Cation Selective Transporters in the Intestine Contribute to the Glucose-Lowering Effect of Metformin

Metformin is the most widely prescribed anti-hyperglycemic agent for Type 2 Diabetes Mellitus (T2DM). Despite its frequent use, the intestinal absorption mechanism of this orally administered drug is still under investigation, and it is not known why up to 36% of diabetics on metformin therapy are nonresponsive. Previous studies in the Thakker laboratory have demonstrated that organic cation transporters (Octs) mediate metformin intestinal absorption and influence its pharmacokinetics in mice. Using a diabetic mouse model of T2DM, this study aims to demonstrate that Octs enhance the contribution of the intestine to the overall glucose-lowering effects of metformin. Mice were administered metformin orally in the presence and absence of the cation-selective transporter inhibitor,pentamidine, and blood glucose levels were measured using an OneTouch Ultra glucometer. Our data suggest that intestinal cation-selective transporters facilitate the glucose-lowering effect of oral metformin, and that inhibition of these transporters by pentamidine diminishes the glucose-lowering efficacy of this drug. Thus, the intestine may play a role in the pharmacodynamic effects of metformin and contribute to the glucose-lowering response.Doctor of Pharmac