scholarly journals C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport

Diabetologia ◽  
2007 ◽  
Vol 50 (4) ◽  
pp. 840-849 ◽  
Author(s):  
C. D’Alessandris ◽  
R. Lauro ◽  
I. Presta ◽  
G. Sesti
Keyword(s):  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Insulin Receptor Substrate ◽  
C Reactive Protein ◽  
Insulin Receptor Substrate 1 ◽  
Reactive Protein ◽  
Insulin Signalling Pathway ◽  
L6 Myocytes

93 C-REACTIVE PROTEIN INHIBITS INSULIN SIGNALLING PATHWAY IN BOTH HUMAN HEPATOCYTES AND ADIPOCYTES

2008 ◽  
Vol 48 ◽  
pp. S40
Author(s):  
A. Bertola ◽  
R. Anty ◽  
S. Bonnafous ◽  
Y. Le Marchand-Brustel ◽  
A. Tran ◽  
...  
Keyword(s):  
Insulin Signalling ◽  
Human Hepatocytes ◽  
Signalling Pathway ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Insulin Signalling Pathway

scholarly journals A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration

2005 ◽  
Vol 392 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Antonio J. Ruiz-Alcaraz ◽  
Hui-Kang Liu ◽  
Daniel J. Cuthbertson ◽  
Edward J. Mcmanus ◽  
Simeen Akhtar ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Insulin Injection ◽  
Underlying Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Receptor Tyrosine Kinase ◽  
Cell Culture Systems ◽  
Or Gene

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

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 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).

Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling

2003 ◽  
Vol 31 (6) ◽  
pp. 1152-1156 ◽  
Author(s):  
Y. Le Marchand-Brustel ◽  
P. Gual ◽  
T. Grémeaux ◽  
T. Gonzalez ◽  
R. Barrès ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307 as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser307 phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

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