Critically ill patients are often hyperglycemic and extremely diverse in their dynamics. Consequently, fixed protocols and sliding scales can result in error and poor control. A two-compartment glucose-insulin system model that accounts for time-varying insulin sensitivity and endogenous glucose removal, along with two different saturation kinetics is developed and verified in proof-of-concept clinical trials for adaptive control of hyperglycemia. The adaptive control algorithm monitors the physiological status of a critically ill patient, allowing real-time tight glycemic regulation. The bolus-based insulin administration approach is shown to result in safe, targeted stepwise glycemic reduction for three critically ill patients.