Fuel Metabolism as a Determinant of Arachidonic Acid Release and Oxygenation

Studies with Intact Rat Islets of Langerhans
  • Stewart A. Metz
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


A variety of stimuli (such as bradykinin, angiotensin, and vasopressin) are believed to interact with cell-surface receptors and evoke a release of arachidonic acid (AA) and its oxygenated metabolites in many cells. One link between the two events is presumed to be the activation of calcium-dependent phospholipases (or possibly calcium-dependent lipoxygenases; Ochi et al.,1983), possibly in some cases via mediation by calmodulin. This Ca2+ might arise from extracellular sources (for example, the calcium influx induced via cell depolarization), in which case the release of the oxygenated products of AA can be blocked by Ca2+ channel blockers (Levine, 1983), or from intracellular stores (blockable by TMB-8, which putatively inhibits release of Ca2+ from intracellular sources; cf. Rittenhouse-Simmons and Deykin, 1978). Alternatively, it has been suggested that receptor occupation can directly activate a phospholipase C, leading to degradation of acidic polyphos-phoinositides. Such breakdown could release membrane-bound Ca2+ (Broekman, 1984), and the concomitant release of inositol phosphates could promote release of Ca2+ from intracellular stores (Streb et al., 1983). Such accumulation of Ca2+ could then potentiate AA release. Whatever the sequence of events leading to arachidonate release in a given cell, the initiating event has usually been considered to take place at the cell surface. In contrast, a possible role for fuel metabolism and related intracellular events in AA release and/or metabolism has received almost no attention. To examine the possibility of such a role, we studied the effect of one fuel (glucose) on the release of the lipoxygenese product 12-hydroxy-eicosatetraenoic acid (12-HETE) from a glucose-sensitive organ, intact rat islets of Langerhans.


