Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats

• Published in: European journal of pharmacology 2013-01, Vol.698 (1-3), p.74-86
• Main Authors: Giannocco, Gisele, Oliveira, Kelen C., Crajoinas, Renato O., Venturini, Gabriela, Salles, Thiago A., Fonseca-Alaniz, Miriam H., Maciel, Rui M.B., Girardi, Adriana C.C.
• Format: Article
• Language: English
• Subjects: adults; Animals; blood pressure; Blood Pressure - drug effects; Body Weight - drug effects; cardiomyocytes; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; gene expression; Glucagon-Like Peptide 1 - blood; Glucagon-like peptide-1; Glucose - metabolism; Glucose transporter type 4; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; glycemic effect; Heart; Heart - drug effects; Homeostasis - drug effects; Hypertension; Intracellular Space - drug effects; Intracellular Space - metabolism; Male; messenger RNA; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; muscles; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; pharmacology; Phosphorylation - drug effects; Protein Transport - drug effects; Pyrazines - pharmacology; Rats; Rats, Inbred SHR; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Sitagliptin Phosphate; Skeletal muscle; Triazoles - pharmacology; Up-Regulation - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.09.043

The purpose of the current study was to test the hypothesis that the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart and skeletal muscle of spontaneously hypertensive rats (SHRs). Ten days of treatment with sitagliptin (40mg/kg twice daily) decreased plasma DPPIV activity in both young (Y, 5-week-old) and adult (A, 20-week-old) SHRs to similar extents (∼85%). However, DPPIV inhibition only lowered blood pressure in Y-SHRs (119±3 vs. 136±4mmHg). GLUT4 translocation, total protein levels and mRNA expression were decreased in the heart, soleus and gastrocnemius muscle of SHRs compared to age-matched Wistar Kyoto (WKY) normotensive rats. These differences were much more pronounced between A-SHRs and A-WKY rats than between Y-SHRs and Y-WKY rats. In Y-SHRs, sitagliptin normalized GLUT4 expression in the heart, soleus and gastrocnemius. In A-SHRs, sitagliptin increased GLUT4 expression to levels that were even higher than those of A-WKY rats. Sitagliptin enhanced the circulating levels of the DPPIV substrate glucagon-like peptide-1 (GLP-1) in SHRs. In addition, stimulation of the GLP-1 receptor in cardiomyocytes isolated from SHRs increased the protein level of GLUT4 by 154±13%. Collectively, these results indicate that DPPIV inhibition upregulates GLUT4 in heart and skeletal muscle of SHRs. The underlying mechanism of sitagliptin-induced upregulation of GLUT4 in SHRs may be, at least partially, attributed to GLP-1.