Evaluation of the Effect of Gain on the Meal Response of an Automated Closed-Loop Insulin Delivery System

Abstract

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)...

Feasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes

“…To adjust for this delay, the contribution of this component was increased relative to that previously reported with intravenous insulin delivery (ϳ10 min [5]) or estimated from the ␤-cell response to a hyperglycemic clamp (ϳ40 min [6]). The values used in the current study (66 and 50 min during a rise and fall in glucose, respectively) were derived from preliminary studies in diabetic canines (23,24). However, the current data suggest that the contribution of the D component could be increased even further and that there is no need to reduce the contribution during a fall in glucose [T D(FALL) does not need to be less than T D(RISE) ].…”

Modeling a simplified regulatory system of blood glucose at molecular levels

“…9 shows that, in both cases, glucose levels stay in the normal range in most of time and do not change dramatically. This less sensitivity of the glucose regulation mechanism to the variations of infusion magnitudes may be just the property of the model and does not reflect the real biological situation because experimental data indicate that postprandial glucose pattern is sensitive to the variations (Panteleon et al, 2006). The experimental study by Grodsky (1972, Fig.…”

“…Mathematical control models of the regulatory system of blood glucose are required for integrating a glucose monitoring system into insulin pump technology to form a closed-loop insulin delivery system on the feedback of blood glucose levels, the so-called ''artificial pancreas'' (Hovorka, 2006;Panteleon et al, 2006;Steil et al, 2006). To make this artificial pancreas close to the natural pancreas, numerous models have been proposed since the pioneering work of Albisser et al (1947a, b) and Clemens et al (1977), including the linear model of Ackerman et al (1965) and various compartmental minimal models proposed by Bergman et al (1979Bergman et al ( , 1981Bergman et al ( , 1985, Bertoldo et al (2006), Li et al (2006a, b), Man et al (2004Man et al ( , 2005Man et al ( , 2007, Sturis et al (1991), Toffolo and Cobelli (2003) and Toffolo et al (2006).…”

Run-to-Run Tuning of Model Predictive Control for Type 1 Diabetes Subjects: In Silico Trial

“…During experiments 2-3 (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], the run-to-run procedure attains a good glycemic regulation within a few days. The subsequent meal perturbations during experiment 4 (days 15-24) produce some excursions that are, however, kept under control.…”