A continuous closed-loop insulin delivery system using subcutaneous insulin delivery was evaluated in eight diabetic canines. Continuous glucose profiles were obtained by extrapolation of blood glucose measurements. Insulin delivery rate was calculated, using a model of -cell insulin secretion, and delivered with a Medtronic MiniMed subcutaneous infusion pump. The model acts like a classic proportional-integral-derivative controller, delivering insulin in proportion to glucose above target, history of past glucose values, and glucose rate of change. For each dog, a proportional gain was set relative to the open-loop total daily dose (TDD) of insulin. Additional gains based on 0.5 ؋ TDD and 1.5 ؋ TDD were also evaluated (gain dose response). Control was initiated 4 h before the meal with a target of 6.7 mmol/l. At the time of the meal, glucose was similar for all three gains (6.0 ؎ 0.3, 5.2 ؎ 0.3, and 4.9 ؎ 0.5 mmol/l for 0.5 ؋ TDD, TDD, and 1.5 ؋ TDD, respectively; P > 0.05) with near-target values restored at the end of experiments (8.2 ؎ 0.9, 6.0 ؎ 0.6, and 6.0 ؎ 0.5, respectively). The peak postprandial glucose level decreased significantly with increasing gain (12.1 ؎ 0.6, 9.6 ؎ 1.0, and 8.5 ؎ 0.6 mmol/l, respectively; P < 0.05). The data demonstrate that closed-loop insulin delivery using the subcutaneous site can provide stable glycemic control within a range of gain. Diabetes 55:1995-2000, 2006 I ntegration of glucose-sensing and insulin delivery technologies can potentially lead to a fully ambulatory closed-loop insulin delivery system or "artificial pancreas." Such a system may achieve glucose and insulin profiles near those observed in individuals with normal glucose tolerance while at the same time decreasing the incidence of hypoglycemia and minimizing the complications of diabetes.Glucose-sensing technology has been rapidly advancing (1-6), and fast-absorbing insulin analogs (7,8) have been available for several years; nonetheless, little data exist demonstrating the feasibility of closed-loop insulin delivery using the subcutaneous route (overview in 9). Early studies in the diabetic canine, using intravenous insulin (10,11), showed promising results, delivering insulin in proportion to glucose above or below target and its rate of change, and later work extended these results with rapidacting insulin analogs and alternate sites of delivery (12)(13)(14).The current study was undertaken with three objectives. The first was to evaluate the ability of a previously proposed multiphasic model of -cell secretion (15) to provide adequate control when the relative amount of insulin in each phase is adjusted to compensate for the delay in subcutaneous insulin delivery. The second was to assess the stability of the system as the closed-loop gain is increased or decreased. The third objective was to assess how well the in vivo closed-loop responses could be described using standard metabolic models.
RESEARCH DESIGN AND METHODSExperiments were performed on eight diabetic dogs (26.8 Ϯ 1.7 kg, range 20.3-35.3)...
