title: Dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits pancreatic beta cell apoptosis in association with its effects suppressing endoplasmic reticulum stress in db/db mice.
abstract: OBJECTIVE
  Vildagliptin promotes beta cell survival by inhibiting cell apoptosis. It has been suggested that chronic ER (endoplasmic reticulum) stress triggers beta cell apoptosis. The objective of the study is to explore whether the pro-survival effect of vildagliptin is associated with attenuation of endoplasmic reticulum stress in islets of db/db mice.
  
  
  METHODS
  Vildagliptin was orally administered to db/db mice for 6 weeks, followed by evaluation of beta cell apoptosis by caspase3 activity and TUNEL staining method. Endoplasmic reticulum stress markers were determined with quantitative RT-PCR, immunohistochemistry and immunoblot analysis.
  
  
  RESULTS
  After 6 weeks of treatment, vildagliptin treatment increased plasma active GLP-1 levels (22.63±1.19 vs. 11.69±0.44, P<0.001), inhibited beta cell apoptosis as demonstrated by lower amounts of TUNEL staining nuclei (0.37±0.03 vs. 0.55±0.03, P<0.01) as well as decreased caspase3 activity (1.48±0.11 vs. 2.67±0.13, P<0.01) in islets of diabetic mice compared with untreated diabetic group. Further, vildagliptin treatment down-regulated several genes related to endoplasmic reticulum stress including TRIB3 (tribbles homolog 3) (15.9±0.4 vs. 33.3±1.7, ×10⁻³, P<0.001), ATF-4(activating transcription factor 4) (0.83±0.06 vs. 1.42±0.02, P<0.001) and CHOP(C/EBP homologous protein) (0.07±0.01 vs. 0.16±0.01, P<0.001).
  
  
  CONCLUSIONS
  Vildagliptin promoted beta cell survival in db/db mice in association with down-regulating markers of endoplasmic reticulum stress including TRIB3, ATF-4 as well as CHOP.
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yan-ju
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Chun-jun
authors.initials: CJ
authors.lastname: Li
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Dai-qing
authors.initials: DQ
authors.lastname: Li
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: De-min
authors.initials: DM
authors.lastname: Liu
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China. Electronic address: xfx22081@vip.163.com.
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Chen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006943:Hyperglycemia / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008817:Mice, Mutant Strains; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077597:Vildagliptin
chemical_list: C081452:Atf4 protein, mouse; D018797:Cell Cycle Proteins; C497250:Ddit3 protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; C474830:TRB3 protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000077597:Vildagliptin; D000218:Adamantane
keywords: Endoplasmic reticulum; Type 2 diabetes; Vildagliptin