Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis

Chang, Yi‐Cheng; Liu, Pi-Hua; Tsai, Yun-Chih; Chiu, Yen‐Feng; Shih, Shyang–Rong; Ho, Low-Tone; Lee, Wen‐Jane; Lu, Chieh-Hua; Quertermous, Thomas; Curb, J. David; Lee, Wei-Jei; Lee, Po‐Chu; He, You-Han; Yeh, Jih‐I; Hwang, Juey‐Jen; Tsai, Shin-Han; Chuang, Lee‐Ming

doi:10.1007/s00109-012-0898-8

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…Furthermore, PGE2, which is released from adipose tissue (Lappas et al 2005a), can also attenuate insulin signalling (Henkel et al 2009). Interestingly, genetic variation in the carbonyl reductase 3 gene, which encodes an enzyme for converting PGE2 to PGF2a, is associated with type 2 diabetes (Chang et al 2012). In this study, the NOD1 ligand induced COX2 gene expression and this was associated with an increase in the secretion of PGE2 and PGF2a from both subcutaneous and omental adipose tissues.…”

Section: Figurementioning

confidence: 50%

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

Lappas¹

2014

Journal of Endocrinology

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Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor kB (NFkB). The aim of this study was to determine whether levels of NOD1 and NOD2 are increased in adipose tissue of women with GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance (NGT). In both omental and subcutaneous adipose tissues from NGTand GDM women, the NOD1 ligand g-D-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesion molecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFkB, as the NFkB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion of pro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM.

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Section: Figurementioning

confidence: 50%

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

Lappas¹

2014

Journal of Endocrinology

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“…Genotyping was performed using the GenomeLab SNPstream genotyping platform (Beckman Coulter) and its accompanying SNPstream software suite. The concordance rate based on this platform was 99.62% [15].…”

Section: Methodsmentioning

confidence: 83%

Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Han Chinese Population: A Replication Study and Meta-Analysis

Chang

Liu

et al. 2014

PLoS ONE

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BackgroundSeveral genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated.MethodsWe analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese.ResultsFive risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations.ConclusionWe confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction.

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“…A recent clinical study [55] showed that a genetic variation in Cbr3 gene in humans correlates with type 2 diabetes and this effect can potentially be attributed to the catalysis of the conversion of prostaglandin E2 to prostaglandin F2 α . In the present study, Cbr3 liver mRNA levels were about 5 times lower in Nrf2-KO mice after HFD compared to WT.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity

Chartoumpekis

Ziros

Zaravinos

et al. 2013

Oxidative Medicine and Cellular Longevity

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Introduction. The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf2 has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD-) induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT) versus Nrf2 knockout (Nrf2-KO) mice after a long-term HFD. Methods. WT and Nrf2-KO mice were fed an HFD for 180 days; total RNA was prepared from liver and used for microarray analysis and quantitative real-time RT-PCR (qRT-PCR). Results. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Selected genes, including ones known to be involved in metabolic regulation, were prioritized for verification by qRT-PCR: Cyp7a1 and Fabp5 were significantly overexpressed in Nrf2-KO mice; in contrast, Car, Cyp2b10, Lipocalin 13, Aquaporin 8, Cbr3, Me1, and Nqo1 were significantly underexpressed in Nrf2-KO mice. Conclusion. Transcriptome profiling after HFD-induced obesity confirms that Nrf2 is implicated in liver metabolic gene networks. The specific genes identified here may provide insights into Nrf2-dependent mechanisms of metabolic regulation.

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Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis

Cited by 9 publications

References 36 publications

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Han Chinese Population: A Replication Study and Meta-Analysis

Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity

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