Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets

Metz, Stewart A.

doi:10.1016/0006-2952(89)90421-8

Cited by 11 publications

(4 citation statements)

References 58 publications

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“…Islets permeabilization was assessed by uptake tests of eosin G dye (624 Da). Almost all islet cells were permeable to the dye (Figure 1a), similar to a previous report 34.…”

Section: Methodssupporting

confidence: 90%

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Hashiguchi

Nakazaki

Koriyama

et al. 2005

Diabetes Metabolism Res

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“…Islets permeabilization was assessed by uptake tests of eosin G dye (624 Da). Almost all islet cells were permeable to the dye (Figure 1a), similar to a previous report 34.…”

Section: Methodssupporting

confidence: 90%

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Hashiguchi

Nakazaki

Koriyama

et al. 2005

Diabetes Metabolism Res

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“…AA stimulates insulin release in islets when calcium is removed from the medium (because calcium chelates AA). Insulin secretion was independent of further AA metabolism by lipoxygenase enzymes, as it was not prevented by lipoxygenase inhibitors (31). Treatment of rat islets with p-hydromercuribenzoic acid, an inhibitor of arachidonylCoA synthase and/or lysophos-phatidyl/acyl-CoA transferase (32), prevented reacylation of lysophospholipids with AA, resulting in insulin release at 1.7 mM glucose and potentiation of insulin release at 16.7 mM glucose (33).…”

Section: Figurementioning

confidence: 99%

Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice

Bleich¹,

Chen²,

Zipser³

et al. 1999

J. Clin. Invest.

149

117

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The leukocyte 12-lipoxygenase (12-LO) gene is expressed in pancreatic β cells and macrophages. Products of the 12-LO enzyme are proinflammatory and may be involved in immune-mediated conditions, but formal proof of this hypothesis is lacking. Leukocyte 12-LO is preferentially expressed over 5-and 15-lipoxygenase in pancreatic β cells and may be involved in cytokine-mediated β-cell damage through generation of the lipid hydroperoxide 12-hydroperoxyeicosatetraenoic acid (12-HPETE) (1-7). Reduction of 12-HPETE to 12-hydroxyeicosatetraenoic acid (12-HETE) is facilitated by the enzyme glutathione peroxidase, and recent work has demonstrated that 12-LO inhibitors can prevent glutamate-induced neuronal cell death when intracellular glutathione stores are depleted (8). Both neuronal cell death and peroxide generation required 12-LO activity in this model and were prevented by treatment with a lipoxygenase inhibitor, baicalein (10 µM). Furthermore, the proinflammatory cytokine IL-1β was shown to increase 12-LO product formation in pancreatic islets (9, 10), whereas nordihydroguaiaretic, a lipoxygenase inhibitor, protected rat islet cells from cytokine-induced destruction (11). Given that 12-HPETE and/or other 12-LO products may damage pancreatic β cells through lipid peroxidation, it is possible that inhibition of the 12-LO pathway may protect pancreatic β cells from cytotoxic conditions.To test this hypothesis, we administered low-dose streptozotocin (STZ) to 12-LO knockout (12-LO KO) mice and genetic controls to evaluate the development of diabetes. In addition, we isolated pancreatic islets and tested them for sensitivity to cytokine-induced dysfunction. We also evaluated the capacity of macrophages to generate nitric oxide (NO) and superoxide when stimulated. We chose the low dose STZ-induced diabetic model because previous studies have demonstrated that β-cell destruction is mediated in part by generation of free radicals and lipid hydroperoxides as well as by immune activation (12, 13). 12-LO KO mice were generated by homologous recombination in embryonic stem cells, as described previously (14).In the present study, we found that 12-LO KO mice were significantly more resistant to STZ-induced diabetes than were C57BL/6 controls and that islets purified from 12-LO KO mice were protected from cytokine-induced dysfunction. Furthermore, macrophages from 12-LO KO mice generated ∼50% of the nitrate/nitrite compared with macrophages from control C57BL/6 mice. Leukocyte 12-lipoxygenase (12-LO) gene expression in pancreatic β cells is upregulated by cytotoxic cytokines like IL-1β. Recent studies have demonstrated that 12-LO inhibitors can prevent glutamateinduced neuronal cell death when intracellular glutathione stores are depleted. Therefore, 12-LO pathway inhibition may prevent β-cell cytotoxicity. To evaluate the role of 12-LO gene expression in immune-mediated islet destruction, we used 12-LO knockout (12-LO KO) mice. Male homozygous 12-LO KO mice and control C57BL/6 mice received 5 consecutive daily injections of low-...

