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1 Department of Medicine, Allegheny General Hospital, Pittsburgh, PA, USA
2 Department of Surgery, University of Massachusetts, Worcester, MA, USA
* To whom correspondence should be addressed. E-mail: rshannon{at}wpahs.org.
Background: We have shown previously the glucagon like peptide-1 (GLP-1) 7-36 amide increases myocardial glucose uptake and improves LV and systemic hemodynamics in both conscious dogs with pacing induced dilated cardiomyopathy (DCM) and humans with left ventricular systolic dysfunction following acute myocardial infarction. However, GLP-1 (7-36) is rapidly degraded in the plasma to GLP-1 (9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. Methods: We compared the efficacy of a 48 hour continuous intravenous infusion of GLP-1 (7-36) [1.5 pmol/kg/min] to GLP-1 (9-36) [1.5 pmol/kg/min] in 28 conscious, chronically instrumented dogs with pacing induced dilated cardiomyopathy (DCM) by measuring LV function and transmyocardial substrate uptake under basal and insulin stimulated conditions using hyperinsulinemic-euglycemic clamps. Results: Dogs with DCM demonstrated myocardial insulin resistance under basal and insulin stimulated conditions. Both GLP-1 (7-36) and GLP-1 (9-36) reduced significantly (p<0.01) LVEDP [GLP-1(7-36) 28±1 to 15±2 mmHg; GLP-1 (9-36) 29±2 to 16±1 mmHg] and increased significantly (p<0.01) LV dP/dt [GLP-1 (7-36) 1315±81 to 2195±102 mmHg/sec; GLP-1 (9-36) 1336±77 to 2208±68 mmHg] and cardiac output [GLP-1 (7-36) 1.5±0.1 to 1.9±0.1 l/min; GLP-1 (9-36) 2.0±0.1 to 2.4±0.05 l/min] while an equi-volume infusion of saline had no effect. Both peptides increased myocardial glucose uptake, but without a significant increase in plasma insulin. During the GLP-1 (9-36) infusion, negligible active (N-terminal) peptide was measured in the plasma. Conclusions: In DCM, GLP-1 (9-36) mimics the effects of GLP-1 (7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics through insulinomimetic as opposed to insulinotropic effects. These data suggest that GLP-1 (9-36) amide is an active peptide.
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