Insulin therapy normalizes reduced myocardial β-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats

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. Ex vivo biodistribution experiments with [3H]CGP12177 were performed in high-fat fed STZ rats after 8weeks of hyperglycemia evaluating cardiac β-AR expression. Western blotting of β-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1week post-STZ (InsE) for 7weeks, or late at 6weeks post-STZ (InsL) for 2weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects. Reduced myocardial [3H]CGP12177 binding occurred 8weeks 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). 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 [11C]CGP12177 positron emission tomography (PET) in assessing cardiac β-AR and their modulation with glycemic therapy. [Display omitted]