Entry
Name
Insulin resistance - Sarcophilus harrisii (Tasmanian devil)
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
BRITE hierarchy
Pathway map
Ortholog table
Organism
Sarcophilus harrisii (Tasmanian devil) [GN:
shr ]
Gene
100920526 PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269 ] [EC:3.1.3.16 ]
100929811 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
100932099 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
105749979 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
100926892 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
100924976 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649 ]
100935230 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649 ]
100933581 STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692 ]
100919788 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158 ]
100919027 NFKBIA; LOW QUALITY PROTEIN: NF-kappa-B inhibitor alpha [KO:K04734 ]
100917619 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
100929154 SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191 ]
100919221 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
105750525 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199 ]
100918024 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
100919530 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
100927282 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
100924975 SLC27A4; long-chain fatty acid transport protein 4 isoform X1 [KO:K08745 ] [EC:6.2.1.-]
100929638 SLC27A1; long-chain fatty acid transport protein 1 isoform X1 [KO:K08745 ] [EC:6.2.1.-]
100922054 SLC27A3; solute carrier family 27 member 3 [KO:K08772 ] [EC:6.2.1.-]
100926963 PTPA; serine/threonine-protein phosphatase 2A activator isoform X2 [KO:K17605 ]
100913395 SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
100923865 SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593 ]
100929575 NR1H2; LOW QUALITY PROTEIN: oxysterols receptor LXR-beta [KO:K08535 ]
100915901 PPARGC1B; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962 ]
100913874 MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
100931691 PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X5 [KO:K07202 ]
100917093 PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
100929019 OGT; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667 ] [EC:2.4.1.255 ]
100915589 SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299 ]
100925565 GFPT1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820 ] [EC:2.6.1.16 ]
100922824 CRTC2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333 ]
100913327 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
100926416 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
100913890 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
100916355 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
100917654 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
100923082 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
100922067 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
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 pathway
shr00514 Other types of O-glycan biosynthesis
shr00520 Amino sugar and nucleotide sugar metabolism
KO pathway
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