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

doi:10.1002/adtp.201900128

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

5 Citations (SciVal)

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 language	English
Article number	1900128
Journal	Advanced Therapeutics
Volume	2
Issue number	11
DOIs	https://doi.org/10.1002/adtp.201900128
State	Published - 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

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)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/adtp.201900128

Cite this

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title = "Long-Lasting Designer Insulin with Glucose-Dependent Solubility Markedly Reduces Risk of Hypoglycemia",

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.",

keywords = "glucose-responsive insulin, hypoglycemia, insulin glargine, macromolecular therapeutics, translational medicine",

author = "Yibo Qiu and Rahul Agrawal and Diao Chen and Nan Zheng and Griffin Durupt and Kim, {Jin Hwan} and Fisher, {Simon J.} and Chou, {Danny Hung Chieh}",

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: {\textcopyright} 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Chen, Diao

AU - Zheng, Nan

AU - Durupt, Griffin

AU - Kim, Jin Hwan

AU - Fisher, Simon J.

AU - Chou, Danny Hung Chieh

N1 - 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

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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