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Significance Glucose-responsive insulin analogs or delivery systems are desirable for enhancing health and improving quality of life of people with diabetes. We describe here a simple strategy to engineer a long-acting insulin analog, which can establish an endogenous Glut-associated delivery reservoir of insulin that can modulate glucose metabolism in a blood glucose-dependent manner. Importantly, after subcutaneous injection, in vivo blood glucose regulation was validated in a type 1 diabetic mouse model with negligible hypoglycemia.

Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia