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Demonstration of the mechanism of action of biguanides

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Riassunto

L’ossidazione dell’acido palmitico in omogenato di diaframma di ratto è depressa da concentrazioni di biguanidi tali da non inibire la fosforilazione ossidativa. L’ossidazione del glucosio non è direttamente influenzata dalle stesse concentrazioni biguanidiche: peraltro, l’effetto inibitore dell’acido palmitico sull’ossidazione del glucosio è in parte rimosso dalle biguanidi. L’inibizione dell’ossidazione degli acidi grassi, che rende conto della maggior parte degli effetti metabolici prodotti da questi farmaci, è da considerarsi come il fondamentale meccanismo d’azione delle biguanidi. Alcuni indizî suggeriscono che questi farmaci potrebbero interagire con la carnitina, impedendo così il trasporto degli acidi grassi a lunga catena attraverso la membrana mitocondriale fino al sito di ossidazione.

Résumé

Des concentrations de biguanides telles qu’elles n’empêchent pas la phosphorilation oxydative, dépriment l’oxydation de l’acide palmitique dans l’homogéné de diaphragme de rat. L’oxydation du glucose, au contraire, n’est pas influencée par ces mêmes concentrations: en outre, les biguanides éliminent en partie l’effet inhibitoire de l’acide palmitique sur l’oxydation du glucose. L’inhibition de l’oxydation des acides gras, responsable des effets métaboliques de ces médicaments, doit être considerée comme le principal mécanisme d’action des biguanides. Un certain nombre d’indices suggèrent que ces mémdicaments pourraient réagir avec la carnitine en empêchant ainsi le transport des acides gras à longue chaîne à travers la membrane mitochondriale jusqu’au site d’oxydation.

Resumen

La oxidación del ácido palmítico en un homogeneizado de diafragma de ratón se deprime por concentraciones tales de biguánidas que no lleguen a inhibir la fosforilación oxidativa. Las concentraciones de biguánidas no influyen directamente en la oxidación de la glucosa: por lo demás, el efecto inhibidor del ácido palmítico sobre la oxidación de la glucosa resulta parcialmente anulado por parte de las biguánidas. La inhibición de la oxidación de los ácidos grasos, que pone en evidencia la mayor parte de los efectos metabólicos producidos por estos fármacos, se puede considerar como el mecanismo de acción fundamental de las biguánidas. Algunos indicios sugieren que estos fármacos podrían actuar interfiriendo la acción de la carnitina, impidiendo con ello el transporte de los ácidos grasos de larga cadena a través de la membrana mitocondrial hasta el punto de oxidación.

Zusammenfassung

Die Oxydation von Palmitinsäure ist im Homogenat von Rattenzwerchfell durch Konzentrationen von Biguaniden eingeschränkt, welche die oxydative Phosphorylierung nicht hemmen. Diese Biguanidkonzentrationen haben keinen direkten Einfluss auf die Glukoseoxydation: die Biguanide heben jedoch teilweise den Hemmeffekt der Palmitinsäure auf die Glukoseoxydation auf. Die Hemmung der Fettsäureoxydation, welche die meisten metabolischen Wirkungen dieser Stoffe erklärt, muss als der grundlegende Wirkungsmechanismus der Biguanide angesehen werden. Einige Anzeichen legen die Vermutung nahe, dass diese Arzneimittel eine Wechselwirkung auf das Carnitin ausüben und so den Transport langkettiger Fettsäuren durch die Mitochondrienmembran bis zum Ort der Oxydation verhindern.

Summary

Palmitic acid oxidation in rat diaphragm homogenate is depressed by biguanide concentrations that are still incapable of inhibiting oxidative phosphorylation. Glucose oxidation is not directly effected by the same biguanide concentrations: however, the inhibitory effect of palmitic acid on glucose oxidation is partly removed by biguanides. Inhibition of fatty acid oxidation, which accounts for most of the metabolic effects caused by these drugs, can be regarded as the fundamental mechanism of action of biguanides. There is some evidence suggesting that these drugs might interact with carnitine, thus preventing long-chain fatty acids from being transported across the mitochondrial membrane to the site of oxidation.

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Muntoni, S., Tagliamonte, P., Sirigu, F. et al. Demonstration of the mechanism of action of biguanides. Acta diabet. lat 10, 1300–1307 (1973). https://doi.org/10.1007/BF02590716

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