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

external resources
NCBI:1272486
KEGG:hsa04931
PUBMED:17130651
PUBMED:20466550
PUBMED:16364488
PUBMED:12765939
PUBMED:15166380
PUBMED:7666792
PUBMED:16756496
PUBMED:23647930
PUBMED:10923637
PUBMED:17141630
PUBMED:9886945
PUBMED:8048519
PUBMED:18309108
PUBMED:15107844
PUBMED:20526383
PUBMED:22360800
PUBMED:16186396
PUBMED:22675355
PUBMED:22677645

genes
ACACB , AKT1 , AKT2 , CD36 , CPT1A , CPT1B , CREB1 , FOXO1 , MTOR , G6PC , GFPT1 , GSK3B , GYS1 , GYS2 , IKBKB , IL6 , INS , INSR , IRS1 , NFKB1 , NFKBIA , NOS3 , PCK1 , PCK2 , PDPK1 , PIK3CA , PIK3CB , PIK3CD , PIK3R1 , PIK3R2 , PPARA , PPP1CA , PPP1CB , PPP1CC , PPP1R3A , PPP1R3C , PPP1R3D , PTPA , PRKAA1 , PRKAA2 , PRKAB1 , PRKAB2 , PRKAG1 , PRKCB , PRKCD , PRKCE , PRKCQ , PRKCZ , MAPK8 , MAPK9 , MAPK10 , PTEN , PTPN1 , PTPN11 , PTPRF , PYGB , PYGL , PYGM , RELA , RPS6KA1 , RPS6KA2 , RPS6KA3 , RPS6KB1 , RPS6KB2 , SLC2A1 , SLC2A2 , SLC2A4 , SREBF1 , STAT3 , MLX , TNF , TNFRSF1A , NR1H2 , OGT , PIK3R3 , IRS2 , SOCS3 , CREB5 , TBC1D4 , GFPT2 , AKT3 , NR1H3 , CREB3 , OGA , PPARGC1A , SLC27A5 , SLC27A4 , SLC27A3 , SLC27A2 , MLXIP , RPS6KA6 , SLC27A6 , MLXIPL , PRKAG2 , PRKAG3 , TRIB3 , G6PC2 , CREB3L2 , PPP1R3B , CREB3L3 , PPP1R3E , CREB3L1 , G6PC3 , PPARGC1B , CREB3L4 , CRTC2 , SLC27A1 ,