title: Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms.
abstract: BACKGROUND
  Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart.
  
  
  METHODS
  Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays.
  
  
  RESULTS
  Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells.
  
  
  CONCLUSIONS
  Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.
authors.affiliation: Instituto de Investigaciones Sanitarias-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Picatoste
authors.forename: Elisa
authors.initials: E
authors.lastname: Ramírez
authors.forename: Alicia
authors.initials: A
authors.lastname: Caro-Vadillo
authors.forename: Cristian
authors.initials: C
authors.lastname: Iborra
authors.forename: Sara
authors.initials: S
authors.lastname: Ares-Carrasco
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: José
authors.initials: J
authors.lastname: Tuñón
authors.forename: Oscar
authors.initials: O
authors.lastname: Lorenzo
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000502:physiology*; D018149:Glucose Intolerance / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000502:physiology*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D047494:PPAR delta / Q000378:metabolism; D020033:Protein Isoforms / Q000494:pharmacology / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D005353:Fibronectins; D007004:Hypoglycemic Agents; D007328:Insulin; D047494:PPAR delta; D020033:Protein Isoforms; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D000068900:Sitagliptin Phosphate