Glucose control in the intensive care unit by use of continuous glucose monitoring: what level of measurement error is acceptable?

BACKGROUND: Accuracy and frequency of glucose measurement is essential to achieve safe and efficacious glucose control in the intensive care unit. Emerging continuous glucose monitors provide frequent measurements, trending information, and alarms. The objective of this study was to establish the level of accuracy of continuous glucose monitoring (CGM) associated with safe and efficacious glucose control in the intensive care unit. METHODS: We evaluated 3 established glucose control protocols [Yale, University of Washington, and Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR)] by use of computer simulations. Insulin delivery was informed by intermittent blood glucose (BG) measurements or CGM levels with an increasing level of measurement error. Measures of glucose control included mean glucose, glucose variability, proportion of time glucose was in target range, and hypoglycemia episodes. RESULTS: Apart from the Washington protocol, CGM with mean absolute relative deviation (MARD) ≤ 15% resulted in similar mean glucose as with the use of intermittent BG measurements. Glucose variability was also similar between CGM and BG-informed protocols. Frequency and duration of hypoglycemia were not worse by use of CGM with MARD ≤ 10%. Measures of glucose control varied more between protocols than at different levels of the CGM error. CONCLUSIONS: The efficacy of CGM-informed and BG-informed commonly used glucose protocols is similar, but the risk of hypoglycemia may be reduced by use of CGM with MARD ≤ 10%. Protocol choice has greater influence on glucose control measures than the glucose measurement method.Edwards Lifesciences provided educational grant to conduct the study but did not play any role in data analysis or interpretation of study results.This is the accepted manuscript version. The final version is available from the American Association for Clinical Chemistry at http://www.clinchem.org/content/60/12/1500.long

Modelling endogenous insulin concentration in type 2 diabetes during closed loop insulin delivery

This is the final published version. It first appeared at http://www.biomedical-engineering-online.com/content/14/1/19.Background: Closed-loop insulin delivery is an emerging treatment for type 1 diabetes (T1D) evaluated clinically and using computer simulations during pre-clinical testing. Efforts to make closed-loop systems available to people with type 2 diabetes (T2D) calls for the development of a new type of simulators to accommodate differences between T1D and T2D. Presented here is the development of a model of posthepatic endogenous insulin concentration, a component omitted in T1D simulators but key for simulating T2D physiology. Methods: We evaluated six competing models to describe the time course of endogenous insulin concentration as a function of the plasma glucose concentration and time. The models were fitted to data collected in insulin-naive subjects with T2D who underwent two 24-h visits and were treated, in a random order, by either closed-loop insulin delivery or glucose-lowering oral agents. The model parameters were estimated using a Bayesian approach, as implemented in the WinBUGS software. Model selection criteria were used to identify the best model describing our clinical data. Results: The selected model successfully described endogenous insulin concentration over 24 h in both study periods and provided plausible parameter estimates. Model-derived results were in concordance with a clinical finding which revealed increased posthepatic endogenous insulin concentration during the control study period (P < 0.05). The modelling results indicated that the excess amount of insulin can be attributed to the glucose-independent effect as the glucose-dependent effect was similar between visits (P > 0.05). Conclusions: A model to describe endogenous insulin concentration in T2D including components of posthepatic glucose-dependent and glucose-independent insulin secretion was identified and validated. The model is suitable to be incorporated in a simulation environment for evaluating closed-loop insulin delivery in T2D.This work was funded in part by a National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Grant, Diabetes UK (BDA07/0003549), and Wellcome Strategic Award (100574/Z/12/Z). The research was conducted with support from Addenbrooke’s Clinical Research Facility (Cambridge, UK). We gratefully acknowledge laboratory support from Angie Watts (University of Cambridge, Cambridge UK), Dr Stephen Luzio and Mr Gareth Dunseath (University of Swansea, Swansea, UK), and Dr Keith Burling (University of Cambridge, UK)

Real-World Evidence Analysis of a Hybrid Closed-Loop System.

BACKGROUND We analyzed real-world evidence to assess the performance of the mylife CamAPS FX hybrid closed-loop system. METHODS Users from 15 countries across different age groups who used the system between May 9, 2022, and December 3, 2022, and who had ≥30 days of continuous glucose monitor data, and ≥30% of closed-loop usage were included in the current analysis (N = 1805). RESULTS Time in range (3.9-10 mmol/L) was 72.6 ± 11.5% (mean ± SD) for all users and increased by age from 66.9 ± 11.7% for users ≤6 years old to 81.8 ± 8.7% for users ≥65 years. Time spent in hypoglycemia (<3.9 mmol/L) was 2.3% [1.3, 3.6] (median [interquartile range]). Mean glucose and glucose management indicator were 8.4 ± 1.1 mmol/L and 6.9%, respectively. Time using closed-loop was high at 94.7% [90.0, 96.9]. CONCLUSIONS Glycemic outcomes from the present real-world evidence are comparable to results obtained from previous randomized controlled studies and confirm the efficacy of this hybrid closed-loop system in real-world settings

Modelling Day-to-Day Variability of Glucose-Insulin Regulation over 12-Week Home Use of Closed-Loop Insulin Delivery.

Parameters of physiological models of glucose-insulin regulation in type 1 diabetes have previously been estimated using data collected over short periods of time and lack the quantification of day-to-day variability. We developed a new hierarchical model to relate subcutaneous insulin delivery and carbohydrate intake to continuous glucose monitoring over 12 weeks while describing day-to-day variability. Sensor glucose data sampled every 10 min, insulin aspart delivery and meal intake were analyzed from 8 adults with type 1 diabetes (male/female 5/3, age 39.9±9.5 years, BMI 25.4±4.4 kg/m2, HbA1c 8.4±0.6%) who underwent a 12-week home study of closed-loop insulin delivery. A compartment model comprised five linear differential equations; model parameters were estimated using the Markov chain Monte Carlo approach within a hierarchical Bayesian model framework. Physiologically plausible a posteriori distributions of model parameters including insulin sensitivity, time-to-peak insulin action, time-to-peak gut absorption, and carbohydrate bioavailability, and good model fit were observed. Day-to-day variability of model parameters was estimated in the range of 38 to 79% for insulin sensitivity and 27 to 48% for time-to-peak of insulin action. In conclusion, a linear Bayesian hierarchical approach is feasible to describe a 12-week glucose-insulin relationship using conventional clinical data. The model may facilitate in silico testing to aid the development of closed-loop insulin delivery systems.This work was supported in part by the European Community Framework Programme 7 FP7-ICT- 2009–4 under Grant 247138, in part by JDRF (22– 2011–668), the National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by IEEE

Mixed-meal tolerance test to assess residual beta-cell secretion: Beyond the area-under-curve of plasma C-peptide concentration.

AIMS: Residual beta-cell secretion in type 1 diabetes is commonly assessed by area-under-curve of plasma C-peptide concentration (AUCCpep ) following mixed-meal tolerance test (MMTT). We aimed to investigate alternative measures of beta-cell responsiveness. METHODS: We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUCCpep with (a) validated mechanistic index of postprandial beta-cell responsiveness MI accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C-peptide concentration corrected for baseline plasma glucose concentration. RESULTS: Postprandial responsiveness MI was correlated with age and BMI SDS (Rs = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUCCpep (Rs = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUCCpep (Rs = 0.94, P < 0.01). CONCLUSIONS: Postprandial responsiveness MI may be more relevant to glucose control than AUCCpep . Baseline C-peptide corrected for baseline glucose appears to be a suitable surrogate of AUCCpep if MMTT is not performed

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