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Research ArticleEndocrine and Diabetes

The Novel GLP-1–Gastrin Dual Agonist ZP3022 Improves Glucose Homeostasis and Increases β-Cell Mass without Affecting Islet Number in db/db Mice

Louise S. Dalbøge, Dorthe L. C. Almholt, Trine S. R. Neerup, Niels Vrang, Jacob Jelsing and Keld Fosgerau
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 353-360; DOI: https://doi.org/10.1124/jpet.114.215293
Louise S. Dalbøge
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Dorthe L. C. Almholt
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Trine S. R. Neerup
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Niels Vrang
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Jacob Jelsing
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Keld Fosgerau
Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
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Abstract

Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)–gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1–gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1–gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.

Footnotes

    • Received April 8, 2014.
    • Accepted June 4, 2014.
  • L.S.D. and D.L.C.A. contributed equally to this work.

  • The study was funded by Zealand Pharma A/S.

  • K.F. is currently employed by Zealand Pharma A/S, and D.L.C.A. and T.S.R.N. were employed by Zealand Pharma A/S at the time of study conduction. L.S.D., N.V., and J.J. are employed by Gubra ApS. No further potential conflicts of interest relevant to this manuscript are reported.

  • dx.doi.org/10.1124/jpet.114.215293.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticleEndocrine and Diabetes

GLP-1–Gastrin Dual Agonism Increases β-Cell Mass

Louise S. Dalbøge, Dorthe L. C. Almholt, Trine S. R. Neerup, Niels Vrang, Jacob Jelsing and Keld Fosgerau
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 353-360; DOI: https://doi.org/10.1124/jpet.114.215293

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Research ArticleEndocrine and Diabetes

GLP-1–Gastrin Dual Agonism Increases β-Cell Mass

Louise S. Dalbøge, Dorthe L. C. Almholt, Trine S. R. Neerup, Niels Vrang, Jacob Jelsing and Keld Fosgerau
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 353-360; DOI: https://doi.org/10.1124/jpet.114.215293
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