Modelling of glucose and insulin kinetics to facilitate the development of a wearable artificial pancreas

A wearable artificial pancreas (AP) has been a research goal for over three decades. The aim of this device is to establish effective closed-loop control of blood glucose in patients with type 1 diabetes mellitus (T1DM) using subcutaneous (SC) glucose measurements and SC insulin delivery. The main difficulties that hamper the successful development of a wearable AP concern the stability and accuracy of SC glucose sensing, the predictability of the absorption kinetics of the injected insulin, and finally the performance of the glucose control algorithm. As clinical tests on humans are costly, time consuming, and demand ethical approval, in silico testing of the AP has become a critical feature to facilitate an accelerated development of the AP and, specifically, the control algorithm. The primary aim of the work reported in this thesis was to explore the use of compartmental modelling techniques with in-built physiological constraints to facilitate the development of a wearable AP. In particular, the study aimed to extend and evaluate an existing model of whole-body glucose kinetics on a set of data obtained in a clinical trial designed to test the AP algorithm. The model was extended to represent the input-output relationship between the SC insulin and intravenous glucose concentrations. The extended model was re-evaluated in subjects with T1DM under new conditions with the objective to obtain sets of parameters to represent ‘virtual’ subjects with T1DM in the AP simulator. The parameter estimation was completed, but the ‘virtual’ subjects for use in the AP simulator could not be generated due to the uncertain validity of the tested model. Further objectives included the support for in silico testing of an AP through investigating insulin lispro and interstitial glucose kinetics. To explore the kinetics of SC administered insulin lispro, ten competing models were proposed assuming a number of physiological effects. The principle of parsimony was used to select the model, which best represented our data. The best model included slow and fast absorption channels, and the presence of local insulin degradation at the injection site. In order to establish the relationship between the interstitial glucose (IG) and plasma glucose (PG), nine models of IG kinetics were postulated. The model which best represented the experimental data was selected using the principle of parsimony. Two mechanisms explaining the temporal variation in the IG-PG ratio were identified, a zero-order removal of glucose from the interstitial fluid (ISF) and the stimulatory effect of insulin on glucose transfer from the plasma to the ISF. This best model found its use in the simulator to represent SC glucose measurements. In conclusion, valuable insights were obtained into the mechanisms involved in the insulin and interstitial glucose kinetics, as well as the whole-body glucose kinetics

Pharmacokinetics of diluted (U20) insulin aspart compared with standard (U100) in children aged 3-6 years with type 1 diabetes during closed-loop insulin delivery: a randomised clinical trial.

AIMS/HYPOTHESIS: The aim of this study was to compare the pharmacokinetics of two different concentrations of insulin aspart (B28Asp human insulin) in children aged 3-6 years with type 1 diabetes. METHODS: Young children with type 1 diabetes underwent an open-label, randomised, two-period crossover study in a clinical research facility, 2-6 weeks apart. In random order, diluted (1:5 dilution with saline [154 mmol/l NaCl]; 20 U/ml) or standard strength (100 U/ml) insulin aspart was administered via an insulin pump as a meal bolus and then overnight by closed-loop insulin delivery as determined by a model predictive algorithm. Plasma insulin was measured every 30-60 min from 17:00 hours on day 1 to 8:00 hours on day 2. We measured the time-to-peak insulin concentration (tmax), insulin metabolic clearance rate (MCR(I)) and background insulin concentration (ins(c)) using compartmental modelling. RESULTS: Eleven children (six male; age range 3.75-6.96 years, HbA1c 7.6% ± 1.3% [60 ± 14 mmol/mol], BMI standard deviation score 1.0 ± 0.8, duration of diabetes 2.2 ± 1.0 years, total daily dose 12.9 [10.6-16.5] U, fasting C-peptide concentration 5 [5-17.1] pmol/l; mean ± SD or median [interquartile range]) participated in the study. No differences between standard and diluted insulin were observed in terms of t max (59.2 ± 14.4 vs 61.6 ± 8.7) min for standard vs diluted, p = 0.59; MCR I (1.98 × 10(-2) ± 0.99 × 10(-2) vs 1.89 × 10(-2) ± 0.82 × 10(-2) 1/kg/min, p = 0.47), and ins c (34 [1-72] vs 23 [3-65] pmol/l, p = 0.66). However, t max showed less intersubject variability following administration of diluted aspart (SD 14.4 vs 8.7 min, p = 0.047). CONCLUSIONS/INTERPRETATION: Diluting insulin aspart does not change its pharmacokinetics. However, it may result in less variable absorption and could be used in young children with type 1 diabetes undergoing closed-loop insulin delivery. TRIAL REGISTRATION: Clinicaltrials.gov NCT01557634. FUNDING: FUNDING was provided by the JDRF, 7th Framework Programme of the European Union, Wellcome Trust Strategic Award and the National Institute for Health Research Cambridge Biomedical Research Centre.Funding was provided by the JDRF (grant number 22-2011- 668), 7th Framework Programme of the European Union (Spidiman project; grant agreement number 305343), Wellcome Trust Strategic Award (100574/Z/12/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre.This is the final published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00125-014-3483-6

