Long-Lasting Designer Insulin with Glucose-Dependent Solubility Markedly Reduces Risk of Hypoglycemia

Yibo Qiu, Rahul Agrawal, Diao Chen, Nan Zheng, Griffin Durupt, Jin Hwan Kim, Simon J. Fisher, Danny Hung Chieh Chou

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Insulin analogs are key to blood glucose management for millions of people with diabetes. Nonetheless, the risk of hypoglycemia still exists because this insulin remains bioactive at normal or low blood glucose conditions. Here, the aim is to incorporate phenylboronic acids on insulin glargine to create a glucose-responsive designer insulin termed “PBA-F-glargine.” It is hypothesized that by inserting a glucose responsive moiety, this designer insulin increases the therapeutic window and reduces the risk of insulin-induced hypoglycemia. Chemical methods are used to incorporate phenylboronic acids into insulin glargine. Biochemical and cell-based assays are used to confirm that the designer insulin PBA-F-glargine preserves insulin bioactivity. In comparison to commercial glargine, in vitro experiments demonstrate that PBA-F-glargine has similar bioactivity and increased solubility that is glucose-dependent. In vivo experiments demonstrate that PBA-F-glargine has 88% bioactivity as compared to glargine at hyperglycemic levels, yet has only 30% bioactivity at euglycemic levels. This threefold difference in bioactivity demonstrates that PBA-F-glargine is responsive to glucose concentrations. In comparison to commercial glargine, PBA-F-glargine reduces iatrogenic hypoglycemia by 15-fold. In conclusion, PBA-F-glargine has a glucose-dependent in vivo bioactivity that markedly reduces the risk of hypoglycemia.

Original languageEnglish
Article number1900128
JournalAdvanced Therapeutics
Volume2
Issue number11
DOIs
StatePublished - Nov 1 2019

Bibliographical note

Publisher Copyright:
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • glucose-responsive insulin
  • hypoglycemia
  • insulin glargine
  • macromolecular therapeutics
  • translational medicine

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Pharmaceutical Science
  • Genetics(clinical)
  • Biochemistry, medical
  • Pharmacology (medical)

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