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Research ArticleENDOCRINE AND REPRODUCTIVE

Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in db/db Mice

Christian Thorkildsen, Søren Neve, Bjarne Due Larsen, Eddi Meier and Jørgen Søberg Petersen
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 490-496; DOI: https://doi.org/10.1124/jpet.103.051987
Christian Thorkildsen
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Søren Neve
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Bjarne Due Larsen
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Eddi Meier
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Jørgen Søberg Petersen
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Abstract

We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated hemoglobin (HbA1C) from 8.4 ± 0.4% (vehicle) to a minimum of 6.2 ± 0.3% (100 nmol/kg b.i.d.; p < 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was associated with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves β-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.

Footnotes

  • DOI: 10.1124/jpet.103.051987.

  • ABBREVIATIONS: GLP-1, glucagon-like peptide 1; CHO, Chinese hamster ovary; OGTT, oral glucose tolerance test; BG, blood glucose; AUC, area under the curve; HbA1C, glycosylated hemoglobin; PCR, polymerase chain reaction; LSD, least significant difference; FBG, fasting blood glucose; ANOVA, analysis of variance.

    • Received March 24, 2003.
    • Accepted July 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleENDOCRINE AND REPRODUCTIVE

Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in db/db Mice

Christian Thorkildsen, Søren Neve, Bjarne Due Larsen, Eddi Meier and Jørgen Søberg Petersen
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 490-496; DOI: https://doi.org/10.1124/jpet.103.051987

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Research ArticleENDOCRINE AND REPRODUCTIVE

Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in db/db Mice

Christian Thorkildsen, Søren Neve, Bjarne Due Larsen, Eddi Meier and Jørgen Søberg Petersen
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 490-496; DOI: https://doi.org/10.1124/jpet.103.051987
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