Assessment of Glucagon-Like Peptide-1 Analogue and Renin Inhibitor on the Binding and Regulation of GLP-1 Receptor in Type 1 Diabetic Rat Hearts

Abstract

This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with 125I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.

Mechanisms for the cardiovascular effects of glucagon-like peptide-1

“…The affinity of GLP-1 to its receptor, at least in the coronary endothelium, is markedly lower in streptozotocin-induced diabetic state (Artinian et al 2011), which is characterized by degeneration in pancreatic b-cells and lack of insulin (Akbarzadeh et al 2007). In these rats, the affinity of GLP-1 to its receptor was greatly enhanced by insulin treatment (Artinian et al 2011). However, in the car-diomyocytes of streptozotocin-induced diabetic rats, the affinity of GLP-1 to its receptor was increased in diabetic state and reduced by insulin treatment but increased by aliskiren (renin inhibitor) (Artinian et al 2011).…”

“…In these rats, the affinity of GLP‐1 to its receptor was greatly enhanced by insulin treatment (Artinian et al . ). However, in the cardiomyocytes of streptozotocin‐induced diabetic rats, the affinity of GLP‐1 to its receptor was increased in diabetic state and reduced by insulin treatment but increased by aliskiren (renin inhibitor) (Artinian et al .…”

“…However, in the cardiomyocytes of streptozotocin‐induced diabetic rats, the affinity of GLP‐1 to its receptor was increased in diabetic state and reduced by insulin treatment but increased by aliskiren (renin inhibitor) (Artinian et al . ). Contrastingly, in another study streptozotocin‐induced diabetic state was associated with increased affinity of GLP‐1 to its receptor in the coronary endothelium but decreased affinity in the cardiomyocytes with normalization in both locations with insulin and DPP4 inhibitor (Barakat et al .…”

“…The dysfunctional myocardial glucose uptake in response to GLP-1 in type 2 diabetic individuals may be because of altered GLP-1R affinity. The affinity of GLP-1 to its receptor, at least in the coronary endothelium, is markedly lower in streptozotocin-induced diabetic state (Artinian et al 2011), which is characterized by degeneration in pancreatic b-cells and lack of insulin (Akbarzadeh et al 2007). In these rats, the affinity of GLP-1 to its receptor was greatly enhanced by insulin treatment (Artinian et al 2011).…”

“…The affinity of GLP‐1 to its receptor, at least in the coronary endothelium, is markedly lower in streptozotocin‐induced diabetic state (Artinian et al . ), which is characterized by degeneration in pancreatic β‐cells and lack of insulin (Akbarzadeh et al . ).…”