Summary
The effect of biguanides (phenethylbiguanide, butylbiguanide and dimethylbiguanide) on absorption of actively transported sugars was examined by incubating rings of hamster small intestinein vitro. Biguanides inhibited transport of D-glucose, D-galactose and 3-0-methyl-D-glucose but had no effect on the transport of D-fructose. Inhibition of D-xylose transport could only be demonstrated if concentrations far below halfmaximal saturation concentration (Km) were used (10−5M), but not with concentrations approaching concentrations during a D-xylose tolerance test (18 mM). Formation of lactate by intestinal tissue was increased in presence of biguanides using D-glucose or D-fructose as substrates. The minimal inhibitory concentrations on transport of D-galactose were 10−3M for phenethylbiguanide, 2×10−3M for butylbiguanide and 6×10−3M for dimethylbiguanide. The metabolite of phenethylbiguanide, 1-(4-hydroxy-β-phenethyl)-biguanide, did not affect glucose uptake but increased glucose metabolism to some extent. The demonstrated inhibition of active intestinal transportin vitro may be the mechanism for the decreased absorption of glucose observed by other authorsin vivo in man and animals after biguanides.
Résumé
En incubant les anneaux de l'intestin grêle chez le hamsterin vitro, on a pu examiner l'effet des biguanides (phénéthylbiguanide, butylbiguanide et diméthylbiguanide) sur l'absorption des sucres transportés activement. Les biguanides ont inhibé le transport de D-glucose, de D-galactose et de 3-0-méthyl-D-glucose, mais n'ont eu aucun effet sur le transport de D-xylose et de D-fructose. La formation de lactate par les tissus intestinaux s'est accrue en présence des biguanides en utilisant le D-glucose et le D-fructose en tant que substratum. Les concentrations minimales inhibitrices du transport de D-galactose étaient de 10−3M pour le phénétylbiguanide, 2×10−3M pour le butylbiguanide et 6×10−3M pour le diméthylbiguanide. Le métabolite du phénéthylbiguanide, 1-(4-hydroxy-β-phénéthyl) -biguanide, n'a pas affecté la captation de glucose, mais a augmenté le métabolisme du glucose dans une certaine proportion. Conformément à de récents rapports de la littérature, on conclue que l'inhibition du transport intestinal peut être un facteur important dans le mécanisme de l'action des biguanides en ce qui concerne le diabète sucré et l'obésité.
Zusammenfassung
Es wurde der Einfluß verschiedener Biguanide (Phenäthylbiguanid, Butylbiguanid und Dimethylbiguanid) auf die Resorption verschiedener aktiv transportierbarer Zucker am Hamsterdünndarmin vitro untersucht. Biguanide hemmten den Transport von D-Glueose, D-Galaktose und 3-0-Methyl-D-Glucose, beeinflussten jedoch den Transport von D-Fructose nicht. Eine Hemmung des D-Xylose-Transportes konnte nur gezeigt werden, wenn Konzentrationen weit unter der halbmaximalen Sättigungskonzentration für D-Xylose benutzt wurden (10−5M), jedoch nicht bei Konzentrationen, wie sie annähernd während eines D-Xylose-Toleranztestes erreicht werden (18 mM). Die Lactatbildung im Darmgewebe aus Glucose und Fructose war in Gegenwart von Biguaniden deutlich gesteigert. Die minimalen Hemmkonzentrationen für den Galaktosetransport betrugen 10−3M für Phenäthylbiguanid, 2×10−3M für Butylbiguanid und 6×10−3M für Dimethylbiguanid. Das nicht blutzuckersenkend wirkende Abbauprodukt des Phenäthylbiguanid, 1-(4-hydroxy-β-phenäthyl)-Biguanid, hatte keinen Einfluß auf die Glucoseaufnahme, bewirkte aber eine Steigerung des Abbaues der aufgenommenen Glucose. Die gezeigte Hemmung des aktiven intestinalen Zuckertransportesin vitro könnte der Mechanismus der herabgesetzten Glucoseresorption nach Biguanidgabein vivo sein, der von anderen Autoren bei Mensch und Tier beschrieben wurde.
