Abstract
Electrolyte fluxes are fundamental to normal endocrine pancreatic function. Adenosine triphosphatases (ATPases) are enzyme systems believed to modulate electrolyte movements across membranes in a number of cell types. This study was undertaken to measure cation-dependent ATPases of rat pancreatic islets. In addition, we compared effects of substances which influence endocrine pancreatic function upon ATPases in homogenates of islets and kidney, the latter being a tissue which would not be expected to have a stimulus-secretion response to substances which activate islets.
Both tissues were generally similar with respect to apparent Michaelis constant (ATP) of Na+K+ATPase, Mg++ATPase, and Ca++ATPase. In islets and kidney, Na+K+ATPase specific activity was increased when the Na:K ratio was lowered from 250:1 (175:0.7 mM) to 5:1 (100:20 mM). Inhibition of Na+K+ATPase at either Na:K ratio by ouabain, an activator of secretion, and enhancement of the high-ratio Na+K+ATPase by diphenylhydantoin, an islet secretory inhibitor, were also common to both tissues.
Because both inhibition and enhancement of Na+K+ATPase could be studied at the high Na:K ratio, we examined the effect of regulators of secretion upon the activity of this enzyme. Like ouabain, substances which induce or support islet secretion, glucose 16 mM or 3.3 mM, arginine 14.2 mM (with 3.3 mM glucose), or Ca++ 1 mM, inhibited high-ratio islet Na+K+ATPase. Like diphenylhydantoin, the inhibitors of insulin secretion, diazoxide 0.22 mM, or NH4Cl 16 mM, enhanced this islet ATPase. Neither valine, which is non-secretogenic, nor arginine without glucose, which is a weak secretagogue, had any effect upon islet Na+K+ATPase. We examined the effect of these substances upon other cation-dependent islet ATPases. Ca++ inhibited Mg++ATPase, and glucose inhibited Ca++ATPase. Leucine, 22.9 mM, which induces insulin secretion in the absence of glucose, suppressed islet Ca++ATPase and had no effect upon high-ratio Na+K+ATPase.
In contrast to the observations in the islets, most substances which influence islet function had no effect on kidney ATPases, or effects which were different from those seen in islets. Except for ouabain, none of these substances influenced the three kidney ATPases in a manner similar to that seen with islets.
These findings support the hypothesis that cation-dependent ATPases are involved in specificity of islet response to substances which influence endocrine pancreatic activity.
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Selected References
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- Baker E., Simmonds W. J. Membrane ATPase and electrolyte levels in marsupial erythrocytes. Biochim Biophys Acta. 1966 Nov 8;126(3):492–499. doi: 10.1016/0926-6585(66)90007-0. [DOI] [PubMed] [Google Scholar]
- Basabe J. C., Lopez N. L., Viktora J. K., Wolff F. W. Insulin secretion studied in the perfused rat pancreas. I. Effect of tolbutamide, leucine and arginine; their interaction with diazoxide, and relation to glucose. Diabetes. 1971 Jul;20(7):449–456. doi: 10.2337/diab.20.7.449. [DOI] [PubMed] [Google Scholar]
- Charles M. A., Lawecki J., Pictet R., Grodsky G. M. Insulin secretion. Interrelationships of glucose, cyclic adenosine 3:5-monophosphate, and calcium. J Biol Chem. 1975 Aug 10;250(15):6134–6140. [PubMed] [Google Scholar]
- Charney A. N., Kinsey M. D., Myers L., Gainnella R. A., Gots R. E. Na+-K+-activated adenosine triphosphatase and intestinal electrolyte transport. Effect of adrenal steroids. J Clin Invest. 1975 Sep;56(3):653–660. doi: 10.1172/JCI108135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chesney T. M., Schofield J. G. Studies on the secretion of pancreatic glucagon. Diabetes. 1969 Sep;18(9):627–632. doi: 10.2337/diab.18.9.627. [DOI] [PubMed] [Google Scholar]
- DE DUVE C., WATTIAUX R., BAUDHUIN P. Distribution of enzymes between subcellular fractions in animal tissues. Adv Enzymol Relat Subj Biochem. 1962;24:291–358. doi: 10.1002/9780470124888.ch6. [DOI] [PubMed] [Google Scholar]
