Abstract：
AIMS: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. MAIN 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. KEY FINDINGS: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). SIGNIFICANCE: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.
journal_name
Life Scijournal_title
Life sciencesauthors
Haley JM,Thackeray JT,Kolajova M,Thorn SL,DaSilva JNdoi
10.1016/j.lfs.2015.03.024subject
Has Abstractpub_date
2015-07-01 00:00:00pages
101-7eissn
0024-3205issn
1879-0631pii
S0024-3205(15)00217-9journal_volume
132pub_type
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