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References
Alvarado, F.: D-xylose active transport in the hamster small intestine. Biochim. biophys. Acta112 292–306 (1966).
Appels, A., Willms, B., Sickinger, K.: Verhalten der D-Xylose-Resorption unter Monotherapie mit N1-Butylbiguanid. Diabetologia6, 71 (1970).
Atkinson, R.M., Parsons, B.J., Smyth, D.H.: Inttestinal absorption of glucose. J. Physiol.135, 581–589 (1957).
Beckmann, R.: Über die Resorption und den biologischen Abbau von 1-(β-phenäthyl)-biguanid (Phenformin). Diabetologia3, 368–376 (1967).
Berchtold, P., Bolli, P., Arbenz, U., Keiser, G.: Intestinale Absorptionsstörung infolge Metforminbehandlung. Diabetologia5, 405–412 (1969).
Bihler, I., Kim, N.D., Sawh, P.C.: Active transport of L-glucose and D-xylose in hamster intestine, in vitro. Canad. J. Physiol. Pharmacol.47, 525–531 (1969).
Berger, W.: The effect of a single dose of 1 g dimethylbiguanide (DMB) on the utilisation of intravenous and orally administered glucose and galactose. Diabetologia4, 382 (abstract) (1968).
—, Künzli, H.: Effect of dimethylbiguanide on insulin, glucose and lactic acid contents in portal vein blood and peripheral venous blood in the course of intraduodenal glucose tolerance test. Diabetologia6, 37 (abstract) (1970).
Biro, L., Bányász, T., Kovacs, M.B., Bajor, M.: Die Wirkung des Phenäthylbiguanids auf die Glukoseresorption. Klin. Wschr.39, 760–762 (1961).
Caspary, W.F., Crane, R.K.: Inclusion of L-glucose within the specificity limits of the active sugar transport system of hamster small intestine. Biochim. biophys. Acta163, 395–400 (1968).
—, Stevenson, N.R., Crane, R.K.: Evidence for an intermediate step in carrier-mediated sugar translocation across the brush border membrane of hamster small intestine. Biochim. biophys. Acta193, 168–178 (1969).
—: Active transport of Myo-Inositol and its relation to the sugar transport system in hamster small intestine. Biochim. biophys. Acta203, 308–316 (1970).
—: Effect of biguanides on intestinal transport of sugars, amino acids, and calcium. Naunyn-Schmiedebergs Arch. Pharmakologie 269, 421 (1971).
Crane, R.K., Mandelstam, P.: The active transport of sugars by various preparations of hamster intestine. Biochim. biophys. Acta45, 460–476 (1960).
—: Absorption of sugars. In: Handbook of Physiology, Section 6, Vol. 3, Alimentary Canal, p. 1323–1354. Ed. C.F. Code. Washington, D.C.: Amer. Physiol. Society 1968.
—: Intestinal absorption of sugars. Physiol. Rev.40, 789–825 (1960).
—: An effect of alloxan diabetes on the active transport of sugars by rat small intestine in vitro. Biochim. biophys. Res. Commun.4, 436–440 (1961).
Creutzfeldt, W., Söling, H.D., Moench, A., Rauh, E., Bol, M.: Die Wirkung von N1, n-Butylbiguanid (W 37) und N1,β-Phenäthylbiguanid (W 32) auf den Alloxanund Phlorrhizin-Diabetes und die intestinale Glucoseabsorption von Ratten. Naunyn-Schmiedebergs Arch. exp. Path. Pharmacol.244, 31–47 (1962).
