Insulin is the only drug that treats hyperglycemia in all forms, but insulin comes with the risk of hypoglycemia, which can be acutely dangerous.
The idea of engineering a glucose-sensitive insulin has been pursued since the 1970’s but has not matured to clinical practice.
We designed a “switch insulin” by conjugating a glucose-binding macrocycle in combination with a glucoside to selected positions on insulin, and we show that this design makes insulin reversibly responsive to glucose in the narrow physiological range. Rat and pig models demonstrated that the “switch insulin” can attenuate hypoglycemia and improve the response to hyperglycemia relative to control insulin.