Article

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: 7.9). 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.

0 Bookmarks
 · 
69 Views
  • [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 01/2014; 9(10):e107656. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus (DM) has emerged into a steadily increasing health problem and the predicted future dimension of the global DM epidemic is alarming: an increase from currently 346 million to over 400 million affected people worldwide by the year 2030 was extrapolated. Thus concerted research efforts are imperative to gain insight into disease mechanisms and to expand the basis for development of preventive and therapeutic strategies. Diabetic rodent models have traditionally been used to follow these goals, but have limitations for translational research. The pig is another classical animal model for diabetes research. Genetic engineering now facilitates tailoring pig models which mimic human disease mechanisms at the molecular level. This article reviews the existing genetically engineered pig models for diabetes research and their current and future applications. Further, the potential role of the pig as donor of pancreatic islets for xenotransplantation or as host for growing human pancreas is outlined.
    Transgenic Research 09/2013; · 2.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The incretin effect describes the augmentation of postprandial insulin secretion by gut hormones. It is not known whether glucagon secretion is also influenced by an incretin effect. A glucagon suppression deficiency has been reported in some patients with type 2 diabetes, but it is unclear whether this abnormality is present prior to diabetes onset. We therefore addressed the questions: (1) Is glucagon secretion different after oral and during intravenous glucose administration? (2) If so, is this related to the secretion of incretin hormones? (3) Is glucagon secretion abnormal in first-degree relatives of patients with type 2 diabetes? We examined 16 first-degree relatives of patients with type 2 diabetes and ten matched control subjects with an oral glucose load (75 g) and with an 'isoglycaemic' intravenous glucose infusion. Glucagon levels were significantly suppressed by both oral and intravenous glucose (p < 0.0001), but glucagon suppression was more pronounced during intravenous glucose administration (76 +/- 2%) than after oral glucose administration (48 +/- 4%; p < 0.001). The differences in the glucagon responses to oral and i.v. glucose were correlated with the increments in gastric inhibitory polypeptide (GIP) (r = 0.60, p = 0.001) and glucagon-like peptide (GLP)-1 (r = 0.46, p < 0.05). There were no differences in glucagon levels between first-degree relatives and control subjects. Despite the glucagonostatic actions of GLP-1, the suppression of glucagon secretion by glucose is diminished after oral glucose ingestion, possibly due to the glucagonotropic actions of GIP and GLP-2. Furthermore, in this group of first-degree relatives, abnormalities in glucagon secretion did not precede the development of other defects, such as impaired insulin secretion.
    Diabetologia 04/2007; 50(4):806-13. · 6.49 Impact Factor

Full-text (2 Sources)

View
79 Downloads
Available from
May 21, 2014