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“…The inhibitory effects of PGE 2 on insulin release from HIT cells (69) suggest that the occasional reports of stimulatory effects of PGE represent the superimposition of a second effect such as stimulation by PGE of glucagon release (71). In contrast, lipoxygenase products appear principally to sensitize the exocytotic apparatus to Ca 2+ (72) and thereby increase secretion. Perhaps they interact with G e (vide supra); alternatively, islet lipoxygenase may serve to make phospholipid substrate more vulnerable to phospholipase-induced hydrolysis (reviewed in 73).…”

Section: What Are the Effects And Mechanisms Of Phospholipase-derivedmentioning

confidence: 99%

“…Studies of the lipoxygenase pathway have chiefly involved the use of multiple, structurally dissimilar pharmacological inhibitors. Some (albeit not all) of the concern about the potential nonspecific effects of these probes on islet function has been addressed (5,72,74). Nonetheless, the exact metabolite or metabolites of AA that are involved remain to be conclusively identified, leaving a residual uncertainty about the role of lipoxygenase.…”

Section: What Are the Effects And Mechanisms Of Phospholipase-derivedmentioning

confidence: 99%

The Pancreatic Islet as Rubik's Cube: Is Phospholipid Hydrolysis a piece of the Puzzle?

Metz

1991

Diabetes

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At least three types of phospholipase exist in the beta-cells of the pancreatic islet. Data regarding their physiological activation are incomplete but suggest that glucose (or its metabolite glyceraldehyde) either activates or potentiates the activation of several phospholipases. At least seven phospholipid hydrolysis by-products (diacylglycerol, myo-inositol 1,4,5-trisphosphate, lysophospholipids, arachidonic acid and its cyclooxygenase- and lipoxygenase-derived metabolites, phosphatidate) have been demonstrated to have effects compatible with their postulated roles as mediators or modulators of islet function. Presumptive mechanisms of action have been tentatively identified for these metabolites. However, key studies in the puzzle are missing, and current methodologies have important limitations. Shortcomings include the paucity of measurements of the mass of metabolites; the frequent use of static incubations rather than perfusions; a lack of complete time- and agonist concentration-dependence curves; the equation of metabolite accumulation with rates of metabolite generation (which ignores metabolite removal as a key variable); the use of nonspecific, insensitive, or ambiguous phospholipase assays; and the need for more studies directly correlating lipid metabolism and insulin secretion in physiologically functioning preparations. Like Rubik's Cube, the pancreatic islet is a dynamic puzzle comprised of many interrelated components requiring proper alignment and integration. Phospholipid turnover is one "panel" in the islet; however, an obligate role for phospholipase activation in glucose-induced insulin secretion is not yet rigorously established, despite tantalizing, inferential evidence. It may be that glucose serves principally to potentiate the phospholipase and secretory responses to other signals that act by initiating phospholipid hydrolysis.

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Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets

Cited by 11 publications

References 58 publications

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice

The Pancreatic Islet as Rubik's Cube: Is Phospholipid Hydrolysis a piece of the Puzzle?

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Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets

Cited by 11 publications

References 58 publications

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca2+ and ATP in rat islet β‐cells

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca2+ and ATP in rat islet β‐cells

Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice

The Pancreatic Islet as Rubik's Cube: Is Phospholipid Hydrolysis a piece of the Puzzle?

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Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells

Cyclic AMP/cAMP‐GEF pathway amplifies insulin exocytosis induced by Ca²⁺ and ATP in rat islet β‐cells