Summary
Oral administration of 3-methyl salicylic acid (3MS) to diabetic and non-diabetic patients in modest doses (0.9–1.8 g/day) over several months produced a significant increase in plasma insulin levels, one hour after a glucose load. In 2 diabetic subjects, acute doses had a similar effect. — Improvement in glucose tolerance after chronic administration of 3 MS to diabetic patients was inconsistent, and could not be conclusively related to the action of the drug. Although acute doses of 3 MS caused a fall in plasma FFA after 3–6h, chronic treatment gave no predictable change in fasting plasma FFA levels. — Because of side effects, 3 MS was not considered suitable for introduction as a therapeutic agent. The results, however, are of academic interest since it is the first demonstration of increased plasma insulin after an oral salicylate.
Résumé
L'administration orale d'acide 3-méthyl salicylique (3MS) à des sujets diabétiques et non-diabétiques, à faibles doses (0.9 –1.8 g/jour) pendant plusieurs mois produisait une augmentation significative des taux d'insuline plasmatique, une heure après une charge en glucose. Chez 2 sujets diabétiques, des doses aiguës avaient un effet semblable. — Une amélioration de la tolérance au glucose, après administration chronique de 3 MS à des patients diabétiques, n'a pas été décelée et n'a pas pu être reliée à l'action de la drogue de façon concluante. Bien que des doses aiguës de 3 MS provoquassent une chute des FFA plasmatiques au bout de 3–6 hs, le traitement chronique ne causait pas de modification prévisible des taux plasmatiques de FFA à jeun. — A cause des effets secondaires, le 3 MS n'a pas été jugé valable en tant qu'agent thérapeutique. Les résultats cependant, sont d'intérêt académique, car c'est la première démonstration d'une élévation de l'insuline plasmatique après administration orale d'un salicylate.
Zusammenfassung
Die orale Zufuhr von 3-Methyl-Salicylsäqure (3MS) in relativ niedrigen Dosen (0.9–1.8 g/Tag) an Diabetiker und stoffwechselgesunde Patienten über mehrere Monate führte zu einem signifikanten Anstieg der Plasmainsulinspiegel eine Stunde nach Glucosebelastung. Bei 2 Diabetikern riefen akute Gaben einen ähnlichen Effekt hervor. — Die Besserung der Glucosetoleranz nach chronischer 3 MS Verabreichung an Diabetiker war nur vorübergehend und konnte nicht mit Sicherheit auf das Medikament zurückgeführt werden. Obwohl es 3–6 Std nach akuten Gaben von 3 MS zu einem Abfall der FFS-Konzentrationen im Plasma kam, löste die chronische Zufuhr keine vorhersagbaren Veränderungen der FFS-Spiegel im Nüchtern-Plasma aus. — Wegen seiner Nebenwirkungen erscheint uns die 3 MS zur Einführung in die Therapie nicht als geeignet. Die Ergebnisse sind aber von akademischem Interesse, da mit ihnen zum ersten Mal ein Anstieg der Plasmainsulinspiegel nach oraler Salicylatzufuhr nachgewiesen werden konnte.
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References
Anderson, W.F., Thompson, J.: Aspirin in the treatment of diabetes mellitus in the elderly. Geront. clin. 5, 234–243 (1963).
Barnett, H.L., Powers, J.R., Benward, J.H., Hartmann, A.F.: Salicylate intoxication in infants and children. J. Pediat. 21, 214–223 (1942).
Bartels, K.: Über die therapeutische Verwertung der Salicylsäure und ihres Natronsalzes in der inneren Medizin. Dtsch. med. Wschr. 4, 423–425 (1878).
Bizzi, A., Garattini, S., Veneroni, E.: The action of salicylate in reducing plasma free fatty acids and its pharmacological consequences. Brit. J. Pharmacol. 25, 187–196 (1965).
Carlson, L.A., Ostman, J.: Effect of salicylates on plasma free fatty acid in normal and diabetic subjects. Metabolism 10, 781–787 (1961).
— —: Inhibition of the mobilisation of free fatty acids from adipose tissue in diabetes. II. Effect of nicotinic acid and acetylsalicylate on blood glucose in human diabetics. Acta med. scand. 178, 71–79 (1965).
Cotton, E.K., Fahlberg, V.I.: Hypoglycemia with salicylate poisoning. A report of two cases. Amer. J. Dis. Child 108, 171–173 (1964).
