The Synergistic Effects of Pioglitazone on the Glucose-Lowering Action of Metformin in Relation to OCT1 and Gluts m-RNA Expression in Healthy Volunteer

Objective: Organic Cation Transporter 1 (OCT1) plays a key role in the disposition of metformin in hepatocytes; a recent non-clinical study reported that the peroxisome-proliferator activated receptor γ agonist pioglitazone increased the expression of Slc22a1 (Oct1) by 3.1-fold as well as its transporting function. We therefore evaluated the effect of pioglitazone on the glucose-lowering effect of metformin in 15 human participants using the Oral Glucose Tolerance Test (OGTT) and measuring the mRNA levels of OCT1, as well as those of Glucose Transporter 1 (GLUT 1) and GLUT4, which are also important in glucose utilization, in peripheral blood cells. Research design and methods: The glucose-lowering effects of metformin were evaluated by the OGTT before and after metformin treatment on Days 1 and 2 of the study and again on Days 18 and 19 after a 14-day course of pioglitazone 30 mg/day. Differences in maximum glucose levels (ΔGmax) and the areas under the glucose-time curve during the first 60 min after glucose ingestion (ΔAUCgluc60) and the entire 180-min test (ΔAUCgluc) caused by metformin treatment were determined before and after pioglitazone administration. Results: Pioglitazone increased ΔGmax by 50.0% (P=0.021), ΔAUCgluc60 by 88.1% (P=0.020), and ΔAUCgluc by 266%. Pioglitazone did not increase OCT1 and GLUT1 mRNA levels in peripheral blood cells. Conclusion: OCT1 induction plays a limited role in the synergistic effect of pioglitazone on the glucose-lowering activity of metformin. However, this synergistic effect lasted 3 days after pioglitazone treatment ended, which warrants further clinical investigation.