Metabolic studies with dichloroacetate in experimental diabetes
Metabolic studies with dichloroacetate in experimental diabetes
Biguanide therapy in diabetic patients increases the blood concentration of lactate, pyruvate and alanine and may lead to the development of lactic acidosis. Dichloroacetate, an activator of pyruvate dehydrogenase, lowers blood lactate and pyruvate concentrations and has a mild hypoglycaemic action. The object of this work was to study the metabolic effects of dichloroacetate in experimental diabetes, and to relate the results to the development of new forms of treatment for maturity-onset diabetic patients. Dichloroacetate had no effect on gluconeogenesis from lactate and fructose in isolated; perfused livers from diabetic rats; its hypoglycaemic action can therefore be attributed to its effect on extra-hepatic tissues. Dichloroacetate did not reverse the inhibition of hepatic gluconeogenesis from lactate by metformin, but it did lower the hepatic production of lactate and pyruvate, resulting from fructose administration. Dichloroacdtate markedly increased ketone body production by perfused livers from diabetic rats. In long-term (28 days) studies, dichloroacetate by itself lowered blood glucose during fasting, but was less effective postprandially in mildly diabetic rats. It also decreased the concentrations of lactate, pyruvate and alanine in blood, liver and muscle, but tended to increase ketone body concentrations. The combined treatment of dichloroacetate with phenformin or metformin gave good control of blood glucose concentration throughout the day, and the metabolic abnormalities induced by biguanides in blood, liverand muscle were largely reversed by dichloroacetate. The metabolic abnormalities apparent during metformin treatment were less severe than during phenfonnin treatment.It is concluded that treatment of mild diabetes with dichloroacetate and biguanides together has advantages over either compound used alone.
University of Southampton
Man, Kwok-Chu
a3ed264d-77be-4993-a36d-641e34f3cff4
1978
Man, Kwok-Chu
a3ed264d-77be-4993-a36d-641e34f3cff4
Man, Kwok-Chu
(1978)
Metabolic studies with dichloroacetate in experimental diabetes.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Biguanide therapy in diabetic patients increases the blood concentration of lactate, pyruvate and alanine and may lead to the development of lactic acidosis. Dichloroacetate, an activator of pyruvate dehydrogenase, lowers blood lactate and pyruvate concentrations and has a mild hypoglycaemic action. The object of this work was to study the metabolic effects of dichloroacetate in experimental diabetes, and to relate the results to the development of new forms of treatment for maturity-onset diabetic patients. Dichloroacetate had no effect on gluconeogenesis from lactate and fructose in isolated; perfused livers from diabetic rats; its hypoglycaemic action can therefore be attributed to its effect on extra-hepatic tissues. Dichloroacetate did not reverse the inhibition of hepatic gluconeogenesis from lactate by metformin, but it did lower the hepatic production of lactate and pyruvate, resulting from fructose administration. Dichloroacdtate markedly increased ketone body production by perfused livers from diabetic rats. In long-term (28 days) studies, dichloroacetate by itself lowered blood glucose during fasting, but was less effective postprandially in mildly diabetic rats. It also decreased the concentrations of lactate, pyruvate and alanine in blood, liver and muscle, but tended to increase ketone body concentrations. The combined treatment of dichloroacetate with phenformin or metformin gave good control of blood glucose concentration throughout the day, and the metabolic abnormalities induced by biguanides in blood, liverand muscle were largely reversed by dichloroacetate. The metabolic abnormalities apparent during metformin treatment were less severe than during phenfonnin treatment.It is concluded that treatment of mild diabetes with dichloroacetate and biguanides together has advantages over either compound used alone.
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Published date: 1978
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Local EPrints ID: 458838
URI: http://eprints.soton.ac.uk/id/eprint/458838
PURE UUID: 95b67874-f74a-47ca-928d-83f4f9fda815
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Date deposited: 04 Jul 2022 16:56
Last modified: 23 Jul 2022 00:21
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Author:
Kwok-Chu Man
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