Association of IRS1 genetic variants with glucose control and insulin resistance in type 2 diabetic patients from Bosnia and Herzegovina

Mahmutović, Lejla; Bego, Tamer; Sterner, Maria; Gremsperger, Gabriella; Ahlqvist, Emma; Velija-Ašimi, Zelija; Prnjavorac, Besim; Hamad, Nour; Čaušević, Adlija; Groop, Leif; Semiz, Sabina

doi:10.1515/dmpt-2018-0031

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…INS sensitivity can be improved by 4-PBA through reversing ER stress in adipose tissue 61. It has been shown that IRS-mediated INS receptor signaling dysregulation is a common underlying mechanism that can produce and exacerbate INS resistance in many genetic and physiological factors 62,63. INS signaling in adipocytes is critical for the development of obesity 64.…”

Section: Discussionmentioning

confidence: 99%

<p>Endoplasmic reticulum stress may be involved in insulin resistance and lipid metabolism disorders of the white adipose tissues induced by high-fat diet containing industrial trans-fatty acids</p>

Zhu¹,

Niu²,

Wang³

et al. 2019

DMSO

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Background Consumption of industrially produced trans-fatty acids (iTFAs) can result in alteration to lipid profile and glucose metabolism. Moreover, a diet high in iTFAs could increase the risk of obesity, cardiovascular diseases (CVDs) and type 2 diabetes mellitus. Glucose and lipid metabolism are closely linked in white adipose tissue (WAT), yet the underlying mechanisms of the effect of iTFAs in WAT are poorly understood. Materials and methods Parameters of glucose homeostasis, lipid profiles and markers of endoplasmic reticulum (ER) stress of WAT were measured in rats maintained on a high-fat diet containing margarine (HFD-M) (n=10) compared to controls maintained on standard chow (n=10) over 16 weeks. Results Fat mass and body weight was significantly increased in rats maintained on the HFD-M compared to controls ( P <0.01). HFD-M rats had increased levels of insulin (INS), homeostasis model assessment of insulin resistance and serum lipid profile was significantly altered. The expression of glucose-regulated protein 78 (GRP78) and the phosphorylation of inositol-requiring enzyme 1-alpha and c-Jun N-terminal kinase (JNK) were significantly increased in subcutaneous and retroperitoneal adipose depots of HFD-M-fed rats. In vitro, wider ER lumens were observed in 100μmol/L elaidic acid (EA)-treated human mature adipocytes. We observed activation of ER stress markers, impaired INS receptor signaling and increased lipogenesis in adipocytes after EA exposure. These effects could be alleviated by inhibiting ER stress in adipocytes in vitro. Conclusion Collectively these data suggest that ER stress may be involved in INS resistance and lipid metabolism disorders induced by high-fat diet containing iTFAs. These findings suggest that WAT could be regarded as a key target organ for inhibiting ER stress to reverse the impaired INS receptor signaling, alleviate lipid metabolism disorders, and provide a novel approach to prevent and treat INS resistance and dyslipidemia-related chronic diseases such as T2MD and CVDs.

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Section: Discussionmentioning

confidence: 99%

<p>Endoplasmic reticulum stress may be involved in insulin resistance and lipid metabolism disorders of the white adipose tissues induced by high-fat diet containing industrial trans-fatty acids</p>

Zhu¹,

Niu²,

Wang³

et al. 2019

DMSO

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“…The individuals with non-insulin dependent diabetes mellitus (NIDDM) have decreased expression and function of IRS-1 in the fat cells. The Gly972Arg polymorphism is the most commonly studied variant of IRS-1 [12]. Downstream IRS-1, the main docking protein found in the cells is IRS-2 [13].…”

Section: Introductionmentioning

confidence: 99%

The combined role of allelic variants of IRS-1 and IRS-2 genes in susceptibility to type2 diabetes in the Punjabi Pakistani subjects

