Entry Name Insulin resistance - Peromyscus leucopus (white-footed mouse)
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 Organism Peromyscus leucopus (white-footed mouse) [GN:
pleu ]
Gene 114680673 Gfpt1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820 ] [EC:2.6.1.16 ]
114680913 Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
114682086 Slc27a1; long-chain fatty acid transport protein 1 isoform X2 [KO:K08745 ] [EC:6.2.1.-]
114682571 Srebf1; LOW QUALITY PROTEIN: sterol regulatory element-binding protein 1 [KO:K07197 ]
114682608 Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
114682786 Stat3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692 ]
114684032 Pik3cd; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
114686011 Mlxipl; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
114688126 Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
114688966 Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649 ]
114689726 Creb5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
114690914 Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202 ]
114691010 Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
114693201 Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191 ]
114693559 Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
114695335 Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
114697557 Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593 ]
114699201 Ppara; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
114699702 Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
114700068 Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
114702725 Ptpa; serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605 ]
114702759 Slc27a4; long-chain fatty acid transport protein 4 [KO:K08745 ] [EC:6.2.1.-]
114703207 Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
114703850 Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
114704570 Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269 ] [EC:3.1.3.16 ]
114704945 Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 isoform X1 [KO:K07299 ]
114705057 Creb1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
114706924 Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649 ]
114707399 Ppargc1b; LOW QUALITY PROTEIN: peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962 ]
114707880 Slc27a3; solute carrier family 27 member 3 isoform X1 [KO:K08772 ] [EC:6.2.1.-]
114707907 Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
114707916 Crtc2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333 ]
114708542 Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200 ]
114708645 Ogt; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667 ] [EC:2.4.1.255 ]
114708799 Tnfrsf1a; LOW QUALITY PROTEIN: tumor necrosis factor receptor superfamily member 1A [KO:K03158 ]
114709328 Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X4 [KO:K07200 ]
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 pleu00514 Other types of O-glycan biosynthesis
pleu00520 Amino sugar and nucleotide sugar metabolism
KO pathway
