Glucose-Induced Regulation of COX-2 Expression in Human Islets of Langerhans

Centre for Reproduction, Endocrinology and Diabetes, King's College London, London, UK.
Diabetes (Impact Factor: 8.1). 03/2004; 53 Suppl 1(supplement 1):S190-2. DOI: 10.2337/diabetes.53.2007.S190
Source: PubMed


Cyclo-oxygenase (COX), the enzyme responsible for conversion of arachidonic acid to prostanoids, exists as two isoforms. In most tissues, COX-1 is a constitutive enzyme involved in prostaglandin-mediated physiological processes, whereas COX-2 is thought to be induced by inflammatory stimuli. However, it has previously been reported that COX-2 is the dominant isoform in islets and an insulin-secreting beta-cell line under basal conditions. We have investigated the relative abundance of COX-1 and COX-2 mRNAs in MIN6 cells, a mouse insulin-secreting cell line, and in primary mouse and human islets. We found that COX-2 was the dominant isoform in MIN6 cells, but that COX-1 mRNA was more abundant than that of COX-2 in freshly isolated mouse islets. Furthermore, COX-2 expression was induced by maintenance of mouse islets in culture, and experiments with human islets indicated that exposure of the islets to hyperglycemic conditions was sufficient to upregulate COX-2 mRNA levels. Given that hyperglycemia has been reported to increase human beta-cell production of interleukin-1beta and that this cytokine can induce COX-2 expression, our observations of glucose-induced induction of COX-2 in human islets suggest that this is one route through which hyperglycemia may contribute to beta-cell dysfunction.

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    • "We also demonstrated that PTX treatment decreases the number of cyclooxygenase (COX-2) immunopositive cells in diabetic pancreas. COX-2 has been previously reported (Persaud et al. 2004) to be the dominant isoform and insulin-secretor in beta-cells under basal conditions. The observation that hyperglycemia increases the production of IL-1beta in human beta-cells and induces COX-2 expression, led these authors to suggest this to be a route by which hyperglycemia contributes to beta-cell dysfunction. "
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    ABSTRACT: Pentoxifylline (PTX), a methyl xanthine derivative, is a phosphodiesterase inhibitor with anti-inflammatory and renoprotective effects in diabetic patients, among other properties. We studied PTX actions and mechanisms in reducing blood biochemical parameters, in diabetic rats. For diabetes induction, alloxan was intravenously administered to male Wistar rats. One group was left untreated and the other ones treated with PTX (25, 50 and 100 mg/kg), glibenclamide or metformin, as references. Forty-eight hours later and after 1-week to 3-month treatments, blood was collected for determination of glycemia, triglycerides, cholesterol, transaminases, fructosamine and glycated hemoglobin. Afterwards, the animals were euthanized and pancreas, liver and kidney processed for histological analyses and immunohistochemistry assays for TNF-alpha, iNOS and COX-2. The results showed that PTX decreased glycemia and also triglyceride levels, starting 1 week after treatments, as compared to the same group before treatments. Glycemia values were brought towards normality, after 1-month treatment. PTX hypoglycemic effects were potentiated by glibenclamide but not by metformin. It also decreased fructosamine and glycated hemoglobin. Some histological and immunohistochemical alterations for TNF-alpha, iNOS and COX-2 in the diabetic pancreas were also reversed by PTX. We conclude that PTX acts similarly to glibenclamide, and its hypoglycemic actions are, partly, a consequence of ATP-sensitive K + channels inhibition. In addition, by its anti-inflammatory and antioxidant properties, PTX may be a therapeutic alternative for the treatment of diabetes and its complications.
    SpringerPlus 06/2014; 3(1). DOI:10.1186/2193-1801-3-283
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    • "Upregulation of COX-2 expression is involved in various physiological and pathological conditions, including pancreatic β-cell dysfunction. Previous studies indicated that COX-2 activation might play a pathogenic role in diabetes [32–34], and COX-2 inhibition can protect rat islets from cytokine-induced inhibition of glucose-stimulated insulin secretion [13], implicating the important role of COX-2 in cytokine-mediated β-cell dysfunction and diabetes development. Thus, understanding the molecular mechanisms involved in the regulation of COX-2 gene expression in β-cells will help to better understand and restrain the dysfunction of pancreatic β-cell. "
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    ABSTRACT: Cyclooxygenase-2 (COX-2) expression is associated with many aspects of physiological and pathological conditions, including pancreatic β -cell dysfunction. Prostaglandin E2 (PGE2) production, as a consequence of COX-2 gene induction, has been reported to impair β -cell function. The molecular mechanisms involved in the regulation of COX-2 gene expression are not fully understood. We previously demonstrated that transcription factor Elk-1 significantly upregulated COX-2 gene promoter activity. In this report, we used pancreatic β -cell line (INS-1) to explore the relationships between Elk-1 and COX-2. We first investigated the effects of Elk-1 on COX-2 transcriptional regulation and expression in INS-1 cells. We thus undertook to study the binding of Elk-1 to its putative binding sites in the COX-2 promoter. We also analysed glucose-stimulated insulin secretion (GSIS) in INS-1 cells that overexpressed Elk-1. Our results demonstrate that Elk-1 efficiently upregulates COX-2 expression at least partly through directly binding to the -82/-69 region of COX-2 promoter. Overexpression of Elk-1 inhibits GSIS in INS-1 cells. These findings will be helpful for better understanding the transcriptional regulation of COX-2 in pancreatic β -cell. Moreover, Elk-1, the transcriptional regulator of COX-2 expression, will be a potential target for the prevention of β -cell dysfunction mediated by PGE2.
    International Journal of Endocrinology 06/2013; 2013(3):843462. DOI:10.1155/2013/843462 · 1.95 Impact Factor
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    • "The prostaglandin-endoperoxidase synthase enzymes (PTGS1 and PTGS2, i.e., COX-1 and COX-2) catalyze the committed step in the PGE2 synthetic pathway, generating PGH2 from arachidonic acid. PTGS1 is constitutively expressed, whereas the expression of PTGS2 in many cells, including pancreatic islets, is induced by numerous stimuli (23,24). It may be the relatively high level of unstimulated PTGS2 expression that distinguishes pancreatic islet cells from most other cell types (25). "
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    ABSTRACT: BTBR mice develop severe diabetes in response to genetically-induced obesity due to a failure of the β-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that the gene for the EP3 isoform of the prostaglandin E2 (PGE2) receptor, Ptger3, was upregulated with diabetes. The EP3 receptor couples to G proteins of the Gi subfamily to decrease intracellular cyclic AMP (cAMP), blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to β-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide 1 (GLP-1) receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for β-cell dysfunction in T2D.
    Diabetes 01/2013; 62(6). DOI:10.2337/db12-0769 · 8.10 Impact Factor
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