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

Aims: Reduced cardiac beta-adrenoceptors (beta-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 beta-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 [H-3]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac beta-AR expression. Western blotting of beta-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 [H-3]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced beta(1)-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 (FIR). Significance: This work supports that glycemic control with insulin normalizes cardiac beta-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [C-11]CGP12177 positron emission tomography (PET) in assessing cardiac beta-AR and their modulation with glycemic therapy. (C) 2015 Elsevier Inc. All rights reserved.