scholarly journals Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice.

1996 ◽  
Vol 16 (6) ◽  
pp. 3074-3084 ◽  
Author(s):  
T Yamauchi ◽  
K Tobe ◽  
H Tamemoto ◽  
K Ueki ◽  
Y Kaburagi ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Map Kinase ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Pi3 Kinase ◽  
Insulin Receptor Substrate ◽  
Wild Type ◽  
Insulin Receptor Substrate 1 ◽  
Kinase Activation ◽  
Deficient Mice

We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).

scholarly journals Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation

2006 ◽  
Vol 26 (1) ◽  
pp. 63-76 ◽  
Author(s):  
Alexandros Tzatsos ◽  
Konstantin V. Kandror
Keyword(s):  
Insulin Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Insulin Dependent Diabetes Mellitus ◽  
Akt Signaling ◽  
Pi3 Kinase ◽  
Dependent Diabetes Mellitus ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Dependent ◽  
Phosphatidylinositol 3

ABSTRACT Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y632MPM motif that is implicated in the binding of p85α/p110α PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

scholarly journals Role of Insulin Receptor Substrate-1 and pp60 in the Regulation of Insulin-induced Glucose Transport and GLUT4 Translocation in Primary Adipocytes

1997 ◽  
Vol 272 (41) ◽  
pp. 25839-25844 ◽  
Author(s):  
Yasushi Kaburagi ◽  
Shinobu Satoh ◽  
Hiroyuki Tamemoto ◽  
Ritsuko Yamamoto-Honda ◽  
Kazuyuki Tobe ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
Insulin Receptor Substrate 1

scholarly journals Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation

2001 ◽  
Vol 21 (7) ◽  
pp. 2521-2532 ◽  
Author(s):  
Hiroshi Miki ◽  
Toshimasa Yamauchi ◽  
Ryo Suzuki ◽  
Kajuro Komeda ◽  
Atsuko Tsuchida ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Adipocyte Differentiation ◽  
Kinase Inhibitor ◽  
Binding Protein ◽  
Insulin Receptor Substrate ◽  
Wild Type ◽  
Double Knockout ◽  
Insulin Receptor Substrate 1 ◽  
Fatty Acid Binding

ABSTRACT To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1−/−), IRS-2 deficient (IRS-2−/−), and IRS-1 IRS-2 double deficient (IRS-1−/−IRS-2−/−), from mouse embryos of the corresponding genotypes. The abilities of IRS-1−/− cells and IRS-2−/− cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1−/− IRS-2−/− cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) is severely decreased in IRS-1−/−IRS-2−/− cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1−/−IRS-2−/− cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1−/−IRS-2−/− cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPα and PPARγ, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1−/− IRS-2−/− double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPα and PPARγ expression and adipocyte differentiation.

scholarly journals RHO-associated protein kinase alpha potentiates insulin-induced MAP kinase activation in Xenopus oocytes

1999 ◽  
Vol 112 (13) ◽  
pp. 2177-2184 ◽  
Author(s):  
N. Ohan ◽  
Y. Agazie ◽  
C. Cummings ◽  
R. Booth ◽  
M. Bayaa ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Map Kinase ◽  
Insulin Receptor ◽  
Xenopus Oocytes ◽  
Germinal Vesicle ◽  
Insulin Receptor Substrate ◽  
Germinal Vesicle Breakdown ◽  
Kinase Activation ◽  
Insulin Signal Transduction

We recently identified Xenopus Rho-associated protein kinase alpha (xROKalpha) as a Xenopus insulin receptor substrate-1 binding protein and demonstrated that the non-catalytic carboxyl terminus of xROKalpha binds Xenopus insulin receptor substrate-1 and blocks insulin-induced MAP kinase activation and germinal vesicle breakdown in Xenopus oocytes. In the current study we further examined the role of xROKalpha in insulin signal transduction in Xenopus oocytes. We demonstrate that injection of mRNA encoding the xROKalpha kinase domain or full length xROKalpha enhanced insulin-induced MAP kinase activation and germinal vesicle breakdown. In contrast, injection of a kinase-dead mutant of xROKalpha or pre-incubation of oocytes with an xROKalpha inhibitor significantly reduced insulin-induced MAP kinase activation. To further dissect the mechanism by which xROKalpha may participate in insulin signalling, we explored a potential function of xROKalpha in regulating cellular Ras function, since insulin-induced MAP kinase activation and germinal vesicle breakdown is known to be a Ras-dependent process. We demonstrate that whereas injection of mRNA encoding c-H-Ras alone induced xMAP kinase activation and GVBD in a very low percentage (about 10%) of injected oocytes, co-injection of mRNA encoding xROKalpha and c-H-Ras induced xMAP kinase activation and germinal vesicle breakdown in a significantly higher percentage (50-60%) of injected oocytes. These results suggest a novel function for xROKalpha in insulin signal transduction upstream of cellular Ras function.

Sign in / Sign up

Export Citation Format

Share Document