Engineered promoter-free insulin-secreting cells provide closed-loop glycemic control

Diabetes mellitus is currently a priority health issue worldwide, but existing therapies suffer from insufficient donors, inability to provide glucose-dependent endogenous insulin secretion, transplantation risks, and immune rejection. Especially, reported engineered cells are mostly promoter-induced glucose-independent insulin producing cells. Here we constructed a closed-loop of insulin secretion with glucose-dependent IRES to achieve glucose-sensitive endogenous insulin secretion. Those cells successfully reversed hyperglycemia in diabetic mice for at least 60 days after transplantation without any significant immune rejection, demonstrating that our constructed engineered cellular grafts have good biocompatibility. Our findings hold great promise in the field of diabetes treatment and provide a new, glucose-dependent genetic engineering approach to insulin production, which is expected to solve many of the current problems faced in the clinical treatment of diabetes mellitus.