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 Ortholog table Orthology K06269 serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16 ]
K07189 protein phosphatase 1 regulatory subunit 3A/B/C/D/E
K16172 insulin receptor substrate 1
K07293 tyrosine-protein phosphatase non-receptor type 11 [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
K04692 signal transducer and activator of transcription 3
K04696 suppressor of cytokine signaling 3
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
K17902 TBC1 domain family member 4
K07191 MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 4
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
K19523 carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21 ]
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
K17605 serine/threonine-protein phosphatase 2A activator
K07197 sterol regulatory element-binding transcription factor 1
K07187 insulin receptor substrate 2
K07201 forkhead box protein O1
K07593 MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2
K17962 peroxisome proliferator-activated receptor gamma coactivator 1-beta
K08765 carnitine O-palmitoyltransferase 1, liver isoform [EC:2.3.1.21 ]
K11533 fatty acid synthase, bacteria type [EC:2.3.1.-]
K07202 alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K07294 peroxisome proliferator-activated receptor alpha
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 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
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