Type 2 diabetes, cardiovascular risk, and the link to insulin resistance

Stolar, Mark W.; Chilton, Robert

doi:10.1016/s0149-2918(03)80240-0

Cited by 53 publications

(38 citation statements)

References 166 publications

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“…Our data are consistent with previous studies that focused on the anti-inflammatory roles of rosiglitazone in kidney diseases; these studies have shown that this PPAR-γ agonist inhibited the expression of many pro-inflammatory cytokines, chemokines, and adhesion molecules by antagonizing the activities of several transcription factors, including AP-1, STAT and NF-ĸB [13,14,15,16,17,18,19]. In the cultured renal mesangial cells, several PPAR agonists, including rosiglitazone, could attenuate IL-1-mediated overexpression of IL-6 and tumor necrosis factor-α (TNF-α), as well as reduce monocyte chemoattractant activity by decreasing NF-ĸB activation and MCP-1 production [20,21,22,23].…”

Section: Discussionsupporting

confidence: 93%

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

Wang¹,

Chen²,

Zhong³

et al. 2011

Am J Nephrol

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Background: Inflammation may play an important role in the pathogenesis of kidney disease. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators. The purpose of this study was to examine the effects of rosiglitazone on lipopolysaccharide (LPS)-induced kidney inflammation and to explore the mechanism of its renoprotection. Methods: Mice were treated with LPS with or without pretreatment with rosiglitazone. Blood urea nitrogen (BUN), creatinine levels, the urinary albumin-to-creatinine ratio, macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, PPAR-γ expression, and NF-ĸB and PPAR-γ activity were investigated. HK-2 cells were maintained under defined in vitro conditions, treated with either rosiglitazone and/or the PPAR-γ antagonist GW9662, and then stimulated with LPS. MCP-1, IL-8, IL-6, NF-ĸB activity and PPAR-γ expression were investigated. Results: Compared to the LPS only group, pretreatment with rosiglitazone in vivo significantly attenuated the BUN levels macrophage infiltration, MCP-1 overexpression and NF-ĸB activity (p < 0.05). Rosiglitazone also restored PPAR-γ expression and protein activity, which were reduced significantly in the LPS only group (p < 0.05). Furthermore, in the LPS-stimulated HK-2 cells, rosiglitazone downregulated MCP-1, IL-8 and IL-6 expression as well as NF-ĸB activation and increased PPAR-γ expression (p < 0.05). These effects were diminished by GW9662. Conclusion: These results showed that pretreatment with rosiglitazone could attenuate kidney inflammation through the activation of PPAR-γ, suppression of MCP-1 overproduction and NF-ĸB activation. Rosiglitazone had a protective effect via a PPAR-γ-dependent pathway in LPS-treated HK-2 cells.

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Section: Discussionsupporting

confidence: 93%

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

Wang¹,

Chen²,

Zhong³

et al. 2011

Am J Nephrol

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“…Similarly, SNP sets associated with metabolic traits, such as 'Fasting blood glucose', 'HDL/LDL cholesterol', were the most frequently enriched in regulatory datasets from pancreatic islets, adipose tissue, liver. Notably, we observed 'Fasting blood glucose' and 'Type 2 diabetes' as being enriched in 'Fetal heart'-specific regulatory datasets (P-values 3.24E-22 and 4.65E-28, respectively), confirming well-known link between diabetes and cardiovascular diseases (reviewed in Stolar and Chilton, (2003). Other trait-associated SNP sets also showed relevant cell type specificity of the regulatory enrichments, such as 'creatine levels' association with lung fibroblast primary cells (P-value 1.57E-21) and muscle cells, 'bone mineral density' association with chondrodyte cells (P-value 1.95E-22) and other similar observations (Supplementary Table S7).…”

Section: Cell Type Regulatory Enrichment Analysis Identifies Known Cesupporting

confidence: 76%

GenomeRunner web server: regulatory similarity and differences define the functional impact of SNP sets

et al. 2016

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Motivation: The growing amount of regulatory data from the ENCODE, Roadmap Epigenomics and other consortia provides a wealth of opportunities to investigate the functional impact of single nucleotide polymorphisms (SNPs). Yet, given the large number of regulatory datasets, researchers are posed with a challenge of how to efficiently utilize them to interpret the functional impact of SNP sets. Results: We developed the GenomeRunner web server to automate systematic statistical analysis of SNP sets within a regulatory context. Besides defining the functional impact of SNP sets, GenomeRunner implements novel regulatory similarity/differential analyses, and cell type-specific regulatory enrichment analysis. Validated against literature-and disease ontology-based approaches, analysis of 39 disease/trait-associated SNP sets demonstrated that the functional impact of SNP sets corresponds to known disease relationships. We identified a group of autoimmune diseases with SNPs distinctly enriched in the enhancers of T helper cell subpopulations, and demonstrated relevant cell type-specificity of the functional impact of other SNP sets. In summary, we show how systematic analysis of genomic data within a regulatory context can help interpreting the functional impact of SNP sets. Availability and Implementation: GenomeRunner web server is freely available at http://www.inte grativegenomics.org/. Contact:

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“…It is associated with considerable morbidity and mortality, particularly involving cardiovascular (CV) complications. Such complications include accelerated atherosclerosis, myocardial infarction and stroke, as well as increased rates of heart failure [2].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitors and Cardiovascular Outcomes: Meta‐Analysis of Randomized Clinical Trials with 55,141 Participants

Hopper

Skiba

et al. 2014

Cardiovascular Therapeutics

119

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Aims:The association between glucose lowering in diabetes mellitus and major cardiovascular (CV) outcomes is weak; indeed, some oral hypoglycemic agents are associated with increased CV events. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are a new class of oral hypoglycemic agent that may have beneficial CV effects. We undertook a systematic review and meta-analysis to appraise the CV safety and efficacy of DPP-4 inhibitors. Methods: Comprehensive search for prospective trials involving DPP-4 inhibitors. Trials included reported at least one of the outcomes examined, recruited minimum 100 patients and minimum follow-up 24 weeks. The risk ratio (RR) was calculated using the MantelHaenszel random-effects model for mortality and major cardiovascular (CV) outcomes. Results: Fifty trials enrolling 55,141 participants were included. Mean follow-up 45.3 weeks. DPP-4 inhibitors compared with all comparators (placebo and active) showed no difference in all-cause mortality (n = 50,982, RR = 1.01, 95% CI 0.91-1.13, P = 0.83), CV mortality (n = 48,151, RR = 0.97, 95% CI 0.85-1.11, P = 0.70), acute coronary syndrome (ACS) (n = 53,034 RR = 0.97, 95% CI 0.87-1.08, P = 0.59), or stroke (n = 42,737, RR = 0.98, 95% CI 0.81-1.18, P = 0.80), and a statistically significant increase in heart failure outcomes (n = 39,953, RR = 1.16, 95% CI 1.01-1.33, P = 0.04). Discussion: Treatment with DPP-4 inhibitors compared with placebo shows no increase in risk with regards to all-cause mortality, CV mortality, ACS, or stroke, but a statistically significant trend toward increased risk of HF outcomes. Conclusion: These findings suggest no cardiovascular harm (or benefit) with DPP-4 inhibitors; further large-scale CV outcome studies will resolve the issue of excess HF risk.

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Type 2 diabetes, cardiovascular risk, and the link to insulin resistance

Cited by 53 publications

References 166 publications

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

GenomeRunner web server: regulatory similarity and differences define the functional impact of SNP sets

Dipeptidyl Peptidase‐4 Inhibitors and Cardiovascular Outcomes: Meta‐Analysis of Randomized Clinical Trials with 55,141 Participants

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