- Fariss B. L., Lutcher C. L. Diphenylhdantoin-induced hyperglycemia and impaired insulin release. Effect of dosage. Diabetes. 1971 Mar;20(3):177–181. [PubMed] [Google Scholar]
- Feldman J. M., Lebovitz H. E. Ammonium ion, a modulator of insulin secretion. Am J Physiol. 1971 Oct;221(4):1027–1032. doi: 10.1152/ajplegacy.1971.221.4.1027. [DOI] [PubMed] [Google Scholar]
- Festoff B. W., Appel S. H. Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase. J Clin Invest. 1968 Dec;47(12):2752–2758. doi: 10.1172/JCI105956. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Formby B., Capito K., Egeberg J., Hedeskov C. J. Ca-activated ATPase activity in subcellular fractions of mouse pancreatic islets. Am J Physiol. 1976 Feb;230(2):441–448. doi: 10.1152/ajplegacy.1976.230.2.441. [DOI] [PubMed] [Google Scholar]
- Formby B., Capito K., Hedeskov C. J. (Na+, K+)-activated ATPase in microsomes from mouse pancreatic islets. Acta Physiol Scand. 1976 Jan;96(1):143–144. doi: 10.1111/j.1748-1716.1976.tb10182.x. [DOI] [PubMed] [Google Scholar]
- Gerich J. E., Charles M. A., Levin S. R., Forsham P. H., Grodsky G. M. In vitro inhibition of pancreatic glucagon secretion by diphenylhydantoin. J Clin Endocrinol Metab. 1972 Dec;35(6):823–824. doi: 10.1210/jcem-35-6-823. [DOI] [PubMed] [Google Scholar]
- Gray G. M. Carbohydrate digestion and absorption. Role of the small intestine. N Engl J Med. 1975 Jun 5;292(23):1225–1230. doi: 10.1056/NEJM197506052922308. [DOI] [PubMed] [Google Scholar]
- Grodsky G. M. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest. 1972 Aug;51(8):2047–2059. doi: 10.1172/JCI107011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grodsky G. M., Bennett L. L. Cation requirements for insulin secretion in the isolated perfused pancreas. Diabetes. 1966 Dec;15(12):910–913. doi: 10.2337/diab.15.12.910. [DOI] [PubMed] [Google Scholar]
- Grodsky G. M., Fanska R., West L., Manning M. Anomeric specificity of glucose-stimulated insulin release: evidence for a glucoreceptor? Science. 1974 Nov 8;186(4163):536–538. doi: 10.1126/science.186.4163.536. [DOI] [PubMed] [Google Scholar]
- Hales C. N., Milner R. D. Cations and the secretion of insulin from rabbit pancreas in vitro. J Physiol. 1968 Nov;199(1):177–187. doi: 10.1113/jphysiol.1968.sp008647. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hales C. N., Milner R. D. The role of sodium and potassium in insulin secretion from rabbit pancreas. J Physiol. 1968 Feb;194(3):725–743. doi: 10.1113/jphysiol.1968.sp008433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hellman B., Sehlin J., Täljedal I. B. Calcium and secretion: distinction between two pools of glucose-sensitive calcium in pancreatic islets. Science. 1976 Dec 24;194(4272):1421–1423. doi: 10.1126/science.795030. [DOI] [PubMed] [Google Scholar]
- Hendler E. D., Torretti J., Epstein F. H. The distribution of sodium-potassium--activated adenosine triphosphatase in medulla and cortex of the kidney. J Clin Invest. 1971 Jun;50(6):1329–1337. doi: 10.1172/JCI106612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henquin J. C., Lambert A. E. Cationic environment and dynamics of insulin secretion. II. Effect of a high concentration of potassium. Diabetes. 1974 Dec;23(12):933–942. doi: 10.2337/diab.23.12.933. [DOI] [PubMed] [Google Scholar]
- Hokin L. E. Purification and properties of the (sodium + potassium)-activated adenosinetriphosphatase and reconstitution of sodium transport. Ann N Y Acad Sci. 1974;242(0):12–23. doi: 10.1111/j.1749-6632.1974.tb19075.x. [DOI] [PubMed] [Google Scholar]
- Howell S. L., Taylor K. W. Potassium ions and the secretion of insulin by islets of Langerhans incubated in vitro. Biochem J. 1968 Jun;108(1):17–24. doi: 10.1042/bj1080017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ismail-Beigi F., Edelman I. S. The mechanism of the calorigenic action of thyroid hormone. Stimulation of Na plus + K plus-activated adenosinetriphosphatase activity. J Gen Physiol. 1971 Jun;57(6):710–722. doi: 10.1085/jgp.57.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jorgensen P. L., Skou J. C. Purification and characterization of (Na+ + K+)-ATPase. I. The influence of detergents on the activity of (Na+ + K+)-ATPase in preparations from the outer medulla of rabbit kidney. Biochim Biophys Acta. 1971 Apr 13;233(2):366–380. doi: 10.1016/0005-2736(71)90334-8. [DOI] [PubMed] [Google Scholar]
