein phosphatase F [EC:3.1.3.48] K00922 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K04456 RAC serine/threonine-protein kinase [EC:2.7.11.1] K07203 serine/threonine-protein kinase mTOR [EC:2.7.11.1] K04688 ribosomal protein S6 kinase beta [EC:2.7.11.1] K19662 classical protein kinase C beta type [EC:2.7.11.13] K05405 interleukin 6 K04692 signal transducer and activator of transcription 3 K04696 suppressor of cytokine signaling 3 K03083 glycogen synthase kinase 3 beta [EC:2.7.11.26] K00693 glycogen synthase [EC:2.4.1.11] 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:2.7.11.24] K07209 inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K04734 NF-kappa-B inhibitor alpha K02580 nuclear factor NF-kappa-B p105 subunit K04735 transcription factor p65 K13242 nitric-oxide synthase, endothelial [EC:1.14.13.39] K18952 atypical protein kinase C zeta type [EC:2.7.11.13] 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:3.1.3.16] K07198 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] 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:6.4.1.2 6.3.4.14 2.1.3.15] K19523 carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21] 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.- 6.2.1.3] 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:6.2.1.7] K08749 solute carrier family 27 (fatty acid transporter), member 6 K06259 CD36 antigen K18052 novel protein kinase C theta type [EC:2.7.11.13] K06068 novel protein kinase C delta type [EC:2.7.11.13] 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:2.4.1.1] K07201 forkhead box protein O1 K01596 phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32] K01084 glucose-6-phosphatase [EC:3.1.3.9] 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:2.3.1.21] K11533 fatty acid synthase, bacteria type [EC:2.3.1.-] K18050 novel protein kinase C epsilon type [EC:2.7.11.13] K07202 alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha K07294 peroxisome proliferator-activated receptor alpha K06276 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1] K01110 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] K15719 protein O-GlcNAcase / histone acetyltransferase [EC:3.2.1.169 2.3.1.48] K09667 protein O-GlcNAc transferase [EC:2.4.1.255] K07299 MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1 K00820 glutamine---fructose-6-phosphate transaminase (isomerizing) [EC:2.6.1.16] 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 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 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