Arachidonic Acid Insulin Secretion Pancreatic Islet Insulin Release Arachidonic Acid Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe. M., Ohno, K., Sato. R.. 1984, Possible identity of lysolecithin acyl-hydrolase with lysolecithin, lysolecithin acyl-transferase in rat-lung soluble fraction, Biochem. Biophys. Acta. 369:361–70.Google Scholar
  2. Agardh, C.-D., Westerberg, E.. and Siesjö, B.K., 1980, Severe hypoglycemia leads to accumulation of arachidonic acid in brain tissue, Acta Physiol. Scand. 109:115–116.PubMedCrossRefGoogle Scholar
  3. Ashcroft, S. J. H. 1981, Metabolic control of insulin secretion, in: The Islets of Langerhans: Biochemistry, Physiology and Pathology (S. J. Cooperstein and D. Watkins, eds.), Academic Press, New York. pp. 117–148.Google Scholar
  4. Ashcroft, S.J.H., Hedeskov, C.J., and Randle, P.J., 1970, Glucose metabolism in mouse pancreatic islets, Biochem. J. 118:153–154.Google Scholar
  5. Bellomo, G., Jewell, S.A., Thor, H., and Orrhenius, S., 1982, Regulation of intracellular calcium compartments: Studies with isolated hepatocytes and t-butyl hydroperoxide, Proc. Natl. Acad. Sci. U.S.A. 79:6842–6846.PubMedCrossRefGoogle Scholar
  6. Best, L., and Malaisse, W.J., 1983, Effects of nutrient secretagogues upon phospholipid metabolism in rat pancreatic islets, Mol. Cell Endocrinol. 32:205–214.PubMedCrossRefGoogle Scholar
  7. Broekman, M.J., 1984, Phosphatidylinositol 4,5-bisphosphate may represent the site of release of plasma membrane-bound calcium upon stimulation of human platelets, Biochem. Biophys. Res. Commun. 120:226–231.PubMedCrossRefGoogle Scholar
  8. Brolin, S.E., and Berne, C, 1967, The enzymatic activities of the initial glycolytic steps in pancreatic islets and acini, Metabolism 16:1024–1028.PubMedCrossRefGoogle Scholar
  9. Clements, R.S., Jr., Evans, M.H., and Pace, C.S., 1981, Substrate requirements for the phospho-inositide response in rat pancreatic islets, Biochim. Biophys. Acta 674:1–9.PubMedCrossRefGoogle Scholar
  10. Evans, M.H., Pace, C.S., and Clements, R.J., Jr., 1983, Endogenous prostaglandin synthesis and glucose-induced secretion from the adult rat pancreatic islet, Diabetes 32:509–515.PubMedCrossRefGoogle Scholar
  11. Haye, B., Champion, S., and Jacquemin, C, 1984, Existence of two pools of prostaglandins during stimulation of the thyroid by TSH, FEBS Lett. 41:89–93.CrossRefGoogle Scholar
  12. Hedeskov, C.J., 1980, Mechanism of glucose-induced insulin secretion, Physiol. Rev. 60:442–509.PubMedGoogle Scholar
  13. Hutton, J.C, Senar, A., Herchuelz, A., Atwater, I., Kawazu, S., Boschero, A.C, Somera, G., Davis, G., and Malaisse, W.J., 1980, Similarities in the stimulus-secretion coupling mechanisms of glucose-and 2-keto acid-induced insulin release, Endocrinology 106:203–219.PubMedCrossRefGoogle Scholar
  14. Kaliner, M., and Austen, K.F., 1973, A sequence of biochemical events in the antigen-induced release of chemical mediators from sensitized human lung tissue, J. Exp. Med. 183:1077–1094.CrossRefGoogle Scholar
  15. Laychock, S.G., 1982, Phospholipase A2 activity in pancreatic islets is calcium-dependent and stimulated by glucose, Cell Calcium 3:43–54.PubMedCrossRefGoogle Scholar
  16. Laychock, S.G., 1983a, Fatty acid incorporation into phospholipids of isolated pancreatic islets of the rat, Diabetes 32:6–13.PubMedCrossRefGoogle Scholar
  17. Laychock, S.G., 1983b, Identification and metabolism of polyphosphoinositides in isolated islets of Langerhans, Biochem. J. 216:101–106.PubMedGoogle Scholar
  18. Lazarewicz, J.W., Leu, V., Sun, G.Y., and Sun. A.Y., 1983, Arachidonic acid release from K +-evoked depolarization of brain synaptosomes, Neurochem. Int. 5:471–478.PubMedCrossRefGoogle Scholar
  19. Levine, L., 1983, Inhibition of the A23187-stimulated leukotriene and prostaglandin biosynthesis of rat basophil leukemia (RBL-1) cells by non-steroidal antiinflammatory drugs, anti-oxidants and calcium channel blockers, Biochem. Pharmacol. 32:3023–3026.PubMedCrossRefGoogle Scholar
  20. Malaisse, W.J., Sener, A., Koser, M., and Herchuelz, A., 1976, Stimulus-secretion coupling of glucose-induced insulin release, J. Biol. Chem. 251:5936–5943.PubMedGoogle Scholar
  21. Malaisse, W.J., Hutton, J.C, Kawazu, S., Herchuelz, A., Valverde, I., and Sener, A., 1979a, The stimulus-secretion coupling of glucose-induced insulin release. XXXV. The links between metabolic and cationic event, Diabetologia 16:331–341.PubMedCrossRefGoogle Scholar
  22. Malaisse, W.J., Sener, A., Herchuelz, A., and Hutton, J.C, 1979b, Insulin release: The fuel hypothesis, Metabolism 28:373–386.PubMedCrossRefGoogle Scholar
  23. Malaisse, W.J., Best, L., Kawazu, S., Malaisse-Lagae, F., and Sener, A., 1983, The stimulus-secretion coupling of glucose-induced insulin release: Fuel metabolism in islets deprived of exogenous nutrient, Arch. Biochem. Biophys. 224:102–110.PubMedCrossRefGoogle Scholar
  24. Meglasson, M.D., and Matschinsky, F.M., 1983, Discrimination of glucose anomers by glucokinase from liver and transplantable insulinoma, J. Biol. Chem. 258:6705–6708.PubMedGoogle Scholar
  25. Metz, S. A., 1984a, Glucose promotes lipoxygenase-mediated metabolism of arachidonic acid (AA) in rat islets, Clin. Res. 32:51a, 403a.Google Scholar
