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One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.

Publication ,  Journal Article
Luginbuhl, KM; Schaal, JL; Umstead, B; Mastria, EM; Li, X; Banskota, S; Arnold, S; Feinglos, M; D'Alessio, D; Chilkoti, A
Published in: Nat Biomed Eng
2017

Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

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Published In

Nat Biomed Eng

DOI

ISSN

2157-846X

Publication Date

2017

Volume

1

Location

England

Related Subject Headings

  • 4003 Biomedical engineering
 

Citation

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Luginbuhl, K. M., Schaal, J. L., Umstead, B., Mastria, E. M., Li, X., Banskota, S., … Chilkoti, A. (2017). One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer. Nat Biomed Eng, 1. https://doi.org/10.1038/s41551-017-0078
Luginbuhl, Kelli M., Jeffrey L. Schaal, Bret Umstead, Eric M. Mastria, Xinghai Li, Samagya Banskota, Susan Arnold, Mark Feinglos, David D’Alessio, and Ashutosh Chilkoti. “One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.Nat Biomed Eng 1 (2017). https://doi.org/10.1038/s41551-017-0078.
Luginbuhl, Kelli M., et al. “One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.Nat Biomed Eng, vol. 1, 2017. Pubmed, doi:10.1038/s41551-017-0078.
Luginbuhl KM, Schaal JL, Umstead B, Mastria EM, Li X, Banskota S, Arnold S, Feinglos M, D’Alessio D, Chilkoti A. One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer. Nat Biomed Eng. 2017;1.

Published In

Nat Biomed Eng

DOI

ISSN

2157-846X

Publication Date

2017

Volume

1

Location

England

Related Subject Headings

  • 4003 Biomedical engineering