Entry
Name
Insulin resistance - Marmota marmota marmota (Alpine marmot)
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
Marmota marmota marmota (Alpine marmot) [GN:
mmma ]
Gene
107136449 Ppp1r3d; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3D [KO:K07189 ]
107142592 Ppp1r3b; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3B [KO:K07189 ]
107148036 Ppp1r3e; LOW QUALITY PROTEIN: protein phosphatase 1 regulatory subunit 3E [KO:K07189 ]
107143149 Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
107149519 Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
107155522 Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
107139438 Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649 ]
107141811 Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
107145061 Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
107150570 Stat3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692 ]
107154973 Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A [KO:K03158 ]
107141352 Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
107157976 Slc2a4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191 ]
107158637 Prkab2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199 ]
107158690 Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
107138705 Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
107148597 Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
107148919 Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
107151439 LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit gamma-1-like [KO:K07200 ]
107152043 Slc27a4; long-chain fatty acid transport protein 4 [KO:K08745 ] [EC:6.2.1.-]
107145049 Slc27a1; long-chain fatty acid transport protein 1 [KO:K08745 ] [EC:6.2.1.-]
107156766 Slc27a3; LOW QUALITY PROTEIN: solute carrier family 27 member 3 [KO:K08772 ] [EC:6.2.1.-]
107152012 Ptpa; serine/threonine-protein phosphatase 2A activator isoform X1 [KO:K17605 ]
107157159 Srebf1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
107149487 Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593 ]
107154108 Ppargc1b; peroxisome proliferator-activated receptor gamma coactivator 1-beta [KO:K17962 ]
107146586 Mlxipl; carbohydrate-responsive element-binding protein isoform X3 [KO:K09113 ]
107139157 Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202 ]
107155798 Ppara; peroxisome proliferator-activated receptor alpha isoform X1 [KO:K07294 ]
107155669 Ogt; UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X1 [KO:K09667 ] [EC:2.4.1.255 ]
107134524 LOW QUALITY PROTEIN: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit-like [KO:K09667 ] [EC:2.4.1.255 ]
107141876 Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299 ]
107136979 Gfpt1; glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1 isoform X1 [KO:K00820 ] [EC:2.6.1.16 ]
107156765 Crtc2; CREB-regulated transcription coactivator 2 isoform X1 [KO:K16333 ]
107138645 Creb1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870 ]
107147808 Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
107135791 Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X3 [KO:K09048 ]
107149021 Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
107156760 Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048 ]
107146134 Creb5; cyclic AMP-responsive element-binding protein 5 isoform X2 [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
mmma00514 Other types of O-glycan biosynthesis
mmma00520 Amino sugar and nucleotide sugar metabolism
KO pathway
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