DESCRIPTION (Adapted from the application: Control of the blood glucose concentration in diabetes mellitus is crucial to avoiding complications of this disease. However, optimal glucose control is difficult, if not impossible for most patients with insulin-dependent diabetes to achieve with currently available therapy. This consists of either multiple daily insulin injections or use of an insulin pump, with dosage adjustment based on finger stick blood glucose readings one or more times each day. This revised application proposes to develop a feedback-controlled insulin delivery system consisting of an implantable glucose sensor linked to an insulin pump. This closed-loop system will be under the control of an algorithm that mimics the function of normal pancreatic beta cells. This algorithm will also be developed and tested in the proposed studies. Experiments will be performed in normal and diabetic dogs, as well as in human subjects with diabetes. In the first specific aim, the glucose sensor and insulin pump will be linked with a feedback algorithm and tested first in normal and then in diabetic dogs under various conditions designed to reflect clinical situations. In the second specific aim, the closed loop system and control algorithms will be tested in humans, with close attention to the sensor response to hypoglycemic challenge. In the third specific aim, the control algorithm will be refined and validated in diabetic humans with varying degrees of insulin sensitivity. In the fourth specific aim, the efficacy and safety of the closed-loop system will be tested for its ability to control blood glucose in diabetic humans. The overall goal is the same: to implement a working closed-loop insulin delivery system for Type I diabetic patients within three years.