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Title: Some metabolic effects of phenformin and sodium dichloroacetate in rats
Author: Evans, Peter Francis
ISNI:       0000 0001 3453 7808
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1981
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An animal model of hyperlactataemia induced by phenformin, an orally-active antidiabetic drug, has been developed using streptozotocin-diabetic rats. A comparison of blood metabolite concentrations of fed, starved and streptozotocin-diabetic rats showed that the diabetic animal most nearly resembled the human maturity-onset diabetic. It was found that several agents commonly used to anaesthetise small animals had profound effects on blood glucose and lactate concentrations, and experiments comparing the effects of phenformin in pentobarbitone-anaesthetised rats with those in conscious animals showed that barbiturate anaesthesia interfered with the metabolic actions of phenformin. An intraperitoneal dose of phenformin of 0.5mmol/kg caused hypoglycaemic and hyperlactataemic effects of a suitable magnitude in diabetic animals, and the animal model was used to assess the pharmacological actions of compounds related to phenformin and the ability of compounds, such as dichloroacetate, to prevent the hyperlactataemia caused by phenformin. Sodium dichloroacetate was found to be an effective orally-active hypoglycaemic agent in starved and streptozotocin-diabetic rats, lowering blood concentrations of the gluconeogenic precursors lactate, pyruvate and alanine and often increasing blood ketone body concentrations. These metabolic actions were probably consequences of activation of tissue pyruvate dehydrogenase. The toxicity of dichloroacetate and its metabolites means that other, more specific activators of pyruvate dehydrogenase are to be preferred for further study. The results of experiments in which glucose and gluconeogenic precursors were given to starved rats were explained by a hypothesis for the mechanism of action of phenformin involving inhibition of NADH dehydrogenase. Substrates with NAD[+]-linked oxidations could be discriminated from those, like succinate and fatty acids, with FAD-linked oxidations, and succinate may be of use in the treatment of clinical lacticacidosis caused by biguanide drugs. The ability of phenformin to improve the tolerance of rats to an intraperitoneal glucose load, with a concomitant increase in blood lactate concentration, indicated that the drug was increasing the rate of anaerobic glycolysis, and glucose uptake into jejunal cells was increased by phenformin. Changes in the tissue concentrations of metabolites measured after phenformin treatment in vivo did not generally support the hypothesis, although elevated 3-hydroxybutyrate concentrations implied a decreased liver mitochondrial NAD[+]/NADH ratio.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry