An insulin infusion device and related operating methods are disclosed. An operating method maintains a configurable, patient-specific, target glucose setpoint for a user of the insulin infusion device, collects historical data associated with operation of the insulin infusion device, and calculates, from the historical data, a target glucose setpoint profile for the user of the insulin infusion device. A current target glucose setpoint value is automatically adjusted over time during a closed-loop operating mode of the insulin infusion device, in accordance with the calculated target glucose setpoint profile. In certain embodiments, the historical data is analyzed to determine a clinically preferred target glucose setpoint value for the user, which is stored for use during the closed-loop operating mode.