Investigation into the association between NLRP3 gene polymorphisms and susceptibility to type 2 diabetes mellitus

S, Wang; Fang, Fude; Wb, Jin; Wang, X; Xs, Zheng

doi:10.4238/2015.december.21.15

Cited by 26 publications

(27 citation statements)

References 16 publications

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“…For example, PPP1R3B, which was differentially methylated in our study, codes for the G L regulatory subunit of protein phosphatase 1 (PP1), which targets PP1 to activate glycogen synthase, thereby increasing insulin sensitivity of liver and skeletal muscle [35,36]. A decreased rate of glycogen synthesis in the skeletal muscle in response to insulin is a characteristic feature of individuals with type 2 diabetes [37], and polymorphisms in another regulatory subunit (PPP1R3A), which also targets PP1 activation of glycogen synthase in the skeletal muscle, were associated with insulin resistance and type 2 diabetes in several different populations [38][39][40][41][42]. Differential methylation of a second gene, PM20D1, could also affect insulin sensitivity via its effect on body weight.…”

Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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Aims/hypothesis Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND). Methods DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed. Results Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10 −5 ). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10 −5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10 ) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways. Conclusions/interpretation Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.

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Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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“…The inflammasome, can be activated by metabolic damage and by infection, has also been proposed to be involved in the pathogenesis of periodontal disease and T2D (Huang et al, ). Inflammasome activation by pathogen‐associated molecular patterns (PAMPs) or by host‐derived danger‐associated molecular patterns (DAMPs) incites a conformational change in the multi‐protein complex and triggers the activation of caspase‐1 and ‐5, proteases required for the activation of pro‐inflammatory cytokines IL‐18 and IL‐1β (Wang, Fang, Jin, Wang, & Zheng, ; Xue, Shu, & Xie, ). NLR family pyrin domain containing 3 (NLRP3) is the most studied and characterised inflammasome, and it contains the adaptor protein apoptosis‐associated speck like protein (ASC) (Schroder, Zhou, & Tschopp, ).…”

Section: Introductionmentioning

confidence: 99%

“…Inflammasome activation by pathogen-associated molecular patterns (PAMPs) or by host-derived danger-associated molecular patterns (DAMPs) incites a conformational change in the multi-protein complex and triggers the activation of caspase-1 and -5, proteases required for the activation of pro-inflammatory cytokines IL-18 and IL-1β (Wang, Fang, Jin, Wang, & Zheng, 2015;Xue, Shu, & Xie, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…NLR family pyrin domain containing 3 (NLRP3) is the most studied and characterised inflammasome, and it contains the adaptor protein apoptosis-associated speck like protein (ASC) (Schroder, Zhou, & Tschopp, 2010). Recent findings indicate that NLRP3 polymorphisms are associated with the development of T2D (Wang et al, 2015) and that the expression of mRNAs for NLRP3 and IL-1β is elevated in the periodontium in patients with periodontitis (Bostanci et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of proteins of the NLRP3 inflammasome in patients with periodontitis and uncontrolled type 2 diabetes

et al. 2018

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Objectives To evaluate the expression of proteins related to activation of the NLRP3 inflammasome in patients with chronic periodontitis (CP) and type 2 diabetes mellitus (T2D), and to determine whether the exacerbated periodontal pathological process observed in diabetic patients is related to its upregulation. Materials and Methods We performed an observational, analytical, cross‐sectional study in three study groups: individuals systemically and orally healthy, and patients with CP with and without T2D. Gingival biopsies were taken from the three study groups. The expression of mRNAs for CASP1, NLRP3 and ASC was detected using real‐time PCR, and the expression of NLRP3 and ASC proteins was determined by immunohistochemistry. The quantification of IL‐18 and IL‐1β was determined in the gingival crevicular fluid using ELISA. The results were analysed by ANOVA followed by Tukey's test to compare differences between individual groups. Results Patients with CP and uncontrolled T2D presented severe periodontal disease and inflammation (PPD, p = 0.0072; CAL, p = 0.0480; bone loss, p = 0.0088), higher levels of CASP1 mRNA expression (p = 0.0026), a stronger pattern of staining for NLRP3 and ASC proteins in the epithelium and connective tissues, and significantly higher production of IL‐18 (p = 0.0063) and IL‐1β (p = 0.0018) in comparison with healthy or CP subjects. Conclusion The upregulation of genes and proteins involved in the activation of the NLRP3 inflammasome components in patients with periodontitis and uncontrolled T2D suggests a possible role in the more severe pathological processes leading to destruction of periodontal tissues observed in these patients.

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“…The prospective clinical relevance of this strategy is also supported by recent investigations on the influence of genetic variability in inflammasome on longterm cardiovascular complications in diabetic patients. A few studies have reported a relationship between NLRP3 genetic polymorphisms and development of type 2 diabetes [189,190] and, most notably, a specific polymorphic NLRP3 allele has been reported to be associated with increased risk for development of macrovascular complications in subjects with long-term diabetes [191].…”

Section: Nlrp3 Inflammasome Inhibitors -mentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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Investigation into the association between NLRP3 gene polymorphisms and susceptibility to type 2 diabetes mellitus

Cited by 26 publications

References 16 publications

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Upregulation of proteins of the NLRP3 inflammasome in patients with periodontitis and uncontrolled type 2 diabetes

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

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