Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population

Albegali, Abdullah Abdo; Shahzad, Muhammad; Mahmood, Saqib; Ullah, Muhammad Ikram

doi:10.1007/s11033-019-05041-w

Cited by 13 publications

(6 citation statements)

References 27 publications

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“…Different studies have linked the p.Gly972Arg variant with IRS1 Gene in Early Gestational Diabetes J Endocrinol Metab. 2022;12(6):188-197 higher risks of T2DM, polycystic ovary syndrome, GDM, and osteoarthritis [43][44][45][46]. Its molecular mechanism was explained using a series of recombinant peptide fragments between IRS1 residues 910 to 1027 containing the polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

et al. 2022

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Background: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and has a rising prevalence worldwide. Environmental and genetic factors contribute to GDM risk. Describing familial cases of GDM can help identify the disease's genetic components.Methods: Here, we report the case of an Emirati female patient affected with early GDM and familial history of diabetes with a significant level of insulin resistance. As a first step, we investigated the GCK and HNF1A gene sequences by direct sequencing and then performed a clinical exome sequencing (CES) of the patient's genomic DNA covering 6,670 genes.Results: Our findings showed the absence of any pathogenic variants in the GCK and HNF1A gene sequences. In addition, the CES excluded all maturity-onset diabetes of the young (MODY)-related genes. However, two rare homozygous variants in the insulin receptor substrate 1 (IRS1) gene were identified: p.Pro948Leu (gnomAD minor allele frequency (MAF) = 7.5 × 10 -5 ) and p.Arg1221Cys (gnomAD MAF = 5.6 × 10 -5 ). These variants were absent in a set of healthy Emirati individuals. Both variants are highly conserved among mammalians but have never previously been reported among the same haplotype or individual. p.Pro948Leu and p.Arg1221Cys are localized close to two important functional phosphorylation sites recognized by PI3K (hTyr941) and SHP2 (hTyr1229), respectively. Moreover, the independent and combined effect of the two variants on protein stability was predicted to be destabilizing. Conclusion:Our investigation emphasized the role of downstream regulators of insulin signaling in GDM pathophysiology and identified IRS1 as a candidate gene to explain chronic insulin resistance. In addition, the patient showed significant health improvement after lifestyle modifications and oral antidiabetic administration, even after withdrawing insulin injections.

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Section: Discussionmentioning

confidence: 99%

Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

et al. 2022

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“…IRS1 also widely distributed in insulin sensitive tissues and closely related to insulin signaling [30,31]. It has been reported that IRS-1 genetic polymorphism was closely associated with insulin resistance [32,33]. Xu et al have demonstrated that Angptl7 mediated insulin resistance and T2DM by inhibiting the IRS1 expression through SOCS3 [20].…”

Section: Discussionmentioning

confidence: 99%

Cytokeratin 8 Inhibits Hepatic Glycogen Synthesis in Type 2 Diabetes Mellitus by Modulating Insulin-dependent IRS1/PI3K/Akt-GSK3β Pathway

