Metformin is an anti-diabetic agent that has been reported to decrease plasma
glucose by multiple mechanisms, such as decreasing hepatic
glucose production and activating peripheral
glucose utilization. In order to elucidate the primary
glucose-lowering mechanism of
metformin, the present study focused on a comparison of the acute effect between
metformin and
CS-917 as a direct gluconeogenesis inhibitor. We examined the effect of
metformin and
CS-917 on
glucose turnover in intravenous
glucose-loaded Goto-Kakizaki (GK) rats, and on gluconeogenesis and
glucose utilization in rat hepatocytes. Moreover, the
glucose-lowering effect of
metformin and
CS-917 was compared in a fed and a fasted state in GK rats. In intravenous
glucose-loaded GK rats,
metformin and
CS-917 lowered plasma
glucose by increasing the
glucose disappearance rate and by decreasing the
glucose appearance rate, respectively. In rat hepatocytes,
CS-917 but not
metformin suppressed gluconeogenesis (IC(50)=0.136microM). Instead,
metformin dose-dependently increased
glucose uptake and the following
lactate production at 30 to 100microM.
Metformin decreased plasma
glucose more in a fed state than in a fasted state in GK rats.
CS-917, however, decreased plasma
glucose more in a fasted state. These results confirm that
metformin primarily decreases plasma
glucose not by gluconeogenesis inhibition but by activating
glucose utilization in GK rats. Moreover,
metformin and
CS-917 have different
glucose-lowering effects depending on the nutrient state, which may be related to differences in their mechanisms of action. Such differences in action may have implications for
metformin and
CS-917 in the treatment of
type 2 diabetes patients.