Cardiac Function in Mice Lacking the Glucagon-Like Peptide-1 Receptor

• Published in: Endocrinology (Philadelphia) 2003-06, Vol.144 (6), p.2242-2252
• Main Authors: Gros, Robert, You, Xiaomang, Baggio, Laurie L, Kabir, M. Golam, Sadi, Al Muktafi, Mungrue, Imran N, Parker, Thomas G, Huang, Qingling, Drucker, Daniel J, Husain, Mansoor
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Pressure; Body Weight; c-Fos protein; Cardiovascular system; Diastolic pressure; Echocardiography; Epinephrine; Fundamental and applied biological sciences. Psychology; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor; Heart - physiology; Heart Diseases - diagnostic imaging; Heart Diseases - pathology; Heart Diseases - physiopathology; Heart Rate; Hemodynamics; Histology; Hypothalamus; Insulin; Male; Mice; Mice, Mutant Strains; Muscle contraction; Myocardium - pathology; Peptides; Receptors; Receptors, Glucagon - genetics; Signal Transduction - physiology; Stress response; Stress, Physiological - physiopathology; Structure-function relationships; Ventricular Pressure
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0007

Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R−/−) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls. At the age of 5 months, echocardiography and histology demonstrate increased LV thickness in GLP-1R−/− mice. Although baseline hemodynamic parameters of GLP-1R−/− did not differ significantly from those of wild type, GLP-1R−/− mice displayed impaired LV contractility and diastolic function after insulin administration. The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R−/− mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R−/− mice. These findings provide new evidence implicating an essential role for GLP-1R in the control of murine cardiac structure and function in vivo.