—, Willms, B., Caspary, W.F.: The mechanism of action of the blood glucose lowering biguanides. In: Reports on Oral Diabetes Therapy, a Selection of Papers presented at the 7th Congress of the International Diabetes Federation, Buenos Aires, August 1970, publ. by Excerpta Medica, Amsterdam, 1971, p. 95–106.
Czyzyk, A., Lawecki, J., Sadowski, J., Ponikowska, J., Szczpanik, Z.: Effect of biguanides on intestinal absorption of glucose. Diabetes17, 492–502 (1968).
— —: Untersuchungen über den Einfluß von Phenäthylbiguanid auf den Verlauf von Belastungsproben mit Insulin, Tolbutamid und Glucose bei Diabetes mellitus. Diabetologia2, 62–67 (1966).
Förster, H., Hager, E., Mehnert, H.: Der Einfluß von Butylbiguanid im Tierversuch auf die Resorption von Glucose und Fructose. Arzneimittel-Forsch.15, 1340–1344 (1963).
Ghareb, A., Botros, M., Saba, J.A., El-Asmar, F.A., El-Shawarby, K., Wahba, N.: Mechanism of action of biguanides on glucose metabolism. Ain Shams Med. J.20, 313–318 (1969).
Hollobaugh, S.L., Rao, B., Kruger, F.A.: Studies on the site and mechanism of action of phenformin. I. Evidence for significant “non-peripheral” effects of phenformin on glucose metabolism in normal subjects. Diabetes19, 45–49 (1970).
Kruger, F.A., Altschuld, R.A., Hollobaugh, S.L.: Studies on the site and mechanism of action of phenformin. II. Phenformin inhibition of glucose transport by rat intestine. Diabetes19, 50–52 (1970).
Levinson, R.A., Englert, E. jr.: Intestinal absorption of sugars, water and sodium in alloxan diabetic rats. Diabetes19, 683–687 (1970).
Love, A.H.G.: The effect of biguanides on intestinal absorption. Diabetologia5, 422 (1969).
Olson, W.A., Rosenberg, I.H.: Intestinal absorption of sugars and ammo acids in diabetic rats. J. clin. Invest.49, 96–105 (1970).
Roe, I.H., Rice, E.W.: A photometric method for the determination of free pentoses in animal tissue. J. biol. Chem.173, 507–512 (1948).
Schäfer, G.: Site-specific uncoupling and inhibition of oxidative phosphorylation by biguanides II. Biochim. biophys. Acta172 334–337, (1969).
Vinnik, I.E., Kern, F., Sussman, K.E.: The effect of diabetes mellitus on glucose absorption by the small intestine in man. J. lab. clin. Med.66, 131–136 (1965).
Wick, A.N., Mobley, P.W., Stewart, C.J.: The hydroxylation ofβ-phenethylbiguanide and some effects of p-hydroxy-β-phenethylbiguanide. Excerpta Medica, International Congress Series209, 154–155 (1970).
Willms, B., Creutzfeldt, W.: Intestinal Absorption of Vitamin B12 (Schilling Test) and D-Xylose during oral Therapy with different Biguanide Derivatives In: Reports on Oral Diabetes Therapy, a Selection of Papers presented at the 7th Congress of the International Diabetes Federation, Buenos Aires, August 1970, publ. by Excerpta Medica, Amsterdam, 1971, p. 230–234.
Wilson, T.H., Wiseman, G.: Metabolic activity of the small intestine of the rat and the golden hamster. J. Physiol.123, 116–130 (1954).
Yoh, Y.-J.: Distribution of n-butylbiguanide-14C-hydrochloride in mouse tissues. Jap. J. Pharmacol.17, 439–449 (1967).
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Caspary, W.F., Creutzfeldt, W. Analysis of the inhibitory effect of biguanides on glucose absorption: Inhibition of active sugar transport. Diabetologia 7, 379–385 (1971). https://doi.org/10.1007/BF01219474
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DOI: https://doi.org/10.1007/BF01219474