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      The COX-2/PGE 2/EP3/G i/o/cAMP/GSIS Pathway in the Islet: The Beat Goes On

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      Diabetes

      American Diabetes Association

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          Abstract

          Interest in regulation of glucose-induced insulin secretion (GSIS) by arachidonic acid (AA) metabolites began in the early 1970s. The metabolite of primary interest has been prostaglandin E2 (PGE2) because it is one of several negative modulators of GSIS yet unique because it is not classified as a hormone, such as epinephrine or somatostatin. Rather, PGE2 is considered an autocoid because it is a substance whose action takes place in the same cell as its synthesis, which in the case of the pancreatic β-cell suggests PGE2 is an endogenous modulator of GSIS. This autocoid, produced via cleavage of AA from phospholipid and further metabolism by cyclooxygenase-2 (COX-2), is the most abundant AA metabolite in the β-cell. The article in this issue of Diabetes by Neuman et al. (1) takes a fresh look at this pathway by focusing on PGE3, an alternate prostaglandin formed when eicosapentaenoic acid (EPA) rather than AA is used as the dominant dietary substrate. (Before reading further, it may be helpful to examine Table 1 of the article by Neuman et al., which identifies the players in this complex lexicon.) Clinical relevance of this consideration of the impact of a diet rich in EPA stems from the fact that this polyunsaturated fatty acid is proposed to be beneficial in chronic conditions such as diabetes. Historically, long before the discovery of prostaglandins, Ebstein (2) reported in 1876 that treatment of his patients with diabetes with oral sodium salicylate reduced urinary glucose levels. It took nearly 100 years for the Nobel prize–winning work of Vane (3) and his colleagues to establish that nonsteroidal anti-inflammatory drugs, such as sodium salicylate, used inhibition of the COX-2 pathway as a major mechanism of action (4). At roughly the same time, several investigative groups were performing experiments in vitro with static incubation of isolated islets or in vivo by infusing PGE2 in animals and humans (5–8) with variable and sometimes contrary results. The result of our own work found consistently that PGE2 inhibited first-phase GSIS specifically and did not inhibit first-phase insulin release in response to nonglucose secretagogues (reviewed in Robertson [9]). The mechanism of action for this inhibitory effect was later discovered in 1987 to involve PGE2-specific binding sites on the plasma membrane of isolated primary mammalian islets as well as the β-cell line HIT-T15, with its postreceptor (EP3) effect of pertussis toxin–sensitive Gi/o protein activation and a decline of cAMP levels (10). Eighteen years later, Kimple et al. (11) published work studying PGE1 rather than PGE2 action in the Ins-1(832/13) β-cell–derived line and reported that the PGE1 effect to inhibit GSIS was not pertussis toxin–sensitive. They identified GαZ as the inhibitory G-protein involved in PGE1 action in their cell line. More recent information using advanced molecular and genetics-based technology has confirmed the inhibitory effects of PGE2 on β-cell structure and function (12,13). The question asked by Neuman et al. (1) was whether shifting plasma membrane polyunsaturated fatty acid composition to favor EPA would alter prostaglandin production toward formation of PGE3 and thereby diminish PGE2 signaling and enhance β-cell function. The authors designed an extensive series of experiments featuring methodologies using BTBR wild-type mice, Leptinob/ob (Ob) mice, and NOD mice; EPA-enriched diets; islet isolation and GSIS; lipid extraction and gas chromatography; cDNA synthesis and gene expression; islet imaging; and PGE2 ELISA. They observed that an AA-enriched diet accelerated the development of diabetes, whereas the EPA-enriched diet shifted prostaglandin production to favor PGE3 as opposed to PGE2 and enhanced GSIS. Notably, they reported that both PGE2 and PGE3 reduced GSIS from BTBR-Ob islets in a dose-dependent manner but that the IC50 for this reduction was 10-fold weaker for PGE3, the effects of both were fully competed by a specific EP3 antagonist, and the EPA-enriched diet also reduced EP3 gene expression fivefold. Other experiments examined the effects of interleukin-1β (IL-1β) on prostaglandin production in BTBR-Ob islets. The study by Neuman et al. confirmed earlier work that showed this cytokine increases COX-2 mRNA levels (14–16) but found uniquely that this effect was diminished by dietary EPA enrichment. The beauty of these experiments lies in the use of dietary manipulation to assess the pathophysiological role of PGE2 in abnormal β-cell function in animal models of diabetes. This approach is more elegant than previously published work that was dependent on the use of pharmacological agents, such as nonsteroidal inflammatory drugs, which by their very nature are nonspecific tools. Dietary enrichment of EPA depends on substrate-driven enhancement of endogenous prostaglandins, which can be measured to document the magnitude of shift in product without concern for off-target effects of drugs that provide only nonspecific enzyme inhibition. In this sense, the work of Neuman et al. puts to rest any lingering doubt that PGE2 is an endogenous inhibitor of GSIS. Does this now mean that no work is left to be done in the research area of prostaglandins and islet function? Not at all. Quite the contrary. Development of therapeutic agents for humans with diabetes and abnormal β-cell function that will suppress inhibitory prostaglandins has not been robust. As illustrated in Fig. 1, there are many attack points that could be used to develop new β-cell–specific therapeutic agents that interrupt PGE2 synthesis or antagonize the postreceptor actions of EP3, especially in states of inflammation that involve IL-1β and perhaps other cytokines that can harm islets. Further laboratory work with islets is needed to better characterize enzymatic pathways in the AA cascade to verify that the islet does or does not conform to conventional thinking about regulation of prostaglandin production. Very little is known about the final step in PGE2 synthesis. In most cells, a set of proteins termed prostaglandin synthases are responsible for the final fine-tuning of the regulation of prostaglandins. Work in this area has indicated that generally regulation of PGE2 in the basal state is regulated by the enzyme cPGES, whereas mPGES-1 regulates cytokine-stimulated PGE2 production. However, we reported in a recent publication the unanticipated discovery that mPGES-1 mRNA and protein is absent in mouse, rat, and human islets (17). This leaves COX-2 itself as the sole regulator of PGE2 synthesis, which carries the implication that drug discovery efforts designed to block PGE2 synthesis should not focus on inhibiting mPGES-1 activity. Rather, pharmacological development of specific inhibitors of β-cell COX-2 that do not affect COX-2 in other cells is a goal that is much more likely to provide a drug that will benefit people with type 2 diabetes and intrinsically impaired GSIS as well as that induced by cytokines. So, I invite you to listen to this developing story as the beat goes on. Figure 1 The COX-2/PGE2/EP3/Gi/o/cAMP/GSIS pathway in the β-cell. The mechanism for IL-1β stimulation of PGE2 synthesis is via increasing COX-2 mRNA and protein levels, which in the presence of AA increase synthesis of PGE2, which in turn binds to its receptor EP3. The postreceptor mechanism of action for EP3 is mediated by an increase in Gi/o activity, which in turn decreases intracellular cAMP levels with a consequent decrease in GSIS. When EPA rather than AA is the dominantly available substrate, PGE3 rather than PGE2 synthesis is favored. PGE3 has only one-tenth of the PGE2 efficacy to decrease GSIS (1). NS-398 and SC-236 are COX-2 inhibitors. Misoprostol is an EP3 agonist. Information taken from Robertson et al. (10), Tran and colleagues (14,15), and Seaquist and colleagues (18,19). IκB, inhibitor of κB; NF-κB, nuclear factor-κB.