Sun

Sun²,

et al. 2021

Preprint

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Purpose: Cytokeratin 8(CK8) is a cytoskeletal protein mainly expressed in the liver. Recent studies have found that CK8 was closely related to glycogen synthesis. However, the role and the underlying mechanisms of CK8 in hepatic glycogen synthesis in type 2 diabetes mellitus (T2DM) have remained to be fully elucidated. Therefore, this study aimed to investigate the effects and the underlying mechanisms of CK8 on hepatic glycogen synthesis in T2DM.Methods The T2D mouse model was constructed by high energy feed of 8-10 weeks old C57BL/6J male mice. The model was validated by OGTT test and ITT test. The liver samples of T2DM patients were collected and the expression levels of CK8, IRS1, PI3K, Akt, GSK3β, p-PI3K p-Akt and p-GSK3β were determined by Western blotting. Then, at the cellular level the murine NCTC 1469 cells were used, and to up-regulate and down-regulate the CK8 gene the overexpression plasmid was constructed and transfected and RNA interference technology was applied, and CK8, IRS1, PI3K, Akt, GSK3β, p-IRS1, p-PI3K p-Akt and p-GSK3β were detected by Western blotting. Immunohistochemistry was used to detect the level of glycogen synthase (GS) and glycogen staining experiments was performed by PAS. At the animal level, the T2D mouse model was used to up-regulate and down-regulate the CK8 gene using an adenovirus vector. The levels of CK8, PI3K, Akt, GSK3β, p-PI3K, p-Akt and p-GSK3β in rat liver were detected by Western blotting, immunohistochemistry was used to detect the level of GS and glycogen staining experiments was performed by PAS.Results The expression levels of IRS1, p-PI3K, p-Akt and p-GSK3β were significantly higher, while the expression levels of CK8 was significantly lower in control group than in the liver of T2D mice or T2DM patients. Upregulation of CK8 in murine NCTC 1469 cells treated with high-glucose medium, we found IRS1, p-IRS1, p-PI3K, p-Akt and p-GSK3β were significantly decreased, the level of GS was significantly decreased, and glycogen synthesis was inhibited compared with NCTC1469 cells transfected with empty vector. Downregulation of CK8 in murine NCTC 1469 cells murine treated with high-glucose medium, we found IRS1, p-IRS1, p-PI3K, p-Akt and p-GSK3β were significantly higher, the level of GS was significantly increased, and glycogen synthesis was promoted compared with NCTC1469 cells transfected with sh-NC. Upregulation of CK8 in the T2D mouse model, we found p-PI3K, p-Akt and p-GSK3β were significantly lower compared with T2D mouse model transfected with empty vector. The level of GS was significantly decreased, and glycogen synthesis was inhibited. Downregulation of CK8 in the T2D mouse model, we found p-PI3K, p-Akt and p-GSK3β were significantly increased, and the level of GS was significantly increased, and glycogen synthesis was promoted compared with T2D mouse model transfected with sh-NC.Conclusions Overall, this experiment provides a new molecular target for the treatment of T2DM by revealing the role of CK8 inhibiting hepatic glycogen synthesis in T2DM via regulating insulin-dependent IRS1/PI3K-Akt-GSK3β pathway. CK8 may play an important role in the pathogenesis of glycogen synthesis in T2DM.

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“…The prevalent polymorphism of IRS1 is a glycine to arginine substitution in codon 972 (Gly972Arg), which is located between two potential tyrosine phosphorylation sites involved in binding with p85. This polymorphism has been linked to the development of T2D in obese Caucasian children [64], Egyptian patients with chronic hepatitis C virus infection and T2D [65], Kurdish ethnic, and Saudi and Pakistani populations [66][67][68]. However, no such association with this genetic variant has been found in Sistan and Baluchistan population of Iran [69], Arab, or Berber and Asian Indian populations [70,71] with T2D (Table 3).…”

Section: Gene Polymorphism Of Irssmentioning

confidence: 99%

Current Studies on Molecular Mechanisms of Insulin Resistance

Pei

Wang

2022

Journal of Diabetes Research

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Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor of insulin resistance may be impaired cell signal transduction mediated by the insulin receptor (IR). Several cell-signaling proteins, including IR, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI3K), have been recognized as being important in the impaired insulin signaling pathway since they are associated with a large number of proteins that are strictly regulated and interact with other signaling pathways. Many studies have found a correlation between IR alternative splicing, IRS gene polymorphism, the complicated regulatory function of IRS serine/threonine phosphorylation, and the negative regulatory role of p85 in insulin resistance and diabetes mellitus. This review brings up-to-date knowledge of the roles of signaling proteins in insulin resistance in order to aid in the discovery of prospective targets for insulin resistance treatment.

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Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population

Cited by 13 publications

References 27 publications

Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

Identification of Two Rare Homozygote Missense Variants in the IRS1 Gene in a Patient With Early Gestational Diabetes: A Case Study

Cytokeratin 8 Inhibits Hepatic Glycogen Synthesis in Type 2 Diabetes Mellitus by Modulating Insulin-dependent IRS1/PI3K/Akt-GSK3β Pathway

Current Studies on Molecular Mechanisms of Insulin Resistance

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