Home Use of Day-and-Night Hybrid Closed-Loop Insulin Delivery in Suboptimally Controlled Adolescents With Type 1 Diabetes: A 3-Week, Free-Living, Randomized Crossover Trial.

OBJECTIVE: This study evaluated the feasibility, safety, and efficacy of day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes under free-living conditions. RESEARCH DESIGN AND METHODS: In an open-label randomized crossover study, 12 suboptimally controlled adolescents on insulin pump therapy (mean ± SD age 14.6 ± 3.1 years; HbA1c 69 ± 8 mmol/mol [8.5 ± 0.7%]; duration of diabetes 7.8 ± 3.5 years) underwent two 21-day periods in which hybrid closed-loop insulin delivery was compared with sensor-augmented insulin pump therapy in random order. During the closed-loop intervention, a model predictive algorithm automatically directed insulin delivery between meals and overnight. Participants used a bolus calculator to administer prandial boluses. RESULTS: The proportion of time that sensor glucose was in the target range (3.9-10 mmol/L; primary end point) was increased during the closed-loop intervention compared with sensor-augmented insulin pump therapy by 18.8 ± 9.8 percentage points (mean ± SD; P < 0.001), the mean sensor glucose level was reduced by 1.8 ± 1.3 mmol/L (P = 0.001), and the time spent above target was reduced by 19.3 ± 11.3 percentage points (P < 0.001). The time spent with sensor glucose levels below 3.9 mmol/L was low and comparable between interventions (median difference 0.4 [interquartile range -2.2 to 1.3] percentage points; P = 0.33). Improved glucose control during closed-loop was associated with increased variability of basal insulin delivery (P < 0.001) and an increase in the total daily insulin dose (53.5 [39.5-72.1] vs. 51.5 [37.6-64.3] units/day; P = 0.006). Participants expressed positive attitudes and experience with the closed-loop system. CONCLUSIONS: Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes is safe, feasible, and improves glucose control without increasing the risk of hypoglycemia. Larger and longer studies are warranted.National Institute of Diabetes and Digestive and Kidney Diseases (Grant ID: 1R01DK085621-01), JDRF, National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome Trust (Strategic Award: 100574/Z/12/Z)This is the author accepted manuscript. The final version is available from American Diabetes Association via http://dx.doi.org/10.2337/dc16-109

Sensor Life and Overnight Closed Loop: A Randomized Clinical Trial.

BACKGROUND: Closed-loop (CL) systems direct insulin delivery based on continuous glucose monitor (CGM) sensor values. CGM accuracy varies with sensor life, being least accurate on day 1 of sensor insertion. We evaluated the effect of sensor life (enhanced Enlite, Medtronic MiniMed, Northridge, CA) on overnight CL. METHODS: In an open-label, randomized, 2-period, inpatient crossover pilot study, 12 adolescents on insulin pump (age 16.7 ± 1.9 years; HbA1c 66 ± 10 mmol/mol) attended a clinical research facility on 2 overnight occasions. In random order, participants received CL on day 1 or on day 3-4 after sensor insertion. During both periods, glucose was automatically controlled by a model predictive control algorithm informed by sensor glucose. Plasma glucose was measured every 30 to 60 min. RESULTS: During overnight CL (22:30 to 07:30), the proportion of time with plasma glucose readings in the target range (3.9-8.0 mmol/l, primary endpoint) when initiated on day 1 of sensor insertion vs day 3-4 were comparable (58 ± 32% day 1 vs 56 ± 36% day 3-4; P = .34), and there were no significant differences between interventions in terms of mean plasma glucose ( P = .26), percentage time above 8.0 mmol/l ( P = .49), and time spent below 3.9 mmol/l ( P = .93). Sensor accuracy varied with sensor life (mean absolute relative difference 19.8 ± 15.0% on day 1 and 13.7 ± 10.2% on day 3 to 4). Sensor glucose tended to under-read plasma glucose inflating benefits of CL on glucose control. CONCLUSIONS: In spite of differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies.This work was funded by the JDRF (#22-2011-668). Additional support for the Artificial Pancreas work by National Institute for Health Research Cambridge Biomedical Research Centre and Wellcome Strategic Award (100574/Z/12/Z). Medtronic supplied study pump, translator device, sensor transmitter, Amber user interface, and supported regulatory approval

Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, parallel-group trial.

BACKGROUND: We assessed whether fully closed-loop insulin delivery (the so-called artificial pancreas) is safe and effective compared with standard subcutaneous insulin therapy in patients with type 2 diabetes in the general ward. METHODS: For this single-centre, open-label, parallel-group, randomised controlled trial, we enrolled patients aged 18 years or older with type 2 diabetes who were receiving insulin therapy. Patients were recruited from general wards at Addenbrooke's Hospital, Cambridge, UK. Participants were randomly assigned (1:1) by a computer-generated minimisation method to receive closed-loop insulin delivery (using a model-predictive control algorithm to direct subcutaneous delivery of rapid-acting insulin analogue without meal-time insulin boluses) or conventional subcutaneous insulin delivery according to local clinical guidelines. The primary outcome was time spent in the target glucose concentration range of 5·6-10·0 mmol/L during the 72 h study period. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774565. FINDINGS: Between Feb 20, 2015, and March 24, 2016, we enrolled 40 participants, of whom 20 were randomly assigned to the closed-loop intervention group and 20 to the control group. The proportion of time spent in the target glucose range was 59·8% (SD 18·7) in the closed-loop group and 38·1% (16·7) in the control group (difference 21·8% [95% CI 10·4-33·1]; p=0·0004). No episodes of severe hypoglycaemia or hyperglycaemia with ketonaemia occurred in either group. One adverse event unrelated to study devices occurred during the study (gastrointestinal bleed). INTERPRETATION: Closed-loop insulin delivery without meal-time boluses is effective and safe in insulin-treated adults with type 2 diabetes in the general ward. FUNDING: Diabetes UK; European Foundation for the Study of Diabetes; JDRF; National Institute for Health Research Cambridge Biomedical Research Centre; Wellcome Trust.This study was supported by Diabetes UK (#14/0004878) and the European Foundation for the Study of Diabetes. Additional support for research on the artificial pancreas was received from the Juvenile Diabetes Research Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/S2213-8587(16)30280-

Short‐term fully closed‐loop insulin delivery using faster insulin aspart compared to standard insulin aspart in type 2 diabetes

We evaluated the efficacy and safety of short‐term fully closed‐loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin‐treated type 2 diabetes underwent 22 hours of closed‐loop insulin delivery with either faster or standard insulin aspart in a double‐blind randomised crossover design. Basal‐bolus regimen was replaced by model predictive control algorithm‐directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6‐10.0mmol/l) and did not differ between treatments (mean difference [95%CI] ‐3.3% [8.2;1.7], p=0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5mmol/l) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95%CI] 3.7U [0.7;6.8], p=0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short‐term fully closed‐loop in type 2 diabetes may require higher dose of faster insulin aspart compared to standard insulin aspart to achieve comparable glucose control.Swiss National Science Foundation (P1BEP3_165297), UDEM Scientific Fund, Cambridge Biomedical Research Centre - NIHR

Closed-loop insulin delivery during pregnancy complicated by type 1 diabetes.