Cummings, A.J., Martin, B.K.: Factors influencing the plasma salicylate concentration and urinary salicylate excretion after oral dosage with aspirin. Biochem. Pharmacol. 13, 767–776 (1964).
Cummings, A.J., Martin, B.K.: A kinetic study of the elimination of 3-methyl salicylic acid and its acetyl derivative in man. Brit. J. Pharmacol. 25, 470–480 (1965).
Dole, V.P: A relation between non-esterified fatty acids in plasma and in the metabolism of glucose. J. clin. Invest. 35, 150–154 (1956).
Ebstein, W.: Zur Therapie des Diabetes mellitus, insbesondere über die Anwendung des salicylsauren Natron bei demselben. Berl. klin. Wschr. 13, 337–340 (1876).
Felber, J.P., Vanotti, A.: Effects of fat infusion on glucose tolerance and insulin plasma levels. Med. Exp. 10, 153–156 (1964).
Field, J.B., Boyle, C., Remer, A.: Effect of salicylate infusion on plasma-insulin and glucose tolerance in healthy persons and mild diabetics. Lancet 1967 I, 1191–1194.
Garattini, S., Bizzi, A.: Effect of drugs on mobilization of free fatty acid. Pharmacol. Rev. 18, 243–251 (1966).
Gilgore, S.G.: The influence of salicylate on hyperglycemia. Diabetes 9, 392–393 (1960).
Gilgore, S.G., Rupp, J.J.: Response of blood glucose to intravenous salicylate. Metabolism 10, 419–421 (1961).
Hales, C.N.: The glucose-fatty acid cycle and the aetiology of diabetes. Proc. nutr. Soc. 25, 61–66 (1966).
—, Randle, P.J.: Immunoassay of insulin with insulinantibody precipitate. Biochem. J. 88, 137–146 (1963).
—, Stein, J., Stowers, J.M.: Rein et Foie, Maladies de la Nutrition, 9, 387–401 (1966).
Hecht, A., Goldner, M.G.: Reappraisal of the hypoglycemic action of acetylsalicylate. Metabolism 8, 418–428 (1959).
Hill, J.B., Kessler, E.: An automated determination of flucose utilising a glucose oxidase-peroxidase system. J. Lab. clin. Med. 57, 970–980 (1961).
Howard, A.N., Gresham, G.A., Bowyer, D.E., Hyams, D.E.: The use of baboons in the evaluation of drugs active against atherosclerosis. In Vagtbord, H. (ed.): Use of non human primates in drug evaluation, pp. 480–493. Austin and London: University of Texas Press 1968.
—, Hyams, D.E., Everett, W., Jennings, I.W., Gresham, G.A., Bizzi, A., Garattini, S., Veneroni, E., Miettinen, T.: 3-methyl salicylic acid: a long-acting salicylate which decreases free fatty acid mobilisation and plasma cholesterol. Europ. J. Pharmacol. 13, 244–253 (1971).
Huggins, A.K., Smith, M.J.H.: Uncoupling reagents and metabolism. 5. Effects of salicylate and of 2∶4 dinitrophenol on the metabolism of isolated rat diaphragm. Biochem. J. 85, 394–402 (1962).
Ingle, D.J., Meeks, R.C.: Suppression of glycosuria during administration of large doses of aspirin to force-fed partially depancreatectomized rate. Amer. J. Physiol. 171, 600–603 (1952).
Kaufman, H.P.: Arzneimittel synthetische Studien I: Die Bedeutung der Acylreste in acylierten Heilmitteln. Ang. Chem. 40, 69 (1927).
Krumholz, W.V., Sheppard, C., Merlis, S.: Studies with aspirin: psychopharmacologic and methodologic considerations. Clin. Pharmacol. Ther. 5, 691–694 (1964).
— — —: Studies with acetylsalicylic acid. II. Psychopharmacologic and methodologic considerations. Clin. Pharmacol. Ther. 6, 359–361 (1965).
Lespagnol, A., Bizard, G., Robelet, A., Devillers, F.: Recherches dans la serie salicylique. Therapie 18, 155–169 (1963).
Lester, D., Lolli, G., Greenberg, L.A.: The fate of acetylsalieylic acid. J. Pharmacol. 87, 329–342 (1946).
Lightbody, T.D., Reid, J.: Ortho-cresotinate and diabetes mellitus. Brit. med. J. 1960 II, 1704–1707.
Limbeck, G.A., Ruvalcaba, R.H.A., Samols, E., Kelley, V.C.: Salicylate and hypoglycemia. Amer. J. Dis. Child 109, 165–167 (1965).
