title: Cardiac β-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.
abstract: OBJECTIVE
  Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.
  
  
  METHODS
  Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.
  
  
  RESULTS
  At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.
  
  
  CONCLUSIONS
  Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: James M
authors.initials: JM
authors.lastname: Haley
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5; Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg Street 1, 30625 Hannover, Germany.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5; Yale Translational Research Imaging Center, Yale University School of Medicine, New Haven, CT, 06520, United States of America.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Thorn
authors.affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5; Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montreal, University of Montreal Hospital Research Centre (CRCHUM), 900 Rue Saint-Denis, Montréal, Québec, Canada H2X 0A9.
authors.forename: Jean N
authors.initials: JN
authors.lastname: DaSilva
mesh_terms: D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D011943:Receptors, Adrenergic, beta