OBJECTIVE: This study evaluated closed-loop insulin delivery with a model predictive control (MPC) algorithm during early (12-16 weeks) and late gestation (28-32 weeks) in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ten women with type 1 diabetes (age 31 years, diabetes duration 19 years, BMI 24.1 kg/m(2), booking A1C 6.9%) were studied over 24 h during early (14.8 weeks) and late pregnancy (28.0 weeks). A nurse adjusted the basal insulin infusion rate from continuous glucose measurements (CGM), fed into the MPC algorithm every 15 min. Mean glucose and time spent in target (63-140 mg/dL), hyperglycemic (>140 to ≥ 180 mg/dL), and hypoglycemic (140 mg/dL) was 7% (0-40%) in early and 0% (0-6%) in late pregnancy (P = 0.25) and hypoglycemic (<63 mg/dL) was 0% (0-3%) and 0% (0-0%), respectively (P = 0.18). Postprandial glucose control, glucose variability, insulin infusion rates, and CGM sensor accuracy were no different in early or late pregnancy. CONCLUSIONS: MPC algorithm performance was maintained throughout pregnancy, suggesting that overnight closed-loop insulin delivery could be used safely during pregnancy. More work is needed to achieve optimal postprandial glucose control.Diabetes UK (07/0003551), TCC (PDF/01/036), MRC (G0600717

Lower plasma insulin levels during overnight closed-loop in school children with type 1 diabetes: Potential advantage? A randomized cross-over trial.

BACKGROUND: Studies have shown that overnight closed-loop insulin delivery can improve glucose control and reduce the risk of hypoglycemia and hence may improve metabolic outcomes and reduce burden for children with type 1 diabetes and their families. However, research so far has not reported insulin levels while comparing closed-loop to open-loop insulin delivery in children. Therefore, in this study we obtained glucose levels as well as plasma insulin levels in children with type 1 diabetes to evaluate the efficacy of a model-based closed-loop algorithm compared to an open-loop administration. METHODS: Fifteen children with type 1 diabetes, 6-12 years, participated in this open-label single center study. We used a randomized cross over design in which we compared overnight closed-loop insulin delivery with sensor augmented pump therapy for two nights in both the hospital and at home (i.e., 1 night in-patient stay and at home per treatment condition). Only during the in-patient stay, hourly plasma insulin and blood glucose levels were assessed and are reported in this paper. RESULTS: Results of paired sample t-tests revealed that although plasma insulin levels were significantly lower during the closed-loop than in the open-loop (Mean difference 36.51 pmol/l; t(13) = 2.13, p = .03, effect size d = 0.57), blood glucose levels did not vary between conditions (mean difference 0.76 mmol/l; t(13) = 1.24, p = .12, d = 0.37). The administered dose of insulin was significantly lower during the closed-loop compared with the open-loop (mean difference 0.10 UI; t(12) = 2.45, p = .02, d = 0.68). CONCLUSIONS: Lower insulin doses were delivered in the closed-loop, resulting in lower plasma insulin levels, whereby glucose levels were not affected negatively. This suggests that the closed-loop administration is better targeted and hence could be more effective

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care.

BACKGROUND: In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care. METHODS: In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. RESULTS: The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group. CONCLUSIONS: Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .)

Feasibility of fully automated closed-loop glucose control using continuous subcutaneous glucose measurements in critical illness: a randomized controlled trial.

INTRODUCTION: Closed-loop (CL) systems modulate insulin delivery according to glucose levels without nurse input. In a prospective randomized controlled trial, we evaluated the feasibility of an automated closed-loop approach based on subcutaneous glucose measurements in comparison with a local sliding-scale insulin-therapy protocol. METHODS: Twenty-four critically ill adults (predominantly trauma and neuroscience patients) with hyperglycemia (glucose, ≥10 mM) or already receiving insulin therapy, were randomized to receive either fully automated closed-loop therapy (model predictive control algorithm directing insulin and 20% dextrose infusion based on FreeStyle Navigator continuous subcutaneous glucose values, n = 12) or a local protocol (n = 12) with intravenous sliding-scale insulin, over a 48-hour period. The primary end point was percentage of time when arterial blood glucose was between 6.0 and 8.0 mM. RESULTS: The time when glucose was in the target range was significantly increased during closed-loop therapy (54.3% (44.1 to 72.8) versus 18.5% (0.1 to 39.9), P = 0.001; median (interquartile range)), and so was time in wider targets, 5.6 to 10.0 mM and 4.0 to 10.0 mM (P ≤ 0.002), reflecting a reduced glucose exposure >8 and >10 mM (P ≤ 0.002). Mean glucose was significantly lower during CL (7.8 (7.4 to 8.2) versus 9.1 (8.3 to 13.0] mM; P = 0.001) without hypoglycemia (<4 mM) during either therapy. CONCLUSIONS: Fully automated closed-loop control based on subcutaneous glucose measurements is feasible and may provide efficacious and hypoglycemia-free glucose control in critically ill adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01440842