Long-acting glucose-responsive insulin with swift onset-of-action

Long-acting glucose-responsive insulin is anticipated to reduce the frequency of injections via replacing both rapid-acting and long-acting insulin. Sequential rapid glucose-responsive insulin release and instant absorption are essential to the swift onset of action. Herein, we have developed injectable long-acting glucose-responsive insulin formulations (GRIF) prepared from glucosamine-modified insulin aspart (ASP-G n ) and phenylboronic acid-modified poly- ʟ -lysine (PLL-FPBA). The complex can form stable GRIF reservoir subcutaneously after injection. Upon food intake, the elevated blood glucose (BG) triggers the release of monomolecular insulin aspart (or ASP-G n ), which can be absorbed immediately to downregulate BG back to the normal range. Among the diverse formulations investigated, GRIF prepared from two-glucosamine-modified insulin aspart and twice weight of PLL-FPBA facilitates the best in vitro glucose-responsive insulin release performance. In type 1 diabetic mouse and minipig models, GRIF exhibit notably swift onset of action and achieve superior BG control. In addition, GRIF reveal no discernible signs of associated toxicity in the studied animals.