The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin

Aims. Combining different drug classes to improve glycemic control is one treatment strategy for type 2 diabetes. The effects on insulin sensitivity of long-term treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin alone or co-administered with the dipeptidyl peptidase-4 inhibitor linagliptin (both approved antidiabetes drugs) were investigated in mice using euglycemic hyperinsulinemic clamps. Materials and Methods. db/db mice (n = 15/group) were treated for 8 weeks with 10 mg/kg/day empagliflozin monotherapy, 10 mg/kg/day empagliflozin plus 3 mg/kg/day linagliptin combination therapy, or 3 mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic hyperinsulinemic clamp studies were performed 4 days after the last dose of treatment. Results. HbA1c and 2-hour fasting glucose concentrations were improved with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. During the clamp, glucose disposal rates increased and hepatic glucose production decreased with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. Glucose uptake in liver and kidney was higher with empagliflozin monotherapy and combination therapy compared with vehicle; glucose uptake into both muscle and adipose tissue was only affected by linagliptin treatment. Empagliflozin and combination therapy altered the expression of genes involved in the inflammatory response, fatty acid synthesis and oxidation. Conclusions. These findings suggest that the insulin-sensitizing effects of SGLT2 inhibition contribute to improvements in glycemic control in insulin-resistant states. (C) 2015 Elsevier Inc. All rights reserved.