Ijaz

Babar

Sarwar

et al. 2019

Diabetol Metab Syndr

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Background Diabetes mellitus is a multifactorial disorder characterized by a high level of glucose in the blood. Both genetic and environmental factors interact to cause diabetes. Insulin receptor substrate ( IRS ) proteins have a significant part in insulin signaling pathways. We aimed to investigate the relationship of type 2 diabetes with a Gly972Arg (G972R) variant of the IRS-1 gene and Gly1057Asp (G1057D) polymorphism of IRS-2 gene in the population of Punjab, Pakistan. Methods We collected 926 samples, 500 healthy controls (fasting blood sugar < 99 mg/dL, random blood sugar < 126 mg/dL) and 426 cases with diabetes (fasting blood sugar > 99 mg/dL, random blood sugar > 126 mg/dL). Several anthropometric measurements were measured. Statistical analysis was performed by using SPSS to determine the allele group/genotype frequency of the selected variants in the study population. Results The genotyping results of G972R by RLFP-PCR showed the allelic frequency of G = 0.68 and R = 0.32 in controls while G = 0.71 and R = 0.29 in the cases. The minor R allele had a slightly higher frequency in the cases than the controls (OR = 0.86, CI 0.706–1.052, p = 0.17). The genotyping results of G1057D showed allelic frequency G = 0.74 and D = 0.26 in the controls while G = 0.961 and D = 0.29 in the cases. The minor D allele appeared to be a risk allele for this SNP although the difference in the allele frequencies was not statistically significant (OR = 1.55, CI 0.961–1.41, p = 0.108). The combined genotype analysis showed that the difference in the allele and genotype frequencies reached statistical difference between the cases and the controls as well as the odds ratio substantially increased when the R allele (G972R) was present together with D allele (G1057D) in any combination. When the association of single variants with the lipid traits was observed, only D allele (G1057D) showed significant association with TG, HDL and LDL, however when the analysis was repeated for combined genotypes using general linear model, many more significant associations between the genotype where D allele and R allele are together, were seen with many lipid traits. Conclusion In conclusion, the single nucleotide polymorphisms with low-modest effect size may not affect the phenotype individually but when in combination, the effect becomes stronger and more visible, therefore, for the SNP association studies, the more the number of SNPs included in the analysis, the more meaningful the results. Electronic supplementary material The online version of this article (10.1186/s13098-019-0459-1) contains supplementary material, which is available to authorized users.

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“…Mutation or abnormal expression of IRS1 is mainly related to type II diabetes, insulin resistance, cognitive dysfunction and tumor. 61 , 62 , 63 , 64 Kapogiannis et al. measured human plasma exosomes, and the results showed that IRS1 (p-Ser312) and its tyrosine phosphorylation in AD group were significantly different from other groups.…”

Section: Discussionmentioning

confidence: 99%

Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al

Zhao

Yang

et al. 2021

Molecular Therapy - Nucleic Acids

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Aluminum is a known neurotoxin that can induce Aβ deposition and abnormal phosphorylation of tau protein, leading to Alzheimer disease (AD)-like damages such as neuronal damage and decreased learning and memory functions. In this study, we constructed a rat model of subchronic aluminum maltol exposure, and the whole-transcriptome sequencing was performed on the hippocampus of the control group and the middle-dose group. A total of 167 miRNAs, 37 lncRNAs, 256 mRNAs, and 64 circRNAs expression changed. The Kyoto Encyclopedia of Genes and Genomes showed that PI3K/AKT pathway was the most enriched pathway of DEGs, and IRS1 was the core molecule in the PPI network. circRNA/lncRNA-miRNA-mRNA networks of all DEGs, DEGs in the PI3K/AKT pathway, and IRS1 were constructed by Cytoscape. Molecular experiment results showed that aluminum inhibited the IRS1/PI3K/AKT pathway and increased the content of Aβ and tau. In addition, we also constructed an AAV intervention rat model, proving that inhibition of miR-96-5p expression might resist aluminum-induced injury by upregulating expression of IRS1. In general, these results suggest that the ceRNA networks are involved in the neurotoxic process of aluminum, providing a new strategy for studying the toxicity mechanism of aluminum and finding biological targets for the prevention and treatment of AD.

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Association of IRS1 genetic variants with glucose control and insulin resistance in type 2 diabetic patients from Bosnia and Herzegovina

Cited by 12 publications

References 26 publications

<p>Endoplasmic reticulum stress may be involved in insulin resistance and lipid metabolism disorders of the white adipose tissues induced by high-fat diet containing industrial trans-fatty acids</p>

<p>Endoplasmic reticulum stress may be involved in insulin resistance and lipid metabolism disorders of the white adipose tissues induced by high-fat diet containing industrial trans-fatty acids</p>

The combined role of allelic variants of IRS-1 and IRS-2 genes in susceptibility to type2 diabetes in the Punjabi Pakistani subjects

Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al

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