Role of glucagon-like peptide-1 analogues on insulin receptor regulation in diabetic rat hearts.
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.
Department of Physiology, Faculty of Medicine, American University of Beirut, Beirut 11-236, Lebanon.
Christine M
CM
Hantouche
Khalil M
KM
Bitar
Georges M
GM
Nemer
Mounir Y
MY
Obeid
Lina N
LN
Kadi
Asdghig H
AH
Der-Boghossian
Anwar B
AB
Bikhazi
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000502:physiology* / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism*; D014688:Venoms / Q000008:administration & dosage / Q000627:therapeutic use
D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D011972:Receptor, Insulin