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: 8.47). 03/2004; 53 Suppl 1:S190-2. DOI: 10.2337/diabetes.53.2007.S190
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Group X secretory phospholipase A2 (GX sPLA2) potently hydrolyzes membrane phospholipids to release arachidonic acid (AA). While AA is an activator of glucose-stimulated insulin secretion (GSIS), its metabolite prostaglandin E2 (PGE2) is a known inhibitor. In this study, we determined that GX sPLA2 is expressed in insulin-producing cells of mouse pancreatic islets and investigated its role in beta cell function. GSIS was measured in vivo in wild-type (WT) and GX sPLA2-deficient (GX KO) mice and ex vivo using pancreatic islets isolated from WT and GX KO mice. GSIS was also assessed in vitro using mouse MIN6 pancreatic beta cells with or without GX sPLA2 overexpression or exogenous addition. GSIS was significantly higher in islets isolated from GX KO mice compared to islets from WT mice. Conversely, GSIS was lower in MIN6 cells overexpressing GX sPLA2 (MIN6-GX) compared to control (MIN6-C) cells. PGE2 production was significantly higher in MIN6-GX cells compared to MIN6-C cells and this was associated with significantly reduced cellular cAMP. The effect of GX sPLA2 on GSIS was abolished when cells were treated with NS-398 (a COX-2 inhibitor) or L-798,106 (a PGE2 EP3 receptor antagonist). Consistent with enhanced beta cell function, GX KO mice showed significantly increased plasma insulin levels following glucose challenge and were protected from age-related reductions in GSIS and glucose tolerance compared to WT mice. We conclude that GX sPLA2 plays a previously unrecognized role in negatively regulating pancreatic insulin secretion by augmenting COX-2 dependent PGE2 production.
    Journal of Biological Chemistry 08/2014; 289(40). DOI:10.1074/jbc.M114.591735 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation.
    PLoS ONE 10/2014; 9(10):e107656. DOI:10.1371/journal.pone.0107656 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aspirin (ASA), as a multifunctional drug has been used as a hypoglycaemic agent in the treatment of diabetes and severe hyperglycaemia and has been established as a secondary strategy which may prevent many cardiovascular events. In this study we investigated high dose (100 mg/kg b.w./i.p) and time-dependent (2, 7 and 14 days) effects of ASA on the heart key enzymes and substrates from glycogen/glucose metabolism in control and diabetic rats. The results accomplished demonstrated that ASA significantly potentiates glycogen accumulation, as well as decreased blood glucose level and heart glycolytic potential in control rats. The treatment of diabetic rats with ASA caused moderation of the diabetic complication-significant inhibition of glycogen accumulation, lowering of blood glucose, as well as elevation of glycolytic potential. In conclusion, we propose that use of high-dose of ASA has anabolic effects in control rats and reduces heart glycogen glucose complications in diabetic rats. The moderation of diabetes-induced changes is time-dependent and involves reduction of glycogenogenesis and inhibited depression of glycolysis, with a tendency to maintenance control values.
    The Journal of Physiological Sciences 09/2014; 64(6). DOI:10.1007/s12576-014-0335-6 · 1.25 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014