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Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.

Publication ,  Journal Article
Gilroy, CA; Capozzi, ME; Varanko, AK; Tong, J; D'Alessio, DA; Campbell, JE; Chilkoti, A
Published in: Sci Adv
August 2020

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.

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Published In

Sci Adv

DOI

EISSN

2375-2548

Publication Date

August 2020

Volume

6

Issue

35

Start / End Page

eaaz9890

Location

United States

Related Subject Headings

  • Peptides
  • Obesity
  • Mice
  • Hyperglycemia
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptide 1
  • Fibroblast Growth Factors
  • Diabetes Mellitus, Type 2
  • Diabetes Mellitus, Experimental
 

Citation

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Gilroy, C. A., Capozzi, M. E., Varanko, A. K., Tong, J., D’Alessio, D. A., Campbell, J. E., & Chilkoti, A. (2020). Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia. Sci Adv, 6(35), eaaz9890. https://doi.org/10.1126/sciadv.aaz9890
Gilroy, C. A., M. E. Capozzi, A. K. Varanko, J. Tong, D. A. D’Alessio, J. E. Campbell, and A. Chilkoti. “Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.Sci Adv 6, no. 35 (August 2020): eaaz9890. https://doi.org/10.1126/sciadv.aaz9890.
Gilroy CA, Capozzi ME, Varanko AK, Tong J, D’Alessio DA, Campbell JE, et al. Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia. Sci Adv. 2020 Aug;6(35):eaaz9890.
Gilroy, C. A., et al. “Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.Sci Adv, vol. 6, no. 35, Aug. 2020, p. eaaz9890. Pubmed, doi:10.1126/sciadv.aaz9890.
Gilroy CA, Capozzi ME, Varanko AK, Tong J, D’Alessio DA, Campbell JE, Chilkoti A. Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia. Sci Adv. 2020 Aug;6(35):eaaz9890.

Published In

Sci Adv

DOI

EISSN

2375-2548

Publication Date

August 2020

Volume

6

Issue

35

Start / End Page

eaaz9890

Location

United States

Related Subject Headings

  • Peptides
  • Obesity
  • Mice
  • Hyperglycemia
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptide 1
  • Fibroblast Growth Factors
  • Diabetes Mellitus, Type 2
  • Diabetes Mellitus, Experimental