title: A novel dipeptidyl peptidase IV inhibitor DA-1229 ameliorates streptozotocin-induced diabetes by increasing β-cell replication and neogenesis.
abstract: We studied the effect of a novel dipeptidyl peptidase IV (DPP IV) inhibitor, DA-1229, on blood glucose profile and pancreatic β-cell mass in established diabetes after streptozotocin (STZ) treatment. Mice that developed diabetes after administration of STZ 100mg/kg were treated with DA-1229 for 13 weeks. DA-1229 significantly reduced plasma DPP IV activity, and enhanced glucagon-like peptide 1 (GLP-1) levels. In STZ-treated mice fed DA-1229 (STZ-DA), blood glucose levels were significantly lower than those in diabetic mice fed normal chow (STZ-NC). Basal and glucose-stimulated insulin secretion and glucose tolerance assessed by intraperitoneal glucose tolerance test were significantly improved by DA-1229 administration. Volume density of β-cell was significantly increased in STZ-DA mice compared to STZ-NC mice, suggesting that DA-1229-mediated amelioration of established diabetes was due to beneficial effect of DA-1229 on β-cell mass. The number of replicating β-cells and that of scattered small β-cell unit representing β-cell neogenesis were significantly increased in STZ-DA mice compared to STZ-NC mice, explaining increased β-cell mass by DA-1229. The expression of PDX-1, a downstream mediator of GLP-1 action, was increased in islets of STZ-DA mice compared to STZ-NC mice. These results suggest a therapeutic potential of DA-1229 in diabetes, particularly that associated with decreased β-cell mass.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Cho
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Jang
authors.forename: Hwanju
authors.initials: H
authors.lastname: Cheon
authors.forename: Yeon Taek
authors.initials: YT
authors.lastname: Jeong
authors.forename: Do-Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Lim
authors.forename: Song-Hyen
authors.initials: SH
authors.lastname: Choi
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Yang
authors.forename: Chang-Yell
authors.initials: CY
authors.lastname: Shin
authors.forename: Moon Ho
authors.initials: MH
authors.lastname: Son
authors.forename: Soon Hoe
authors.initials: SH
authors.lastname: Kim
authors.forename: Heung-Jae
authors.initials: HJ
authors.lastname: Kim
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D012038:Regeneration / Q000187:drug effects; D013311:Streptozocin / Q000633:toxicity; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D018398:Homeodomain Proteins; D007328:Insulin; D010879:Piperazines; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse