Aim: To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. Methods: Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3. Results: Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P <.01), whereas the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dL; P <.01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulinmediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg<min; P <.05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2. Conclusion: Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and <-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves <-cell function without significantly affecting insulin sensitivity.