Macdougall, A.I., Alexander, W.D.: Effects of Salicylates on Cholesterol Metabolism. Salicylates — An International Symposium. Editors: Dixon, A.St.J., Martin, B.K., Smith M.J.H., Wood P.H.N. p. 92–96. London: J. &A. Churchill Ltd. 1963.
Manchester, K.L., Randle, P.J., Smith, G.H.: Some effects of sodium salicylate on muscle metabolism. Brit. med. J. 1958 I, 1028–1030.
May, R.: The action of cresotinic acids and toluic acids. Brit. med. J. 1909 II, 791–793.
Nature: Free fatty acid mobilization. Nature 214, 758 (1967).
Pfeiffer, C.C., Goldstein, L., Murphree, H.B.: The C.N.S. effect in man of mild analgesics as measured by quantitative analysis of the electroencephalogram. J. new Drugs 5, 260 (1965).
Randle, P.J., Garland, P.B., Hales, C.N., Newsholme, E.A.: The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbance of diabetes mellitus. Lancet 1963 I, 785–789.
—, Smith, G.H.: Regulation of glucose uptake by muscle. I. The effects of insulin, anaerobiosis and cell poisons on the uptake of glucose and the release of potassium by isolated rat diaphragm. Biochem. J. 70, 490–500 (1958).
Reid, J.: Dinitrophenol and diabetes mellitus: A comparison with salicylate. Brit. med. J. 1958 II, 724–727.
Reid, J., Lightbody, T.D.: The insulin equivalence of salicylate. Brit. med. J. 1959 I, 897–900.
Reid, J., Macdougall, A.I., Andrews, M.M.: Aspirin and diabetes. Brit. med. J. 1957 II, 1071–1074.
Renton, R.: Personal communication (1968).
Reynolds, R.C., Cluff, L.E.: Interaction of serum and sodium salicylate. Changes during acute infection and its influence on pharmacological activity. Bull. Johns Hopkins Hosp. 107, 278–290 (1960).
Segal, S., Blair, A., Weinberg, A.: In vitro effects of salicylate on carbohydrate metabolism. Metabolism 9, 1033–1046 (1960).
Seltzer, H.S.: Quantitative effects of glucose, sulphonylureas, salicylate and indole-3-acetic acid on the secretion of insulin activity into pancreatic venous blood. J. clin. Invest. 41, 289–300 (1962).
Smith, M.J.H., Meade, B.W., Bornstein, J.: The effect of salicylate on glycosuria, blood glucose and liver glycogen of the alloxan-diabetic rat. Biochem. J. 51, 18–20 (1952).
Stafford, W.L.: The binding by bovine plasma and plasma fractions of salicylic acid and some of its 3-alkyl analogues. Biochem. Pharmacol. 2, 685–692 (1962).
Stockman, R.: The therapeutic actions of the cresotinic acids. J. Pharmacol. exp. Ther. 4, 97–102 (1912).
Stowers, J.M.: Salicylates and clinical diabetes, and remarks on other endocrine effects. Salicylates — An International Symposium. Editors: Dixon, A.St.J., Martin B.K., Smith, M.J.H., Wood, P.H.N., p. 65–70, Boston: Little and Brown 1963.
—, Constable, L.W., Hunter, R.B.: A clinical and pharmacological comparison of chlorpropamide and other sulphonylureas. Ann. N.Y. Acad. Sci. 74, 689–695 (1959).
Thorell, J., Persson, B., Sterkey, G.: Effect of fat infusion on plasma glucose, FFA, glycerol and insulin levels during intravenous and oral glucose tolerance tests. Diabetologia 2, 232 (1966).
Williamson, R.T.: On the treatment of glycosuria and diabetes mellitus with sodium salicylate. Brit. med. J. 1901 I, 750–762.
Wood, P.H.N., Harvey-Smith, E.A., Dixon, A.St.J.: Salicylates and gastro-intestinal bleeding. Acetylsalicylic acid and aspirin derivatives. Brit. med. J. 1962 I, 669–675.
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Hyams, D.E., Howard, A.N., Evans, I.E. et al. The effect of 3-methyl salicylic (0-cresotinic) acid on plasma insulin and glucose tolerance in diabetic and non-diabetic subjects. Diabetologia 7, 94–101 (1971). https://doi.org/10.1007/BF00443888
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DOI: https://doi.org/10.1007/BF00443888