  26. Metz, S. A., 1984b, Glucose stimulation of arachidonic acid (AA)-derived mediators of insulin release shows anomeric preference and requires hexose metabolism, Diabetes 33:(Suppl. 1):42a.Google Scholar
  27. Metz, S., 1984c, Is phospholipase A2 a “glucose sensor” responsible for the phasic pattern of insulin release? Prostaglandins 27:147–158.PubMedCrossRefGoogle Scholar
  28. Metz, S.A., 1985, Glucose increases the synthesis of lipoxygenase-mediated metabolites of arachidonic acid in intact rat islets, Proc. Natl. Acad. Sci. USA. 82:198–202.PubMedCrossRefGoogle Scholar
  29. Metz, S.A., Fujimoto, W.Y., and Robertson, R.P., 1982, Lipoxygenation of arachidonic acid: A pivotal step in stimulus-secretion coupling in the pancreatic beta cell, Endocrinology111:2141-2143. Metz, S. A., Fujimoto, W. Y., and Robertson, R. P., 1983a, A role for the lipoxygenase pathway of arachidonic acid metabolism in glucose-and glucagon-induced insulin secretion, Life Sci. 32:903–910.CrossRefGoogle Scholar
  30. Metz, S., VanRollins, M., Strife, R., Fujimoto, W., and Robertson, R. P., 1983b, Lipoxygenase pathway in islet endocrine cells: Oxidative metabolism of arachidonic acid promotes insulin release, J. Clin. Invest. 71:1191–1205.PubMedCrossRefGoogle Scholar
  31. Metz, S.A., Fujimoto, W., and Robertson, R.P., 1984a, Oxygenation products of arachidonic acid: Third messengers for insulin release, J. Allergy Clin. Immunol. 74:391–402.PubMedCrossRefGoogle Scholar
  32. Metz, S.A., Murphy, R.C, and Fujimoto, W.Y., 1984b, Effects on glucose-induced insulin release of lipoxygenase-mediated metabolites of arachidonic acid, Diabetes 33:119–124.PubMedCrossRefGoogle Scholar
  33. Montague, W., and Taylor, K.W., 1969, Islet cell metabolism during insulin release, Biochem. J. 115:257–262.PubMedGoogle Scholar
  34. Morrison, A.R., Winokur, T.S., and Brown, W.A., 1982, Inhibition of soybean lipoxygenase by mannitol, Biochem. Biophys. Res. Commun. 108:1757–1762.PubMedCrossRefGoogle Scholar
  35. Ochi, Y., Yoshimoto, T., Yamamoto, S., Taniguchi, K., and Miyamoto, T., 1983, Arachidonate 5-lipoxygenase of guinea pig peritoneal polymorphonuclear leukocytes. Activation by adenosine 5′-triphosphate, J. Biol. Chem. 258:5754–5758.PubMedGoogle Scholar
  36. Pong, S.-S., Levine, L., 1977, Prostaglandin production by methylcholanthrene-transformed mouse BALB/3T3: Effect of oxidative phosphorylation inhibitors, Protaglandins 13:65–71.CrossRefGoogle Scholar
  37. Rittenhouse-Simmons, S., and Deykin, D., 1977, The mobilization of arachidonic acid in platelets exposed to thrombin or ionophore A23187, J. Clin. Invest. 60:495–498.PubMedCrossRefGoogle Scholar
  38. Rittenhouse-Simmons, S., and Deykin, D., 1978, The activation by Ca2+ of platelet phospholipase A2. Effects of dibutyryl cyclic adenosine monophosphate and 8(-N,N-diethylamino)-octyl-3,4,5-tri-methoxybenzoate, Biochim. Biophys. Acta 543:409–422.PubMedCrossRefGoogle Scholar
  39. Sagone, A.L., Jr., Greenwald, J., Kraut, E.H., Bianchine, J., and Singh, D., 1983, Glucose: A role as a free radical scavenger in biological systems, J. Lab. Clin. Med. 101:97–104.PubMedGoogle Scholar
  40. Schwartzman, M., and Raz, A., 1982, Purinergic vs peptidergic stimulation of lipolysis and prostaglandin generation in the perfused rabbit kidney, Biochem. Pharmacol. 31:2453–2458.PubMedCrossRefGoogle Scholar
  41. Streb, H., Irvine, R.F., Berridge, M.J., and Schulz, I., 1983, Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-l,4,5-trisphosphate, Nature 306:67–69.PubMedCrossRefGoogle Scholar
  42. Sugden, M.D., and Ashcroft, S.J.H., 1978, Effects of phosphoenolpyruvate, other glycolytic intermediates and methylxanthine on calcium uptake by a mitochondrial fraction from rat pancreatic islets, Diabetologica 15:173–180.CrossRefGoogle Scholar
  43. Tannenbaum, J., Sweetman, B.J., Nies, A.S., Aulsebrook, K., and Oates, J.A., 1979, The effect of glucose on the synthesis of protaglandins by the renal papilla of the rat in vitro, Prostaglandins 17:337–350.PubMedCrossRefGoogle Scholar
  44. Trotter, J., Flesch, I., Schmidt, B., Ferber, E., 1982, Acyltransferase-catalyzed cleavage of arachidonic acid from phospholipids and transfer to lysophosphatides in lymphocytes and macrophages, J. Biol. Chem. 257:1816–1823.PubMedGoogle Scholar
  45. Turk, J., Kotagal, N., and Greider, M., 1983, Arachidonic acid metabolism in isolated pancreatic islets from the rat, Diabetes (Suppl.) 32:139a.Google Scholar
  46. Walker, J.R., and Parish, H.A., 1981, Metabolic requirements for rabbit polymorphonuclear leucocyte lipoxygenase activity, Int. Arch. Allergy Appl. Immunol. 66:83–90.PubMedCrossRefGoogle Scholar
  47. Yamamoto, S., Ishii, M., Nakadate, T., Nakadi,T., and Kato, R., 1983, Modulation of insulin secretion by lipoxygenase products of arachidonic acid, J. Biol. Chem. 258:12149–12152.PubMedGoogle Scholar
  48. Zawalich, W.S., 1979, Intermediary metabolism and insulin secretion from isolated rat islets of Langerhans, Diabetes 28:252–260.PubMedGoogle Scholar
  49. Ziltener, HJ., Chavaillaz, P.-A., and Jörg, A., 1983, Leukotriene formation by eosinophil leukocytes, Hoppe Seylers J. Physiol. Chem. 364:1029–1037.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1985

Authors and Affiliations

  • Stewart A. Metz
    • 1
    • 2
  1. 1.Division of Clinical PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA
  2. 2.Denver VA Medical CenterDenverUSA

Personalised recommendations