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Entry 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 diseaseBRITE hierarchy
Pathway map Orthology 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 ]
K01596 E4.1.1.32, pckA, PCK; phosphoenolpyruvate carboxykinase (GTP) [EC:4.1.1.32 ]
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
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 ]
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
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
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
K09821 AGT, SERPINA8; angiotensinogen
K11533 fas; fatty acid synthase, bacteria type [EC:2.3.1.-]
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
K19518 TRIB3; tribbles homolog 3
K19523 CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21 ]
Compound C00043 UDP-N-acetyl-alpha-D-glucosamine
C00352 D-Glucosamine 6-phosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
C06156 alpha-D-Glucosamine 1-phosphate
Reference 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 Reference 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 Reference Authors Choi K, Kim YB
Title Molecular mechanism of insulin resistance in obesity and type 2 diabetes.
Journal Reference 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 Reference 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 Reference 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 Reference Authors Morino K, Petersen KF, Shulman GI
Title Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction.
Journal Reference 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 Reference Authors Kim JA, Wei Y, Sowers JR
Title Role of mitochondrial dysfunction in insulin resistance.
Journal Reference 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 Reference Authors Ruderman NB, Saha AK, Vavvas D, Witters LA
Title Malonyl-CoA, fuel sensing, and insulin resistance.
Journal Reference 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 Reference Authors Blachnio-Zabielska AU, Koutsari C, Tchkonia T, Jensen MD
Title Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance.
Journal Reference Authors Larter CZ, Farrell GC
Title Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
Journal Reference 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 Reference Authors Slawson C, Copeland RJ, Hart GW
Title O-GlcNAc signaling: a metabolic link between diabetes and cancer?
Journal Reference Authors Ruan HB, Singh JP, Li MD, Wu J, Yang X
Title Cracking the O-GlcNAc code in metabolism.
Journal Reference Authors Muoio DM, Newgard CB
Title Obesity-related derangements in metabolic regulation.
Journal Reference 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 Related ko00010 Glycolysis / Gluconeogenesis
ko00514 Other types of O-glycan biosynthesis
ko00520 Amino sugar and nucleotide sugar metabolism
