Metformin primarily decreases plasma glucose not by gluconeogenesis suppression but by activating glucose utilization in a non-obese type 2 diabetes Goto-Kakizaki rats

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 (IC50 = 0.136 µM). Instead, metformin dose-dependently increased glucose uptake and the following lactate production at 30 to 100 µM.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.