Insulin therapy normalizes reduced myocardial β-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats.
OBJECTIVE
Reduced cardiac β-adrenoceptors (β-AR) and cardiovascular (CV) dysfunction occur in diabetes mellitus (DM) and can be normalized by insulin. It is unclear how the duration of untreated hyperglycemia prior to intervention impacts insulin's effects. This study assesses insulin's effect on reduced myocardial β-AR and CV function, comparing insulin therapy at the onset of hyperglycemia and after a sustained period of hyperglycemia in streptozotocin (STZ) rats.


METHODS
Ex vivo biodistribution experiments with [(3)H]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac β-AR expression. Western blotting of β-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8 weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1 week post-STZ (InsE) for 7 weeks, or late at 6 weeks post-STZ (InsL) for 2 weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects.


RESULTS
Reduced myocardial [(3)H]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced β1-AR in hyperglycemics, but not in either treatment. InsE and InsL treatments improved prolonged mitral valve deceleration (MVD) observed in hyperglycemic animals, but hyperglycemic and InsL still displayed reduced heart rates (HR).


CONCLUSIONS
This work supports that glycemic control with insulin normalizes cardiac β-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [(11)C]CGP12177 positron emission tomography (PET) in assessing cardiac β-AR and their modulation with glycemic therapy.
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario K1H8M5, Canada.
James M
JM
Haley
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario K1H8M5, Canada; Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg Street 1, 30625 Hannover, Germany.
James T
JT
Thackeray
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada.
Maria
M
Kolajova
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario K1H8M5, Canada; Yale Translational Research Imaging Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Stephanie L
SL
Thorn
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario K1H8M5, Canada; Department of Radiology, Radio-Oncology and Nuclear Medicine, University of Montreal, Montréal, Québec H2X 0A9, Canada; University of Montreal Hospital Research Centre (CRCHUM), 900 Rue Saint-Denis, Montréal, Québec H2X 0A9, Canada. Electronic address: jean.dasilva@umontreal.ca.
Jean N
JN
DaSilva
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006943:Hyperglycemia / Q000188:drug therapy*; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D007328:Insulin; D011943:Receptors, Adrenergic, beta
Beta-adrenoceptors; CGP12177; Diabetes; Echocardiography; Norepinephrine; PET; Sympathetic nervous system