Inhibition of Cyclooxygenase-1 or -2 on Insulin Sensitivity in Healthy Subjects

González-Ortı́z, Manuel; Martı́nez-Abundis, Esperanza; Br, Balcázar-Muñoz; Ja, Robles-Cervantes

doi:10.1055/s-2001-14949

Cited by 31 publications

(23 citation statements)

References 11 publications

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“…Knockout of 12,15-lipoxygenase, an enzyme converting arachidonic acid to hydroperoxide metabolites, prevents obesity, insulin resistance, and adipose tissue inflammation induced by high-fat diet in mice [9]. Pharmacological inhibition of cyclooxygenase-1or cyclooxygenase-2 has also been shown to improve insulin sensitivity in both rodents and humans [10,11]. Collectively, these data strongly support the importance of prostaglandin metabolism in adipocyte physiology.…”

Section: Introductionsupporting

confidence: 54%

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

et al. 2012

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Prostaglandins are potent modulators of insulin sensitivity. We systemically evaluated the association of 61 tag single-nucleotide polymorphisms (SNP) in 14 genes involved in prostaglandin metabolism with type 2 diabetes. Among all genotyped SNPs, rs10483032 in the CBR3 (carbonyl reductase 3) gene, which encodes for an enzyme converting prostaglandin E(2) to prostaglandin F2(α), was associated with type 2 diabetes in 760 type 2 diabetic cases and 760 controls (stage-1 study) (P = 2.0 × 10(-4)). The association was validated in 1,615 cases and 1,162 controls (stage-2 study) (P = 0.009). The A allele at rs10483032 was associated with increased risk of type 2 diabetes (odds ratio = 1.29; 95% confidence interval = 1.14-1.47; combined P < 0.0001). The association was externally validated in the Finland-United States Investigation of NIDDM Genetics (FUSION) study (P = 3.7 × 10(-4)). The risk A allele was associated with higher homeostasis model assessment of insulin resistance (HOMA-IR) in 1,012 non-diabetic controls and 1,138 non-diabetic subjects from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. CBR3 gene expression in human abdominal adipose tissue was negatively associated with fasting insulin and HOMA-IR. CBR3 gene expression increased during differentiation of 3T3-L1 preadipocytes into adipocytes. Knockdown of CBR3 in 3T3-L1 preadipocytes enhanced adipogenesis and peroxisome proliferator-activator receptor-γ response element reporter activity. Our results indicated that genetic polymorphism in the CBR3 gene conferred risk of type 2 diabetes and insulin resistance in Chinese. The association was probably mediated through modulation of adipogenesis.

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Section: Introductionsupporting

confidence: 54%

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

et al. 2012

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“…For example, in humans, in addition to reports of improved insulin sensitivity (10,6,41,7), several reports describe worsening of insulin resistance (42–44) or attribute improved metabolism to an increase in insulin concentrations (9). Here, we confirm variable efficacy of salicylate in different settings.…”

Section: Discussionmentioning

confidence: 99%

“…Salicylate anti-inflammatory agents, including acetylsalicylic acid (aspirin) and salicylsalicylic acid (salsalate) (1), improve insulin sensitivity in animal models (2–5) and in healthy or obese humans (6–9) and improve glycemic control in patients with type 2 diabetes (10–12). The mechanism of insulin sensitization is uncertain and may involve blockade of inhibitor of κB kinase-β and, hence, nuclear factor-κB effects (13,3,14) and/or interference with phosphorylation and activity of CCAAT enhancer binding protein-β (a transcription factor involved in metabolic and inflammatory pathways) (15,16), with associated reductions in proinflammatory cytokines.…”

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confidence: 99%

Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization

et al. 2012

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Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1–deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with 3H-steroid. Two weeks’ administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1–deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates.

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“…COX2 gene expression is induced in livers of diet-induced and genetic obesity mouse models (Henkel et al 2012). Pharmacological inhibition of COX2 has also been shown to improve insulin sensitivity in both rodents and humans (Gonzalez-Ortiz et al 2001, Hsieh et al 2008). Furthermore, PGE2, which is released from adipose tissue (Lappas et al 2005a), can also attenuate insulin signalling (Henkel et al 2009).…”

Section: Figurementioning

confidence: 99%

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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Inhibition of Cyclooxygenase-1 or -2 on Insulin Sensitivity in Healthy Subjects

Cited by 31 publications

References 11 publications

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

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

Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization

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

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