title: Effects of saxagliptin and sitagliptin on glycaemic control and pancreatic β-cell mass in a streptozotocin-induced mouse model of type 2 diabetes.
abstract: OBJECTIVE
  We examined the effects of the oral dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin on glycaemic control and pancreatic β-cell mass and morphology in a mouse model of type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Male C57BL/6 mice (n = 12/group) aged 4 to 6 weeks and weighing >15 g received a high-fat diet throughout this 45-day study. After a 7-day handling period, baseline levels of plasma glucose, plasma insulin and glycated haemoglobin (HbA1c) were assessed. Animals were allocated to one of six groups: compound vehicle control, intraperitoneal streptozotocin (STZ, 50 mg/kg)-treated control and saxagliptin (10 mg/kg) or sitagliptin (10 mg/kg, positive control) initiated 7 days before or 1 day after STZ administration. Endpoints included changes in body weight, food and water consumption, glucose tolerance (approximately 3 weeks post-STZ), fasting glucose and HbA1c and immunohistochemical analyses of the pancreas.
  
  
  RESULTS
  Body weight, weight gain and food intake were reduced in STZ versus control mice. DPP-4 inhibitor treatment did not affect these changes, but the increase in water intake observed post-STZ administration was significantly attenuated with DPP-4 inhibitors whether initiated before or after STZ injury. Small but significant improvements in glycaemic control were observed with DPP-4 inhibitors versus the STZ control. Improved β-cell mass and morphology were observed with saxagliptin given pre- or post-STZ and sitagliptin given post-STZ.
  
  
  CONCLUSIONS
  Saxagliptin mitigated damage to β-cells and improved glycaemic control in this mouse model of T2DM.
authors.affiliation: CVGI Discovery iMED, AstraZeneca Pharmaceuticals, Macclesfield, UK. Simon.Poucher@astrazeneca.com
authors.forename: S M
authors.initials: SM
authors.lastname: Poucher
authors.forename: S
authors.initials: S
authors.lastname: Cheetham
authors.forename: J
authors.initials: J
authors.lastname: Francis
authors.forename: B
authors.initials: B
authors.lastname: Zinker
authors.forename: M
authors.initials: M
authors.lastname: Kirby
authors.forename: S P
authors.initials: SP
authors.lastname: Vickers
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D059305:Diet, High-Fat; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004326:Drinking; D004435:Eating; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000218:Adamantane; D001786:Blood Glucose; D004151:Dipeptides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles; C502994:saxagliptin