title: The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  db/db mice (n=15/group) were treated for 8weeks with 10mg/kg/day empagliflozin monotherapy, 10mg/kg/day empagliflozin plus 3mg/kg/day linagliptin combination therapy, or 3mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic-hyperinsulinemic clamp studies were performed 4days 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.
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kern
authors.affiliation: IFB Obesity Diseases, Junior Research Group Animal Models, University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Mayoux
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany. Electronic address: bluma@medizin.uni-leipzig.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects; D000069476:Linagliptin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D006027:Glycosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000069476:Linagliptin; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; C570240:empagliflozin; D005947:Glucose
keywords: DPP-4 inhibitor; Glycemic control; Insulin resistance; SGLT2 inhibitor