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

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5 Citations (SciVal)


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
Issue number11
StatePublished - Nov 1 2019

Bibliographical note

Funding Information:
Y.Q. and R.A. contributed equally to this work. Y.Q., R.A., S.J.F., and D.H.C. conceived the research and wrote the manuscript. Y.Q., R.A., D.C., N.Z., J.H.K., and G.D., performed experiments. Y.Q., R.A., S.J.F., and D.H.C. performed data analysis. The authors thank Michael Kay and Jared Rutter for their helpful suggestions. This work was funded by the American Diabetes Association Junior Faculty Development Award (1-16-JDF-018 to D.H.C.), the Juvenile Diabetes Research Foundation (3-SRA-2015-120-Q-R to D.H.C.), Department of Defense (W81XWH1910061 to D.H.C.) and the Driving Out Diabetes Initiative at University of Utah (S.J.F.). The authors would also like to acknowledge support from the Diabetes and Metabolism Research Center at the University of Utah and the Undergraduate Research Opportunities Program (UROP) at the University of Utah. D.C. is a Juvenile Diabetes Research Foundation (JDRF) postdoctoral fellow. N.Z. is an American Diabetes Association (ADA) postdoctoral fellow.

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


  • 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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