Compared with the viral delivery/expression system, the ex vivo implantation of engineered cells, and the exogenous inducer system, the GAIS system combines the advantages of biosafety, effectiveness, persistence, precision, and convenience, providing therapeutic potential for the treatment of type 1 diabetes. Additionally, this system offers sufficient biosafety, as evidenced by the assays of immunological and inflammatory safety, ER stress, and histological evaluation. In vitro and in vivo experiments systematically demonstrated the effects of the GAIS system, including glucose-activated and repeatable SIA secretion, long-term precise blood glucose control, recovered HbA 1c levels, improved glucose tolerance, and ameliorated oxidative stress. In the GAIS system, the conditional aggregation domain–furin cleavage sequence–SIA fusion protein was encoded by the intramuscularly delivered plasmid and temporarily kept in the endoplasmic reticulum (ER) because it binds to the GRP78 protein then, upon hyperglycemia, the SIA was released and secreted into the blood. In this study, a glucose-activated single-strand insulin analog (SIA) switch (GAIS) was constructed to achieve repeatable pulse activation of SIA secretion in response to hyperglycemia.

Genetic modification of non–β-cells to produce insulin is a promising therapeutic strategy for type 1 diabetes however, it is associated with issues, including biosafety and precise regulation of insulin supply.

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