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Research ArticleDrug Discovery and Translational Medicine

The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy

Anna Thorsø Larsen, Nina Sonne, Kim Vietz Andreassen, Morten Asser Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 74-83; DOI: https://doi.org/10.1124/jpet.119.263392
Anna Thorsø Larsen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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  • ORCID record for Anna Thorsø Larsen
Nina Sonne
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Kim Vietz Andreassen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Morten Asser Karsdal
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Kim Henriksen
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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Abstract

Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what extent the additional benefits reside in their higher potency or their targeting of the calcitonin receptor remains unclear. Here we deconstruct the receptors involved in the effects of a DACRA, KBP-088, by comparing it to rat amylin (rAMY), rat calcitonin (rCT), and their combination in obese high-fat diet (HFD) and diabetic Zucker diabetic fatty (ZDF) rats. HFD-fed Sprague-Dawley rats and ZDF rats were treated for 4 weeks with KBP-088 (5 µg/kg per day), rAMY (300 µg/kg per day), rCT (300 µg/kg per day), and the combination of rAMY and rCT (300+300 µg/kg per day) using infusion pumps. Body weight, food intake, fasting glycemia, glycated hemoglobin type A1c levels, and glucose tolerance were assessed. In obese HFD-fed rats, KBP-088, rAMY, and the combination of rAMY and rCT significantly reduced body weight and improved glucose tolerance, whereas rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, whereas dual activation by KBP-088 and the combination of rAMY and rCT were superior to activating either receptor alone. In conclusion, calcitonin therapy regulates fasting blood glucose in a diabetic rat model, thereby underscoring the importance of calcitonin receptor activation as well as the known role of amylin receptor agonism in the potent metabolic benefits of this group of peptides.

SIGNIFICANCE STATEMENT We deconstruct the receptors activated by dual amylin and calcitonin receptor agonist (DACRA) therapy to elucidate through which receptor the beneficial metabolic effects of the DACRAs are mediated. We show that calcitonin receptor activation is important for blood glucose regulation in diabetes. This is in addition to the known metabolic beneficial role of amylin receptor activation. These data help in understanding the potent metabolic benefits of the DACRAs and underline the potential of DACRAs as treatment for diabetes and obesity.

Footnotes

    • Received October 22, 2019.
    • Accepted April 20, 2020.
  • M.A.K. and K.H. own stock in Nordic Bioscience. M.A.K., K.V.A. and K.H. hold patent in KBP-088. All other authors disclose no conflict of interest.

  • https://doi.org/10.1124/jpet.119.263392.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 1
1 Jul 2020
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Research ArticleDrug Discovery and Translational Medicine

DACRA Effects Are Mediated through Both AMY-R and CTR

Anna Thorsø Larsen, Nina Sonne, Kim Vietz Andreassen, Morten Asser Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 74-83; DOI: https://doi.org/10.1124/jpet.119.263392

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Research ArticleDrug Discovery and Translational Medicine

DACRA Effects Are Mediated through Both AMY-R and CTR

Anna Thorsø Larsen, Nina Sonne, Kim Vietz Andreassen, Morten Asser Karsdal and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 74-83; DOI: https://doi.org/10.1124/jpet.119.263392
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