Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

Joel P. Giblett; Richard G. Axell; Paul A. White; Sophie J. Clarke; Liam McCormick; Philip A. Read; Johannes Reinhold; Adam J. Brown; Michael O'Sullivan; Nick E. J. West; David P. Dutka; Stephen P. Hoole

doi:10.1186/s12933-016-0416-3

Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

Joel P. Giblett
, Richard G. Axell
, Paul A. White
, Sophie J. Clarke
, Liam McCormick
, Philip A. Read
, Johannes Reinhold
, Adam J. Brown
, Michael O'Sullivan
, Nick E. J. West
, David P. Dutka
, Stephen P. Hoole

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

31 Downloads (Pure)

Abstract

Background: Glucagon-like peptide-1 (7–36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans.

Methods: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure–volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment.

Results: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: −0.8 ± 9.0 % (p = 0.04) compared to control: −11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: −12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: −14.9 ± 9.2 % (p = 0.02) compared to control: −25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74).

Conclusions: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia.

Original language	English
Article number	99
Number of pages	12
Journal	Cardiovascular Diabetology
Volume	15
DOIs	https://doi.org/10.1186/s12933-016-0416-3
Publication status	Published - 19 Jul 2016
Externally published	Yes

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SDG 3 Good Health and Well-being

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10.1186/s12933-016-0416-3Licence: CC BY

Published_VersionFinal published version, 1.73 MBLicence: CC BY

https://www.repository.cam.ac.uk/handle/1810/260577Licence: CC BY

Johannes Reinhold
- J.Reinholduea.acuk
- Norwich Medical School - Honorary Associate Professor
- Metabolic Health - Member
Person: Honorary, Research Centre Member

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Giblett, J. P., Axell, R. G., White, P. A., Clarke, S. J., McCormick, L., Read, P. A., Reinhold, J., Brown, A. J., O'Sullivan, M., West, N. E. J., Dutka, D. P., & Hoole, S. P. (2016). Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies. Cardiovascular Diabetology, 15, Article 99. https://doi.org/10.1186/s12933-016-0416-3

@article{709424a19ebe4d688ac3e5d690aa84b4,

title = "Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies",

abstract = "Background: Glucagon-like peptide-1 (7–36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. Methods: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure–volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. Results: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ \% dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 \% (p = 0.02) and GLP-1 + glibenclamide: −0.8 ± 9.0 \% (p = 0.04) compared to control: −11.5 ± 10.0 \%. GLP-1 also reduced cumulative stunning after BO2: −12.8 ± 10.5 \% (p = 0.02) as did GLP-1 + glibenclamide: −14.9 ± 9.2 \% (p = 0.02) compared to control: −25.7 ± 9.6 \%. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). Conclusions: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia.",

author = "Giblett, \{Joel P.\} and Axell, \{Richard G.\} and White, \{Paul A.\} and Clarke, \{Sophie J.\} and Liam McCormick and Read, \{Philip A.\} and Johannes Reinhold and Brown, \{Adam J.\} and Michael O'Sullivan and West, \{Nick E. J.\} and Dutka, \{David P.\} and Hoole, \{Stephen P.\}",

year = "2016",

month = jul,

day = "19",

doi = "10.1186/s12933-016-0416-3",

language = "English",

volume = "15",

journal = "Cardiovascular Diabetology",

issn = "1475-2840",

publisher = "BioMed Central",

}

Giblett, JP, Axell, RG, White, PA, Clarke, SJ, McCormick, L, Read, PA, Reinhold, J, Brown, AJ, O'Sullivan, M, West, NEJ, Dutka, DP & Hoole, SP 2016, 'Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies', Cardiovascular Diabetology, vol. 15, 99. https://doi.org/10.1186/s12933-016-0416-3

TY - JOUR

T1 - Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

AU - Giblett, Joel P.

AU - Axell, Richard G.

AU - White, Paul A.

AU - Clarke, Sophie J.

AU - McCormick, Liam

AU - Read, Philip A.

AU - Reinhold, Johannes

AU - Brown, Adam J.

AU - O'Sullivan, Michael

AU - West, Nick E. J.

AU - Dutka, David P.

AU - Hoole, Stephen P.

PY - 2016/7/19

Y1 - 2016/7/19

N2 - Background: Glucagon-like peptide-1 (7–36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. Methods: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure–volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. Results: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: −0.8 ± 9.0 % (p = 0.04) compared to control: −11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: −12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: −14.9 ± 9.2 % (p = 0.02) compared to control: −25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). Conclusions: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia.

AB - Background: Glucagon-like peptide-1 (7–36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. Methods: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure–volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. Results: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: −0.8 ± 9.0 % (p = 0.04) compared to control: −11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: −12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: −14.9 ± 9.2 % (p = 0.02) compared to control: −25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). Conclusions: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia.

U2 - 10.1186/s12933-016-0416-3

DO - 10.1186/s12933-016-0416-3

M3 - Article

SN - 1475-2840

VL - 15

JO - Cardiovascular Diabetology

JF - Cardiovascular Diabetology

M1 - 99

ER -

Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

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