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Research ArticleEndocrine and Diabetes

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Wei Gu, David J. Lloyd, Narumol Chinookswong, Renée Komorowski, Glenn Sivits Jr, Melissa Graham, Katherine A. Winters, Hai Yan, Laszlo G. Boros, Richard A. Lindberg and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 70-81; DOI: https://doi.org/10.1124/jpet.111.179986
Wei Gu
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David J. Lloyd
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Narumol Chinookswong
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Renée Komorowski
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Glenn Sivits Jr
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Melissa Graham
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Katherine A. Winters
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Hai Yan
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Laszlo G. Boros
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Richard A. Lindberg
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Murielle M. Véniant
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Abstract

Pharmacologic contributions of directly agonizing glucagon-like peptide 1 (GLP-1) receptor or antagonizing glucagon receptor (GCGR) on energy state and glucose homeostasis were assessed in diet-induced obese (DIO) mice. Metabolic rate and respiratory quotient (RQ), hyperglycemic clamp, stable isotope-based dynamic metabolic profiling (SiDMAP) studies of 13C-labeled glucose during glucose tolerance test (GTT) and gene expression were assessed in cohorts of DIO mice after a single administration of GLP-1 analog [GLP-1-(23)] or anti-GCGR antibody (Ab). GLP-1-(23) and GCGR Ab similarly improved GTT. GLP-1-(23) decreased food intake and body weight trended lower. GCGR Ab modestly decreased food intake without significant effect on body weight. GLP-1-(23) and GCGR Ab decreased RQ with GLP-1, causing a greater effect. In a hyperglycemic clamp, GLP-1-(23) reduced hepatic glucose production (HGP), increased glucose infusion rate (GIR), increased glucose uptake in brown adipose tissue, and increased whole-body glucose turnover, glycolysis, and rate of glycogen synthesis. GCGR Ab slightly decreased HGP, increased GIR, and increased glucose uptake in the heart. SiDMAP showed that GLP-1-(23) and GCGR Ab increased 13C lactate labeling from glucose, indicating that liver, muscle, and other organs were involved in the rapid disposal of glucose from plasma. GCGR Ab and GLP-1-(23) caused different changes in mRNA expression levels of glucose- and lipid metabolism-associated genes. The effect of GLP-1-(23) on energy state and glucose homeostasis was greater than GCGR Ab. Although GCGR antagonism is associated with increased circulating levels of GLP-1, most GLP-1-(23)-associated pharmacologic effects are more pronounced than GCGR Ab.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.179986.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    GLP-1
    glucagon-like peptide 1
    GLP-1R
    GLP-1 receptor
    GCGR
    glucagon receptor
    SiDMAP
    stable isotope-based dynamic metabolic profiling
    HGP
    hepatic glucose production
    DIO
    diet-induced obese
    Ab
    antibody
    GTT
    glucose tolerance test
    ipGTT
    intraperitoneal GTT
    RQ
    respiratory quotient
    PBS
    phosphate-buffered saline
    2-[14C]DG
    2-deoxy-d-[1-14C] glucose
    TCA
    tricarboxylic acid
    WAT
    white adipose tissue
    BAT
    brown adipose tissue
    G6PDH
    glucose-6-phosphate dehydrogenase
    Pepck
    phosphoenolpyruvate carboxykinase
    Pklr
    pyruvate kinase
    PEG
    polyethylene glycol.

  • Received January 26, 2011.
  • Accepted March 28, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleEndocrine and Diabetes

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Wei Gu, David J. Lloyd, Narumol Chinookswong, Renée Komorowski, Glenn Sivits, Melissa Graham, Katherine A. Winters, Hai Yan, Laszlo G. Boros, Richard A. Lindberg and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 70-81; DOI: https://doi.org/10.1124/jpet.111.179986

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Research ArticleEndocrine and Diabetes

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Wei Gu, David J. Lloyd, Narumol Chinookswong, Renée Komorowski, Glenn Sivits, Melissa Graham, Katherine A. Winters, Hai Yan, Laszlo G. Boros, Richard A. Lindberg and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 70-81; DOI: https://doi.org/10.1124/jpet.111.179986
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