Long‐Lasting Designer Insulin with Glucose‐Dependent Solubility Markedly Reduces Risk of Hypoglycemia. Issue 11 (13th September 2019)

• Record Type: Journal Article
• Authors: Qiu, Yibo; Agrawal, Rahul; Chen, Diao; Zheng, Nan; Durupt, Griffin; Kim, Jin Hwan; Fisher, Simon J.; Chou, Danny Hung‐Chieh
• Is Part Of: Advanced therapeutics. Volume 2:Issue 11(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-09-13
• Subjects: glucose‐responsive insulin -- hypoglycemia -- insulin glargine -- macromolecular therapeutics -- translational medicine; Therapeutics -- Periodicals; Pharmaceutical technology -- Periodicals; Pharmacogenetics -- Periodicals; 615.5
• DOI: 10.1002/adtp.201900128
• Languages: English
• ISSNs: 2366-3987

Abstract

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. Abstract : A designer insulin glargine derivative with glucose‐regulated solubility is developed. This molecule, PBA‐F‐glargine, can respond to increased glucose levels through glucose binding, which results in increased solubility in physiological pH. The increased solubility leads to increased insulin release in response to hyperglycemic conditions.