title: Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice.
abstract: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, alogliptin dose-dependently inhibited DPP-4 activity by 28-82% and increased active GLP-1 by 3.2-6.4-fold. After 4 weeks, alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4-0.9%, plasma glucose by 7-28% and plasma triglycerides by 24-51%, increased plasma insulin by 1.5-2.0-fold, and decreased plasma glucagon by 23-26%, with neutral effects on body weight and food consumption. In addition, after drug washout, alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration-time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes.
authors.affiliation: Takeda Pharmaceutical Company Ltd, Pharmaceutical Research Division I, Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Moritoh
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asakawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Kataoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Odaka
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010880:Piperidines / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D010880:Piperidines; D014280:Triglycerides; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C520853:alogliptin