title: Sitagliptin prevents aggravation of endocrine and exocrine pancreatic damage in the Zucker Diabetic Fatty rat - focus on amelioration of metabolic profile and tissue cytoprotective properties.
abstract: BACKGROUND
  The purpose of this study was to investigate some of the possible mechanisms underlying the protective effects of a dipeptidyl peptidase IV (DPP-IV) inhibitor, sitagliptin, on pancreatic tissue in an animal model of type 2 diabetes mellitus (T2DM), the Zucker Diabetic Fatty (ZDF) rat, focusing on glycaemic, insulinic and lipidic profiles, as well as, on apoptosis, inflammation, angiogenesis and proliferation mediators.
  
  
  METHODS
  Male obese diabetic ZDF (fa/fa) rats, aged 20 weeks, were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks and compared to untreated diabetic and lean control littermates. Metabolic data was evaluated at the beginning and at the end of the treatment, including glycaemia, HbA1c, insulinaemia, HOMA-beta and TGs. Endocrine and exocrine pancreas lesions were assessed semiquantitatively by histopathological methods. Pancreas gene (mRNA) and protein expression of mediators of apoptotic machinery, inflammation and angiogenesis/proliferation (Bax, Bcl2, IL-1β, VEGF, PCNA and TRIB3) were analyzed by RT-qPCR and/or by immunohistochemistry.
  
  
  RESULTS
  Sitagliptin treatment for 6 weeks (between 20 and 26 week-old) was able to significantly (p < 0.001) ameliorate all the metabolic parameters, by preventing the increase in blood glucose and in serum TGs contents (16.54% and 37.63%, respectively, vs untreated), as well as, by preventing the decrease in serum insulin levels and in the functional beta cells capacity accessed via HOMA-beta index (156.28% and 191.74%, respectively, vs untreated). Sitagliptin-treated diabetic rats presented a reduced pancreas Bax/Bcl2 ratio, suggestive of an antiapoptotic effect; in addition, sitagliptin was able to completely reduce (p < 0.001) the pancreas overexpression of IL-1β and TRIB3 found in the untreated diabetic animals; and promoted a significant (p < 0.001) overexpression of VEGF and PCNA.
  
  
  CONCLUSIONS
  In this animal model of obese T2DM (the ZDF rat), sitagliptin prevented β-cell dysfunction and evolution of pancreatic damage. The protective effects afforded by this DPP-IV inhibitor may derive from improvement of the metabolic profile (viewed by the amelioration of glucose and TGs levels and of insulin resistance) and from cytoprotective properties, such as antiapoptotic, anti-inflammatory, pro-angiogenic and pro-proliferative.
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, Sub-Unit 1 (Polo III), University of Coimbra, 3000-548 Coimbra, Portugal.|ESAV, Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mega
authors.affiliation: ESAV, Polytechnic Institute of Viseu, Viseu, Portugal.|Center for Studies in Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Vala
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology, Coimbra, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues-Santos
authors.affiliation: ESAV, Polytechnic Institute of Viseu, Viseu, Portugal.|Center for Studies in Education, Technologies and Health (CI&DETS), Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, Sub-Unit 1 (Polo III), University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Frederico
authors.initials: F
authors.lastname: Teixeira
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, Sub-Unit 1 (Polo III), University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Rosa
authors.initials: R
authors.lastname: Fernandes
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, Sub-Unit 1 (Polo III), University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, Sub-Unit 1 (Polo III), University of Coimbra, 3000-548 Coimbra, Portugal.|ESAV, Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Edite Teixeira
authors.initials: ET
authors.lastname: de Lemos