Regulation of insulin expression and release in gene and cell therapy of insulin-deficient diabetes

Achieving physiological glucose homeostasis in insulin-deficient diabetes remains challenging because exogenous insulin and devices cannot recapitulate the real-time, glucose-responsive secretion of pancreatic β-cells. This review aims to delineate the conceptual framework and recent advances in regulating insulin expression and release through gene- and cell-based therapies, emphasizing strategies that approximate native β-cell dynamics. We summarize progress in glucose-responsive insulin gene expression in hepatocytes, skeletal muscle, intestinal K/L cells, and residual pancreatic β-cells via synthetic promoters and circuit engineering that couple metabolic cues to transcription. We then evaluate rapid-release platforms that uncouple biosynthesis from secretion. These include endoplasmic reticulum retention-release switches and engineered vesicle-based exocytosis modules that, when actuated by metabolic, optical, electrical, or small-molecule cues, reproduce first-phase-like insulin kinetics. Finally, we highlight synthetic-biology frameworks integrating chemical, metabolic, optical, electrical, and magnetic inputs to program autonomous and reversible insulin output. We conclude with a focused translational agenda: strengthen biosafety and genetic stability; induce immune tolerance and alleviate reticulum retention stress; ensure durable, tissue-specific expression; standardize non-viral/viral delivery systems for scalable manufacturing; and integrate molecular circuits with continuous glucose monitors to achieve closed-loop, hypoglycemia-safe control. These priorities will accelerate clinical translation toward intelligent, patient-tailored insulin therapy.