- Katz A. I., Epstein F. H. Physiologic role of sodium-potassium-activated adenosine triphosphatase in the transport of cations across biologic membranes. N Engl J Med. 1968 Feb 1;278(5):253–261. doi: 10.1056/NEJM196802012780506. [DOI] [PubMed] [Google Scholar]
- Kizer J. S., Vargas-Gordon M., Brendel K., Bressler R. The in vitro inhibition of insulin secretion by diphenylhydantoin. J Clin Invest. 1970 Oct;49(10):1942–1948. doi: 10.1172/JCI106413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
- Lacy P. E., Walker M. M., Fink C. J. Perifusion of isolated rat islets in vitro. Participation of the microtubular system in the biphasic release of insulin. Diabetes. 1972 Oct;21(10):987–998. doi: 10.2337/diab.21.10.987. [DOI] [PubMed] [Google Scholar]
- Lane L. K., Copenhaver J. H., Jr, Lindenmayer G. E., Schwartz A. Purification and characterization of and (3H)ouabain binding to the transport adenosine triphosphatase from outer medulla of canine kidney. J Biol Chem. 1973 Oct 25;248(20):7197–7200. [PubMed] [Google Scholar]
- Langer G. A. The intrinsic control of myocardial contraction--ionic factors. N Engl J Med. 1971 Nov 4;285(19):1065–1071. doi: 10.1056/NEJM197111042851910. [DOI] [PubMed] [Google Scholar]
- Leclercq-Meyer V., Marchand J., Malaisse W. J. The effect of calcium and magnesium on glucagon secretion. Endocrinology. 1973 Dec;93(6):1360–1370. doi: 10.1210/endo-93-6-1360. [DOI] [PubMed] [Google Scholar]
- Lernmark A., Nathans A., Steiner D. F. Preparation and characterization of plasma membrane-enriched fractions from rat pancreatic islets. J Cell Biol. 1976 Nov;71(2):606–623. doi: 10.1083/jcb.71.2.606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levin S. R., Booker J., Jr, Smith D. F., Grodsky G. M. Inhibition of insulin secretion by diphenylhydantoin in the isolated perfused pancreas. J Clin Endocrinol Metab. 1970 Mar;30(3):400–401. doi: 10.1210/jcem-30-3-400. [DOI] [PubMed] [Google Scholar]
- Levin S. R., Charles M. A., O'connor M., Grodsky G. M. Use of diphenylhydantoin and diazoxide to investigate insulin secretory mechanisms. Am J Physiol. 1975 Jul;229(1):49–54. doi: 10.1152/ajplegacy.1975.229.1.49. [DOI] [PubMed] [Google Scholar]
- Levin S. R., Grodsky G. M., Hagura R., Smith D. Comparison of the inhibitory effects of diphenylhydantoin and diazoxide upon insulin secretion from the isolated perfused pancreas. Diabetes. 1972 Aug;21(8):856–862. doi: 10.2337/diab.21.8.856. [DOI] [PubMed] [Google Scholar]
- Levin S. R., Reed J. W., Ching K. N., Davis J. W., Blum M. R., Forsham P. H. Diphenylhydantoin. Its use in detecting early insulin secretory defects in patients with mild glucose intolerance. Diabetes. 1973 Mar;22(3):194–201. doi: 10.2337/diab.22.3.194. [DOI] [PubMed] [Google Scholar]
- Levy J., Herchuelz A., Sener A., Malaisse W. J. The stimulus-secretion coupling of glucose-induced insulin release. XX. fasting: a model for altered glucose recognition by the B-cell. Metabolism. 1976 May;25(5):583–591. doi: 10.1016/0026-0495(76)90012-3. [DOI] [PubMed] [Google Scholar]
- Malaisse-Lagae F., Malaisse W. J. The stimulus-secretion coupling of glucose-induced insulin release. 3. Uptake of 45 calcium by isolated islets of Langerhans. Endocrinology. 1971 Jan;88(1):72–80. doi: 10.1210/endo-88-1-72. [DOI] [PubMed] [Google Scholar]
- Malaisse W. J. Insulin secretion: multifactorial regulation for a single process of release. The Minkowski award lecture delivered on September 7, 1972 before the European Association for the study of Diabetes at Madrid, Spain. Diabetologia. 1973 Jun;9(3):167–173. doi: 10.1007/BF01219778. [DOI] [PubMed] [Google Scholar]
- Malaisse W. J., Malaisse-Lagae F. Stimulation of insulin secretion by noncarbohydrate metabolites. J Lab Clin Med. 1968 Sep;72(3):438–448. [PubMed] [Google Scholar]
- Malaisse W., Malaisse-Lagae F. [A possible role for calcium in the stimulus-secretion coupling for glucose-induced insulin secretion]. Acta Diabetol Lat. 1970 Sep;7 (Suppl 1):264–277. [PubMed] [Google Scholar]
- Malherbe C., Burrill K. C., Levin S. R., Karam J. H., Forsham P. H. Effect of diphenylhydantoin on insulin secretion in man. N Engl J Med. 1972 Feb 17;286(7):339–342. doi: 10.1056/NEJM197202172860702. [DOI] [PubMed] [Google Scholar]
- Milner R. D., Hales C. N. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia. 1967 Mar;3(1):47–49. doi: 10.1007/BF01269910. [DOI] [PubMed] [Google Scholar]
- Milner R. D. The stimulation of insulin release by essential amino acids from rabbit pancreas in vitro. J Endocrinol. 1970 Jul;47(3):347–356. doi: 10.1677/joe.0.0470347. [DOI] [PubMed] [Google Scholar]
- Nagayama A., Dales S. Rapid purification and the immunological specificity of mammalian microtubular paracrystals possessing an ATPase activity. Proc Natl Acad Sci U S A. 1970 Jun;66(2):464–471. doi: 10.1073/pnas.66.2.464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamaru Y., Kosakai M., Konishi K. Some properties of brain microsome adenosine triphosphatases activated by magnesium and calcium. Arch Biochem Biophys. 1967 Apr;120(1):15–21. doi: 10.1016/0003-9861(67)90592-9. [DOI] [PubMed] [Google Scholar]
- Niki A., Niki H., Miwa I., Okuda J. Insulin secretion by anomers of d-glucose. Science. 1974 Oct 11;186(4159):150–151. doi: 10.1126/science.186.4159.150. [DOI] [PubMed] [Google Scholar]
- Parkinson D. K., Radde I. C. Properties of a Ca 2+ -and Mg 2+ -activated ATP-hydrolyzing enzyme in rat kidney cortex. Biochim Biophys Acta. 1971 Jul 21;242(1):238–246. doi: 10.1016/0005-2744(71)90104-5. [DOI] [PubMed] [Google Scholar]
- Peters B. H., Samaan N. A. Hyperglycemia with relative hypoinsulinemia in diphenylhydantoin toxicity. N Engl J Med. 1969 Jul 10;281(2):91–92. doi: 10.1056/NEJM196907102810208. [DOI] [PubMed] [Google Scholar]
- Robinson J. D. Cation interactions with different functional states of the Na+, K+-ATPase. Ann N Y Acad Sci. 1974;242(0):185–202. doi: 10.1111/j.1749-6632.1974.tb19090.x. [DOI] [PubMed] [Google Scholar]
- SKOU J. C. ENZYMATIC BASIS FOR ACTIVE TRANSPORT OF NA+ AND K+ ACROSS CELL MEMBRANE. Physiol Rev. 1965 Jul;45:596–617. doi: 10.1152/physrev.1965.45.3.596. [DOI] [PubMed] [Google Scholar]
- Schatzmann H. J., Vincenzi F. F. Calcium movements across the membrane of human red cells. J Physiol. 1969 Apr;201(2):369–395. doi: 10.1113/jphysiol.1969.sp008761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sehlin J., Täljedal I. B. Sodium uptake by microdissected pancreatic islets: effects of ouabain and chloromercuribenzene-p-sulphonic acid. FEBS Lett. 1974 Feb 15;39(2):209–213. doi: 10.1016/0014-5793(74)80052-9. [DOI] [PubMed] [Google Scholar]
- Siegel G. J., Goodwin B. B. Sodium-potassium-activated adenosine triphosphatase of brain microsomes: modification of sodium inhibition by diphenylhydantoins. J Clin Invest. 1972 May;51(5):1164–1169. doi: 10.1172/JCI106909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Torretti J., Hendler E., Weinstein E., Longnecker R. E., Epstein F. H. Functional significance of Na- K-ATPase in the kidney: effects of ouabain inhibition. Am J Physiol. 1972 Jun;222(6):1398–1405. doi: 10.1152/ajplegacy.1972.222.6.1398. [DOI] [PubMed] [Google Scholar]
- Triner L., Killian P., Nahas G. G. Ouabain hypoglycemia: insulin mediation. Science. 1968 Nov 1;162(3853):560–561. doi: 10.1126/science.162.3853.560. [DOI] [PubMed] [Google Scholar]
- WHEELER K. P., WHITTAM R. Fome properties of a kidney adenosine triphosphatase relevant to active cation transport. Biochem J. 1962 Dec;85:495–507. doi: 10.1042/bj0850495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- WOODBURY D. M. Effect of diphenylhydantoin on electrolytes and radiosodium turnover in brain and other tissues of normal, hyponatremic and postictal rats. J Pharmacol Exp Ther. 1955 Sep;115(1):74–95. [PubMed] [Google Scholar]