Role of glucagon-like peptide-1 analogues on insulin receptor regulation in diabetic rat hearts

Abstract

This study focused on the regulation and affinity modulation of the insulin receptor of coronary endothelium and cardiomyocytes in nondiabetic and STZ-induced type 1 diabetic rats. Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. The results showed that diabetes (D) decreased the tau value on the coronary endothelium and increased it on cardiomyocytes compared with the nondiabetic group (N). Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. On the coronary endothelium, tau values of DI and DIDp were normalized. Western blots of the insulin receptor showed upregulation in D, downregulation in DI, and normalization in DE and DDp. Immunohistochemistry and RT-PCR findings indicated atrial natriuretic factor (ANF) in all diabetic ventricles, thus ascertaining hypertrophy. Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4.

Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

“…Nonetheless, other studies have consistently shown GLP-1 to protect cardiomyocytes from apoptosis both in vivo and in vitro [ 15 , 30 ], although reported effects on cardiomyocyte hypertrophy have been varied. Whilst some have reported the DPP-4 inhibitor, sitagliptin, and exendin-4 to have no effect on cardiomyocyte hypertrophy in experimental MI and type 1 diabetes, respectively, others have shown that GLP-1R activation with liraglutide reduces cardiomyocyte hypertrophy after both MI and high-fat feeding [ 15 , 44 – 46 ]. Therefore, it is maybe not surprising that exendin-4 exerted only modest effects on post-MI cardiomyocyte remodelling, which may have occurred directly or secondary to more pronounced effects on the ECM.…”

Role of glucagon-like peptide-1 and its agonists on early prevention of cardiac remodeling in type 1 diabetic rat hearts

“…with exendin-4 (Sigma Aldrich Co., St. Louis, USA), 0.03 μg/kg b.w., twice daily, and gavaged H 2 O 4 ml/kg b.w., once daily (placebo) (Hantouche et al 2010).…”