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. In this study, a glucose-activated singlestrand insulin analogue (SIA) switch (GAIS) was constructed to achieve repeatable pulse activation of SIA secretion in response to hyperglycemia. In the GAIS system, the CAD-FCS-SIA fusion protein was encoded by the intramuscularly delivered plasmid and temporarily kept in the endoplasmic reticulum (ER) as it binds to the GRP78 protein, then upon hyperglycemia, SIA was released and secreted into the blood. 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 HbA1c level, improved glucose tolerance, and ameliorated oxidative stress. Additionally, this system offers sufficient biosafety as evidenced by the assays of immunological and inflammatory safety, ER stress, histological evaluation, etc. Compared with the viral delivery/expression system, the ex vivo implantation of engineered cells, and the exogenous inducer system, the GAIS system combined the advantages of biosafety, effectiveness, persistence, precision, and convenience, providing therapeutic potential for the treatment of type 1 diabetes.

Article Highlights

  • We undertake this study to establish a glucose-responsive SIA self-supply system in vivo.

  • Whether ER can serve as a safe and temporary repository to store designed fusion proteins and release SIAs under hyperglycemia condition for efficient blood glucose regulation.

  • Intramuscularly expressed plasmid-encoded CAD-FCS-SIA fusion protein can be temporarily stored in ER and SIA can be released under the stimulation of hyperglycemia, resulting in efficient and long-term regulation of blood glucose stable in T1D mice.

  • GAIS system provides applicable potential for type 1 diabetes therapy integrating regulation and monitor of blood glucose level.

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