title: Hepatic role in an early glucose-lowering effect by a novel dipeptidyl peptidase 4 inhibitor, evogliptin, in a rodent model of type 2 diabetes.
abstract: Although multiple dipeptidyl peptidase 4 (DPP4) inhibitors have shown glucose-lowering effects by preserving pancreatic cells in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, the hepatic role in regulation of glucose homeostasis by DPP4 inhibitors in HFD/STZ mice remains elusive. In herein study, parallel comparison of effects on the liver (expression of gluconeogenic genes and the linked signaling molecules) and pancreas (islet morphology and relative area of alpha or beta cells) in combination with glucose-lowering effects were made at the end of 2- and 10-week of evogliptin treatment in HFD/STZ mice. Significant control of hyperglycemia was observed from the second week and persisted during 10-week treatment of 0.3% evogliptin in HFD/STZ mice. This effect was accompanied by increased level of plasma glucagon-like peptide-1 and preserved pancreas islet structure. Furthermore, the hepatic increases in gluconeogenic gene expression in HFD/STZ mice was significantly reduced by evogliptin treatment, which was accompanied by the suppression of cAMP response element-binding protein (CREB) phosphorylation and expression of transducer of regulated CREB protein 2. This hepatic effect of evogliptin treatment was reproduced in 2-week study, however, pancreatic beta-cell area was not altered yet although the expression of pancreatic and duodenal homeobox protein 1 was increased. We conclude that the suppression of hepatic gluconeogenesis by evogliptin is followed by preservation of pancreatic islet, leading to remarkable and persistent glucose-lowering effect in HFD/STZ mice. Our findings provide further insight for the hepatic role in DPP4 inhibitor-mediated glucose control in diabetes.
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Ye-Hwang
authors.initials: YH
authors.lastname: Cheong
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Yu-Na
authors.initials: YN
authors.lastname: Chae
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea.
authors.forename: Youngyi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Chonbuk National University Medical School, Jeonju-si, Jeollabuk-do, Republic of Korea.
authors.forename: Sun-O
authors.initials: SO
authors.lastname: Ka
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Il-Hoon
authors.initials: IH
authors.lastname: Jung
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors.forename: Chang-Yell
authors.initials: CY
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea. Electronic address: ejbae@woosuk.ac.kr.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Bae
authors.affiliation: Drug Discovery Research Laboratories, Dong-A ST Research Institute, #21 Geumhwa-ro, 105Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-905, Republic of Korea. Electronic address: ssonmh@donga.co.kr.
authors.forename: Moon-Ho
authors.initials: MH
authors.lastname: Son
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D017362:Cyclic AMP Response Element-Binding Protein; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D010879:Piperazines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D005947:Glucose
keywords: Dipeptidyl peptidase-4; Evogliptin; Evogliptin (PubChem CID: 25022354); Liver; PDX-1; Pancreas; Streptozotocin (24899428); TORC2