Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms

Objectives: Insulin receptor substrate 1 (IRS1) is a crucial factor in the insulin signaling pathway. IRS1 gene polymorphism rs1801278 in mothers has been reported to be associated with gestational diabetes mellitus (GDM). However, it is not clear whether IRS1 gene polymorphism rs1801278 in fetuses is associated with their mothers’ GDM morbidity. The purpose of this study is to analyze the association between maternal, fetal, or maternal/fetal IRS1 gene polymorphism rs1801278 and GDM risk. Design: The study was a single-center, prospective cohort study. In total, 213 pairs of GDM mothers/fetuses and 191 pairs of control mothers/fetuses were included in this study. They were recruited after they underwent oral glucose tolerance test during 24–28 weeks of gestation and followed up until delivery. All participants received the conventional interventions (diet and exercise), and no special therapy except routine treatment. Methods: A total of 213 pairs of GDM mothers/fetuses and 191 pairs of normal blood glucose pregnant mothers/fetuses were genotyped using PCR and DNA sequencing from January 2015 to September 2016. Maternal/fetal IRS1 gene polymorphism rs1801278 was analyzed and compared between 2 groups. Results: There were no significant differences in the frequency of individual mothers’ or fetuses’ IRS1 rs1801278 polymorphisms between 2 groups; if both the mothers and fetuses carried A allele, significantly lower GDM morbidity was observed in the mothers. Limitations: The sample size was relatively small as a single-center study. Conclusions: Our study suggested that maternal/fetal rs1801278 polymorphism of IRS1 is a modulating factor in GDM; both mothers/fetuses carrying the A allele of rs1801278 may protect the mothers against the development of GDM.

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A mutant insulin receptor induces formation of a Shc-growth factor receptor bound protein 2 (Grb2) complex and p21ras-GTP without detectable interaction of insulin receptor substrate 1 (IRS1) with Grb2. Evidence for IRS1-independent p21ras-GTP formation

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)30104-6 ◽

1994 ◽

Vol 269 (52) ◽

pp. 33116-33122

Author(s):

D M Ouwens ◽

G C van der Zon ◽

G J Pronk ◽

J L Bos ◽

W Möller ◽

...

Keyword(s):

Growth Factor ◽

Insulin Receptor ◽

Growth Factor Receptor ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Growth Factor Receptor Bound ◽

Mutant Insulin ◽

Mutant Insulin Receptor

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Gly972Arg Variant of Insulin Receptor Substrate 1 Gene and Colorectal Cancer Risk in Overweight/Obese Subjects

The International Journal of Biological Markers ◽

10.5301/jbm.5000159 ◽

2016 ◽

Vol 31 (1) ◽

pp. 68-72 ◽

Cited By ~ 3

Author(s):

Touraj Mahmoudi ◽

Keivan Majidzadeh-A ◽

Khatoon Karimi ◽

Hamid Farahani ◽

Reza Dabiri ◽

...

Keyword(s):

Colorectal Cancer ◽

Insulin Receptor ◽

Case Control Study ◽

Insulin Receptor Substrate ◽

Protective Effects ◽

Insulin Receptor Substrate 1 ◽

Pcr Rflp ◽

Obese Subjects ◽

Control Study

Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

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Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding

Cell Metabolism ◽

10.1016/j.cmet.2008.05.007 ◽

2008 ◽

Vol 8 (1) ◽

pp. 49-64 ◽

Cited By ~ 145

Author(s):

Naoto Kubota ◽

Tetsuya Kubota ◽

Shinsuke Itoh ◽

Hiroki Kumagai ◽

Hideki Kozono ◽

...

Keyword(s):

Insulin Receptor ◽

Insulin Signaling ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Hepatic Insulin Signaling

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Cell Adhesion and Focal Adhesion Kinase Regulate Insulin Receptor Substrate-1 Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m006162200 ◽

2000 ◽

Vol 275 (49) ◽

pp. 38371-38377 ◽

Cited By ~ 45

Author(s):

Patricia Lebrun ◽

Véronique Baron ◽

Christof R. Hauck ◽

David D. Schlaepfer ◽

Emmanuel Van Obberghen

Keyword(s):

Cell Adhesion ◽

Insulin Receptor ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1

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Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance

Molecular and Cellular Biology ◽

10.1128/mcb.24.21.9668-9681.2004 ◽

2004 ◽

Vol 24 (21) ◽

pp. 9668-9681 ◽

Cited By ~ 83

Author(s):

Yan-Fang Liu ◽

Avia Herschkovitz ◽

Sigalit Boura-Halfon ◽

Denise Ronen ◽

Keren Paz ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Insulin Signaling ◽

Insulin Treatment ◽

Binding Domain ◽

Serine Phosphorylation ◽

Insulin Receptor Substrate ◽

Control Mechanisms ◽

Insulin Receptor Substrate 1 ◽

Phosphotyrosine Binding Domain

ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.

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