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The relationship between the biguanide inhibition of oxidations and their effect on glucose metabolism in vitro has been investigated. We found a good correlation between the concentration of biguanide causing a halfmaximal inhibition of pyruvate oxidation (Ki) and the concentration eliciting a half-maximal stimulation (Ks) of glucose uptake in several tissues from rat, guinea pig and pigeon. Guinea pig epididymal fat pad was the most sensitive tissue tested. Gluconeogenesis by minced guinea pig liver was inhibited by the biguanides. The ability of the biguanides to inhibit gluconeogenesis correlated well with their ability to inhibit pyruvate oxidation. Inhibition of oxidations by the biguanides does not appear to be a result of a direct inhibition of the enzymes catalyzing these oxidations but seems to be secondary to a primary effect on the coupled processes of electron transport and oxidative phosphorylation. We have summarized and discussed objections to the theory that the metabolic actions of the biguanides are a result of their inhibition of oxidative processes. Our conclusion is that the inhibition of oxidations caused by the biguanides is directly related to their metabolic and hypoglycemic effects. DIABETES 77: 96-104, February, 1968. The biguanides, phenformin (phenethylbiguanide, DBI), metformin (dimethylbiguanide, Glucophage) and buformin (butylbiguanide, Silubin) are oral hypoglycemic agents used in the treatment of diabetes mellitus. Phenformin was first reported to be a hypoglycemic agent of low toxicity by Ungar, Freedman and Shapiro. 1 This observation was followed up by Tyberghein and Williams 2 and Williams et al., 3 who reported that phenformin caused an increase in glucose uptake and lactate production and a decrease in glycogen levels and oxygen uptake by isolated rat diaphragm, muscle and liver. In addition, they obtained evidence suggesting that phenformin caused a decrease in gluconeogenesis in vivo. suggested that the inhibitory effects of the biguanides on aerobic processes were related to their effects on glucose metabolism. This hypothesis received support from Kruger et al, 6 and Wick and co-workers. 7 Krall and Bradley 8 also tentatively supported this hypothesis and pointed out the similarity between the metabolic effects of phenformin and those of the guanidines. The guanidines had earlier been reported to be hypoglycemic agents, 9 ' 10 the action of which resulted from respiratory inhibition. 11 -12 Hollunger 13 localized the action of the guanidines on the electron transport chain, suggesting that they inhibit the transfer of high energy bonds to ADP, causing a secondary block of electron transport and oxygen uptake. Recent work with the biguanides has demonstrated that they too interfere with the reactions of a high energy intermediate of oxidative phosphorylation. 14 ' 15 There seems to be some site specificity involved, 10 with phenformin inhibiting the reaction of a high energy intermediate at Site II of the electron transport chain, which is associated with cytochrom...

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