Present address: Novo Nordisk A/S, Diabetes and Obesity Pharmacology 2, Novo Nordisk Park, 2760 Måløv, Denmark.
Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts
Article first published online: 23 MAR 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2736–2748, April 2012
How to Cite
Axelsen, L., Keung, W., Pedersen, H., Meier, E., Riber, D., Kjølbye, A., Petersen, J., Proctor, S., Holstein-Rathlou, N.-H. and Lopaschuk, G. (2012), Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts. British Journal of Pharmacology, 165: 2736–2748. doi: 10.1111/j.1476-5381.2011.01714.x
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 20 OCT 2011 10:18AM EST
- Received; 10 May 2011; Revised; 12 September 2011; Accepted; 30 September 2011
- glucagon-GLP-1 dual-agonist;
- cardiac metabolism;
- cardiac function;
- cardiac energetics;
- inotropic compounds;
- working hearts;
- diabetic cardiomyopathy
BACKGROUND AND PURPOSE The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA-cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495).
EXPERIMENTAL APPROACH Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function and metabolism before and after addition of vehicle, glucagon, ZP131 or ZP2495. Subsequently, cardiac levels of nucleotides and short-chain CoA esters were measured by HPLC.
KEY RESULTS Hearts from IR rats showed decreased rates of glycolysis and glucose oxidation, plus increased palmitate oxidation rates, although cardiac function and energy state (measured by ATP/AMP ratios) was normal compared with control rats. Glucagon increased glucose oxidation and glycolytic rates in control and IR hearts, but the increase was not enough to avoid AMP and ADP accumulation in IR hearts. ZP131 had no significant metabolic or functional effects in either IR or control hearts. In contrast, ZP2495 increased glucose oxidation and glycolytic rates in IR hearts to a similar extent to that of glucagon but with no concomitant accumulation of AMP or ADP.
CONCLUSION AND IMPLICATIONS Whereas glucagon compromised the energetic state of IR hearts, glucagon-GLP-1 dual-agonist ZP2495 appeared to preserve it. Therefore, a glucagon-GLP-1 dual-agonist may be beneficial compared with glucagon alone in the treatment of severe heart failure or cardiogenic shock in subjects with IR.