title: The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes.
abstract: OBJECTIVE
  Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes.
  
  
  METHODS
  Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation.
  
  
  RESULTS
  Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis.
  
  
  CONCLUSIONS
  Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Jong Shin
authors.initials: JS
authors.lastname: Woo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Arah
authors.initials: A
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Yang-Gyun
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Se-Yeun
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Kyung Hye
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Sung-Jig
authors.initials: SJ
authors.lastname: Lim
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kyung Hee University, College of Medicine, Seoul, Korea.
authors.forename: Weon
authors.initials: W
authors.lastname: Kim
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000150:complications; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000097:blood / Q000150:complications / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006442:Glycated Hemoglobin / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D010881:Piperidones / Q000494:pharmacology / Q000627:therapeutic use; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D018754:Ventricular Dysfunction / Q000097:blood / Q000150:complications / Q000503:physiopathology
chemical_list: D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D019255:NADPH Oxidases; D010881:Piperidones; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; C474033:FoxO3 protein, mouse; C534891:LC15-0444