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          Most cited references 19

          • Record: found
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          Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.

           J R Vane (1971)
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            Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function.

            Previous work has suggested that functional interrelationships may exist between inhibition of insulin secretion by interleukin (IL)-1beta and the endogenous synthesis of prostaglandin E(2) (PGE(2)) in the pancreatic islet. These studies were performed to ascertain the relative abundance of E prostaglandin (EP) receptor mRNAs in tissues that are major targets, or major degradative sites, of insulin; to identify which EP receptor type mediates PGE(2) inhibition of insulin secretion in pancreatic islets; and to examine possible sites of action through which sodium salicylate might affect IL-1beta/PGE(2) interactions. Real-time fluorescence-based RT-PCR indicated that EP3 is the most abundant EP receptor type in islets, liver, kidney, and epididymal fat. EP3 mRNA is the least, whereas EP2 mRNA is the most, abundant type in skeletal muscle. Misoprostol, an EP3 agonist, inhibited glucose-induced insulin secretion from islets, an event that was prevented by preincubation with pertussis toxin, by decreasing cAMP. Electromobility shift assays demonstrated that sodium salicylate inhibits IL-1beta-induced nuclear factor-kappaB (NF-kappaB) activation. Sodium salicylate also prevented IL-1beta from inducing EP3 and cyclooxygenase (COX)-2 gene expression in islets and thereby prevented IL-1beta from inhibiting glucose-induced insulin secretion. These findings indicate that the sites of action through which sodium salicylate inhibits these negative effects of IL-1beta on beta-cell function include activation of NF-kappaB as well as generation of PGE(2) by COX-2.
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              • Record: found
              • Abstract: found
              • Article: not found

              Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets.

              Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E(2) (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE(2) signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                June 2017
                15 May 2017
                : 66
                : 6
                : 1464-1466
                Affiliations
                Pacific Northwest Diabetes Research Institute and Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN
                Author notes
                Corresponding author: R. Paul Robertson, rpr@ 123456pnri.org .
                Article
                0017
                10.2337/dbi17-0017
                5440014
                28533298
                © 2017 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 19, Pages: 3
                Product
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases grants
                Award ID: RO1-39994 (27)
                Award ID: RO1-38325 (35)
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                Endocrinology & Diabetes

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