Metabolic studies in the whole animal of the oral antidiabetic drug Phenformin

Holloway, Paul Adrian Hunter (1978) Metabolic studies in the whole animal of the oral antidiabetic drug Phenformin. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The oral hypoglycaemic agent phenformin has been associated with many cases of hyperlactataemia and lactic acidosis during the twenty years since its introduction into clinical use as therapy for maturity onset diabetics and some types of obese patient. The cause for this phenomenon has been controversial for some years, whether the lesion is overproduction or underutilisation of lactate by the body or a combination of the two. There is strong evidence of underutilisation by the liver and kidneys but some investigators have proposed that there is also overproduction by the peripheral tissues which overloads the normal lactate clearing mechanisms. This project was set up in part to investigate the extrasplanehic effects, if any, of phenformin on carbohydrate metabolism. The other aim was to establish a reproducible model for phenformin-induced lactic acidosis in the rat and to investigate the effects on this lactic acidosis of an activator of pyruvate dehydrogenase - dichloroacetate (DCA).In Section III investigations on the metabolic effects of phenformin in functionally hepatectomised and nephrectomised normal and streptozotocin diabetic rats show that peripheral lactate and pyruvate production was decreased while there appeared to be no increase in glucose uptake. This suggests that the major lesion with phenformin usage is an inhibition of hepatic lactate utilisation. In Section IV a reproducible model of lactic acidosis is described by infusing phenformin firstly into whole rats, secondly into totally nephrectomised rats, and thirdly into whole rats following pretreatment with an hydroxylase inhibitor. This third model produced a severe lactic acidosis. Tho development of lactic acidosis was prevented in each case by the addition of DCA. In Section V recommended therapies for lactic acidosis of insulin plus glucose, with or without bicarbonate, failed to cure this condition but treatment with DCA caused considerable improvement except when the acidosis was very severe. This agent may prove a useful therapy for the treatment of this normally fatal condition.

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