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Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy
Abstract
We have shown previously that the glucagon-like peptide-1 (GLP-1)-(7–36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after 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. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7–36) (1.5 pmol·kg−1·min−1) to GLP-1-(9–36) (1.5 pmol·kg−1·min−1) in 28 conscious, chronically instrumented dogs with pacing-induced DCM by measuring LV function and transmyocardial substrate uptake under basal and insulin-stimulated conditions using hyperinsulinemic-euglycemic clamps. As a result, dogs with DCM demonstrated myocardial insulin resistance under basal and insulin-stimulated conditions. Both GLP-1-(7–36) and GLP-1-(9–36) significantly reduced ( P < 0.01) LV end-diastolic pressure [GLP-1-(7–36), 28 ± 1 to 15 ± 2 mmHg; GLP-1-(9–36), 29 ± 2 to 16 ± 1 mmHg] and significantly increased ( P < 0.01) the first derivative of LV pressure [GLP-1-(7–36), 1,315 ± 81 to 2,195 ± 102 mmHg/s; GLP-1-(9–36), 1,336 ± 77 to 2,208 ± 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], whereas an equivolume 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 (NH 2-terminal) peptide was measured in the plasma. In conclusion, 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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“GLP-1 agonists improve cardiac output and blood pressure (BP) in dogs with pacing-induced cardiomyopathy (28).”
From Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans (2008) · cites this paper as [28]
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Metadata
- Authors
- Nikolaidis, L. A., Elahi, D., Shen, Y.-T., & Shannon, R. P.
- Affiliations
- Allegheny General Hospital (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2005-12
- Volume
- 289
- Issue
- 6
- Pages
- H2401-H2408
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2169976140
- Cited by
- 274
- References
- 27
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 12 · 2018: 12 · 2017: 8 · 2016: 19 · 2015: 15 · 2014: 29 · 2013: 22 · 2012: 26
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01da010480-09, 5r01ag023125-05)
- National Institute on Aging (AG-023125)
- National Institute on Drug Abuse (DA 10480)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- glucagon-like peptide-1, GLP-1(7-36), dipeptidyl peptidase IV, dilated cardiomyopathy, pacing-induced cardiomyopathy, myocardial glucose uptake, myocardial insulin resistance, left ventricular function, hemodynamics, cardiac output, myocardial substrate metabolism, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Animals, Blood Pressure, Cardiomyopathy, Dilated, Consciousness, Coronary Circulation, Dogs, Dose-Response Relationship, Drug, Glucagon-Like Peptides, Female, Glucagon, Glucose, Heart, Heart Ventricles, Male, Myocardium, Peptide Fragments, Peptides, Stroke Volume, Treatment Outcome, Ventricular Dysfunction, Left, Glucagon-Like Peptide 1
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