title: Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet.
abstract: OBJECTIVE
  Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes.
  
  
  METHODS
  Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10weeks.
  
  
  RESULTS
  Both doses of anagliptin significantly inhibited the plasma DPP-4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the β-cell mass in both genotypes of mice.
  
  
  CONCLUSIONS
  High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nakaya
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Katsuyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Moritaka
authors.initials: M
authors.lastname: Goto
authors.forename: Takahito
authors.initials: T
authors.lastname: Jomori
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000150:complications / Q000517:prevention & control; D057895:Haploinsufficiency; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000209:etiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D011743:Pyrimidines; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase; D018819:Dipeptidyl Peptidase 4; C583175:anagliptin