Abstract
ObjectivesReduced 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.ResultsAt 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.ConclusionsCardiac 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.
Highlights
Type-2 diabetes mellitus (DM) and associated complications are increasing globally [1]
Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic Zucker diabetic fatty (ZDF) rats
Type-2 DM is characterized by insulin and leptin resistance, contributing to hyperglycemia and dyslipidemia, which are associated with altered sympathetic nervous system (SNS) signaling and CV dysfunction [5,6,7,8]
Summary
Type-2 diabetes mellitus (DM) and associated complications are increasing globally [1]. Type-2 DM is characterized by insulin and leptin resistance, contributing to hyperglycemia and dyslipidemia, which are associated with altered sympathetic nervous system (SNS) signaling and CV dysfunction [5,6,7,8]. NE binding to cardiac β-adrenergic receptors (β-AR) activates adenylate cyclase increasing cyclic adenosine monophosphate and calcium cycling, which elevates heart rate (HR) and contractility [10]. Chronic activation of the SNS as indicated by elevated circulating NE has been observed in DM and HF, and correlates with reduced NET expression and CV risk. Zucker diabetic fatty (ZDF) rats were selectively bred from the Zucker obese strain to exhibit hyperglycemia and have a knock out for the gene encoding the leptin receptor contributing to hyperleptinemia and increased fat mass. ZDF rats show early insulin resistance and hyperinsulinemia and progressive hyperglycemia as pancreatic β-cell failure impairs insulin secretion, similar to human type-2 DM [16,17]
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