The mechanism of the acute hypoglycemic action of phenformin (DBI).

The mechanisms by which biguanide (phenformin) acutely brings about a reduction in blood glucose in diabetic subjects has been studied with the aid of C-6 14C glucose. Six diabetic subjects were studied, each at three separate dose levels of phenformin. Two of these same subjects were studied with placebo. Consistent and increasingly pronounced effects of drug versus placebo were noted as the level of biguanide was increased. Biguanide consistently lowered hepatic glucose output while not significantly affecting the removal of glucose from the circulation. It was noted that glucogenesis from lactate was not significantly curtailed. However, a lack of stimulation in Cori Cycle activity in the presence of significant elevations of circulating lactate were taken as an indication of inhibition of glucogenesis from this substrate. On balance, it is concluded that the acute hypoglycemic action of this biguanide is mediated primarily through a restriction in the supply of glucose from the liver to the circulation. The data support the contention that these drugs inhibit hepatic glucogenesis even though Cori Cycle activity may be increased and also suggest that a portion of the decrease in hepatic glucose supply may be the result of impaired glycogenolysis.