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Long‐Lasting Designer Insulin with Glucose‐Dependent Solubility Markedly Reduces Risk of Hypoglycemia
Author(s) -
Qiu Yibo,
Agrawal Rahul,
Chen Diao,
Zheng Nan,
Durupt Griffin,
Kim Jin Hwan,
Fisher Simon J.,
Chou Danny HungChieh
Publication year - 2019
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201900128
Subject(s) - insulin glargine , hypoglycemia , insulin , medicine , in vivo , endocrinology , pharmacology , biology , microbiology and biotechnology
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.