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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Luginbuhl, KM; Schaal, JL; Umstead, B; Mastria, EM; Li, X; Banskota, S; Arnold, S; Feinglos, M; D'Alessio, D; Chilkoti, A

Published Date

  • 2017

Published In

Volume / Issue

  • 1 /

PubMed ID

  • 29062587

Pubmed Central ID

  • PMC5650111

International Standard Serial Number (ISSN)

  • 2157-846X

Digital Object Identifier (DOI)

  • 10.1038/s41551-017-0078


  • eng

Conference Location

  • England