Studies on the mechanism of action of Wy 23675: A novel hypoglycaemic agent.

The mode of action of the novel hypoglycaemic agent, Wy 23675, has been compared with that of the sulphonylurea, tolbutamide, and that of the biguanide, phenformin. Wy 23675 has been shown, like tolbutamide, to stimulate insulin release, but it has also been shown to have an insulin-indeoendant hypoglycaemic activity. Wy 23675 lowers blood glucose levels in both normal and alloxan-diabetic rats in contrast to phenformin, which does not affect blood glucose levels in the normoglycaemic rat. Wy 23675 has been shown to stimulate glucose utilisation in vivo independant of any effect on insulin release, whereas tolbutamide is only active when it can stimulate insulin release. Phenformin stimulated glucose utilization in vivo, but only in hyperglycaemic conditions. Phenformin stimulated glucose utilization by hemidiaphragms at a lower concentration when they were prepared from alloxan-diabetic rats than from normal rats. Phenformin caused a decreased glycogen content and an increase in lactate production in the hemidiaphragm, suggesting an increase in glycolysis and a possible inhibition of lactate oxidation. Phenformin, in high concentrations, stimulated glucose utilization by adipocytes prepared from normal and alloxan-diabetic rats. Wy 23675 stimulated glucose uptake into isolated hemidiaphragms and adipocytes prepared from normal and alloxan-diabetic rats. In hemidiaphragms, Wy 23675 caused an increase in glycogen synthesis with no effect on lactate or pyruvate production. The measured increase in glucose uptake could not be solely accounted for by the measured increase in glycogen content, suggesting an increase in glucose oxidation. The possibility that Wy 23675 could activate pyruvate dehydrogenase is discussed. Both phenformin and Wy 23675 inhibited gluconeogenesis from lactate plus pyruvate and from dihydroxyacetone, but not from xylitol in hepatocytes prepared from fasted, normal or alloxan-diabetic rats. Hepatocytes from fasted, normal rats required a higher concentration of these drugs to inhibit gluconeogenesis than did hepatocytes from alloxan-diabetic rats or hepatocytes from fasted, normal rats which were stimulated by glucagon. The pattern of hepatic metabolite levels following phenformin treatment of alloxan-diabetic rats showed a negative cross-over between 3-phosphoglycerate and dihydroxyacetone phosphate. Measurement of appropriate metabolite ratios showed a more reduced state in the cytosol and mitochondria and these redox changes are discussed. Wy 23675 treatment resulted in a negative cross-over between malate and phosphoenolpyruvate indicating a possible effect on the enzyme phosphoenolpyruvate carboxykinase, although this was hot supported in a preliminary in vitro experiment