Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts

Abstract

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.

Figure 1

Effects of vehicle, a GLP-1 receptor agonist (ZP131), glucagon and a glucagon-GLP-1 dual-agonist (ZP2495) on (A) heart rate in control JCR:LA rat hearts; (B) heart rate in insulin-resistant (IR) JCR:LA rat hearts; (C) cardiac output in control hearts; (D) cardiac output in IR hearts; (E) developed pressure in control hearts; (F) developed pressure in IR hearts; (G) cardiac power in control hearts; and (H) cardiac power in IR hearts. Values are presented as mean + SEM. *P < 0.05; **P < 0.01 compared with baseline by one-way anova for repeated measures followed by Dunnett's multiple comparison test.

Figure 2

Effects of vehicle, a GLP-1 receptor agonist (ZP131), glucagon and a glucagon-GLP-1 dual-agonist (ZP2495) on (A) glucose oxidation rates in control hearts; (B) glucose oxidation rates in IR hearts; (C) palmitate oxidation rates in control hearts; and (D) palmitate oxidation rates in IR hearts. Values are presented as mean + SEM. *P < 0.05; **P < 0.01 compared with baseline by one-way anova for repeated measures followed by Dunnett's multiple comparison test.

Figure 3

Effects of glucagon and a glucagon-GLP-1 dual-agonist (ZP2495) on (A) glucose oxidation rates in control hearts; (B) glucose oxidation rates in IR hearts; (C) glycolysis rates in control hearts; and (D) glycolysis rates in IR rat hearts. Values are presented as mean + SEM. *P < 0.05; **P < 0.01 compared with baseline by Student's paired t-test.

Figure 4

Short chain CoA concentrations in control and IR JCR:LA rat hearts after perfusion with vehicle, a GLP-1 receptor agonist (ZP131), glucagon and a glucagon-GLP-1 dual-agonist (ZP2495). (A) Malonyl CoA levels, (B) acetyl CoA levels, (C) free CoA levels and (D) succinyl CoA levels. Values are presented as mean + SEM. *P < 0.05; **P < 0.01 compared with vehicle by one-way anova for repeated measures followed by Dunnett's multiple comparison test. (For specific group sizes, see Figures 1 and 2).

Figure 5

Measured energy state in hearts from control and IR JCR:LA rats after perfusion with vehicle, a GLP-1 receptor agonist (ZP131), glucagon and a glucagon-GLP-1 dual-agonist (ZP2495). (A) AMP levels following a total of 65 min perfusion with increasing concentrations of vehicle, ZP131, glucagon or ZP2495. (B) ADP levels following perfusion with increasing concentrations of vehicle, ZP131, glucagon or ZP2495. (C) ATP levels following perfusion with increasing concentrations of vehicle, ZP131, glucagon or ZP2495. (D) ATP/AMP ratios following perfusion with increasing concentrations of vehicle, ZP131, glucagon or ZP2495. (E) ATP/ADP ratios following perfusion with increasing concentrations of vehicle, ZP131, glucagon or ZP2495. Values are presented as mean + SEM. *P < 0.05; **P < 0.01 compared with vehicle by one-way anova for repeated measures followed by Dunnett's multiple comparison test. (For specific group sizes, see Figure 1).