Abstract
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.
Highlights
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L-cells in response to nutrient ingestion [1]
We provide evidence that an energetically-favorable metabolic substrate switch from use of predominantly fat oxidation to use of predominantly glucose and other carbohydrates occur in the area not at risk (ANAR) of ischemia-reperfusion (I/R) injured rat hearts following treatment with GLP-1 peptide
GLP-1 was tested in the rat I/R model in order to study its cardioprotective effects in the presence of optimal insulin stimulation [33]
Summary
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L-cells in response to nutrient ingestion [1]. The major physiological function of GLP-1 is associated with glycemic control, GLP1 has further been shown to have beneficial impact on cardiovascular function independent of its effects on systemic glucose homeostasis [1,2]. Intravenous infusion of GLP-1 improved regional and global left ventricular (LV) function in patients with severe systolic dysfunction [3,4], and perioperative use of GLP-1 during coronary artery bypass grafting improved glycemic control and hemodynamic recovery without requiring a high dose of inotropes [5]. GLP-1 infusion dramatically improved LV function and systemic hemodynamics in dogs with advanced dilated cardiomyopathy and enhanced recovery from ischemic myocardial stunning [6,7]. We and others have demonstrated that long acting GLP-1 agonists provide infarct-limiting effects following myocardial ischemia/reperfusion injury in vivo [9,10,11,12]
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