Trial of Hybrid Closed-Loop Control in Young Children with Type 1 Diabetes.

BACKGROUND: Closed-loop control systems of insulin delivery may improve glycemic outcomes in young children with type 1 diabetes. The efficacy and safety of initiating a closed-loop system virtually are unclear. METHODS: In this 13-week, multicenter trial, we randomly assigned, in a 2:1 ratio, children who were at least 2 years of age but younger than 6 years of age who had type 1 diabetes to receive treatment with a closed-loop system of insulin delivery or standard care that included either an insulin pump or multiple daily injections of insulin plus a continuous glucose monitor. The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. Secondary outcomes included the percentage of time that the glucose level was above 250 mg per deciliter or below 70 mg per deciliter, the mean glucose level, the glycated hemoglobin level, and safety outcomes. RESULTS: A total of 102 children underwent randomization (68 to the closed-loop group and 34 to the standard-care group); the glycated hemoglobin levels at baseline ranged from 5.2 to 11.5%. Initiation of the closed-loop system was virtual in 55 patients (81%). The mean (±SD) percentage of time that the glucose level was within the target range increased from 56.7±18.0% at baseline to 69.3±11.1% during the 13-week follow-up period in the closed-loop group and from 54.9±14.7% to 55.9±12.6% in the standard-care group (mean adjusted difference, 12.4 percentage points [equivalent to approximately 3 hours per day]; 95% confidence interval, 9.5 to 15.3; P<0.001). We observed similar treatment effects (favoring the closed-loop system) on the percentage of time that the glucose level was above 250 mg per deciliter, on the mean glucose level, and on the glycated hemoglobin level, with no significant between-group difference in the percentage of time that the glucose level was below 70 mg per deciliter. There were two cases of severe hypoglycemia in the closed-loop group and one case in the standard-care group. One case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In this trial involving young children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with a closed-loop system than with standard care. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; PEDAP ClinicalTrials.gov number, NCT04796779.).

Use of diabetes technology in children.

Children with type 1 diabetes and their caregivers face numerous challenges navigating the unpredictability of this complex disease. Although the burden of managing diabetes remains significant, new technology has eased some of the load and allowed children with type 1 diabetes to achieve tighter glycaemic management without fear of excess hypoglycaemia. Continuous glucose monitor use alone improves outcomes and is considered standard of care for paediatric type 1 diabetes management. Similarly, automated insulin delivery (AID) systems have proven to be safe and effective for children as young as 2 years of age. AID use improves not only blood glucose levels but also quality of life for children with type 1 diabetes and their caregivers and should be strongly considered for all youth with type 1 diabetes if available and affordable. Here, we review key data on the use of diabetes technology in the paediatric population and discuss management issues unique to children and adolescents.

A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes.

BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes. METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (±SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53±17% at baseline to 67±10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51±16% to 55±13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group. CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).

Outcomes of hybrid closed-loop insulin delivery activated 24/7 versus evening and night in free-living prepubertal children with type 1 diabetes: A multicentre, randomized clinical trial.

AIM: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 versus only evening and night (E/N), and on extended 24/7 use, in free-living children with type 1 diabetes. MATERIALS AND METHODS: Prepubertal children (n = 122; 49 females/73 males; age, 8.6 ± 1.6 years; diabetes duration, 5.2 ± 2.3 years; insulin pump use, 4.6 ± 2.5 years; HbA1c 7.7% ± 0.7%/61 ± 5 mmol/mol) from four centres were randomized for 24/7 versus E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (TIR). RESULTS: HCL was active 94.1% and 51.1% of the time in the 24/7 and E/N modes, respectively. TIR from baseline increased more in the 24/7 versus the E/N mode (52.9% ± 9.5% to 67.3% ± 5.6% [+14.4%, 95% CI 12.4%-16.7%] vs. 55.1% ± 10.8% to 64.7% ± 7.0% [+9.6%, 95% CI 7.4%-11.6%]; P = .001). Mean percentage time below range was similarly reduced, from 4.2% and 4.6% to 2.7%, and the mean percentage time above range decreased more in the 24/7 mode (41.9% to 30.0% [-11.9%, 95% CI 9.7%-14.6%] vs. 39.8% to 32.6% [-7.2%, 95% CI 5.0%-9.9%]; P = .007). TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during the extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycaemia occurred. CONCLUSIONS: The current study shows the safety and efficacy of the Tandem Control-IQ system in free-living children with type 1 diabetes for both E/N and 24/7 use; 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issues.

Closed-loop driven by control-to-range algorithm outperforms threshold-low-glucose-suspend insulin delivery on glucose control albeit not on nocturnal hypoglycaemia in prepubertal patients with type 1 diabetes in a supervised hotel setting.

This randomized control trial investigated glucose control with closed-loop (CL) versus threshold-low-glucose-suspend (TLGS) insulin pump delivery in pre-pubertal children with type 1 diabetes in supervised hotel conditions. The patients [n = 24, age range: 7-12, HbA1c: 7.5 ± 0.5% (58 ± 5 mmol/mol)] and their parents were admitted twice at a 3-week interval. CL control to range or TLGS set at 3.9 mmoL/L were assessed for 48 hour in randomized order. Admissions included three meals and one snack, and physical exercise. Meal boluses followed individual insulin/carb ratios. While overnight (22:00-08:00) per cent continuous glucose monitoring (CGM) time below 3.9 mmol/L (primary outcome) was similar, time in ranges 3.9 to 10.0 and 3.9 to 7.8 mmoL/L and mean CGM were all significantly improved with CL (P < 0.001). These results were confirmed over the whole 48 hour. Disconnections between devices and limited accuracy of glucose sensors in the hypoglycaemic range appeared as limiting factors for optimal control. CL mode was well accepted while fear of hypoglycaemia was unchanged. CL did not minimize nocturnal hypoglycaemia exposure but improved time in target range compared to TLGS. Although safe and well-accepted, CL systems would benefit from more integrated devices.

Closed loop control in adolescents and children during winter sports: Use of the Tandem Control-IQ AP system.

OBJECTIVE: Artificial pancreas (AP) systems have been shown to improve glycemic control throughout the day and night in adults, adolescents, and children. However, AP testing remains limited during intense and prolonged exercise in adolescents and children. We present the performance of the Tandem Control-IQ AP system in adolescents and children during a winter ski camp study, where high altitude, low temperature, prolonged intense activity, and stress challenged glycemic control. METHODS: In a randomized controlled trial, 24 adolescents (ages 13-18 years) and 24 school-aged children (6-12 years) with Type 1 diabetes (T1D) participated in a 48 hours ski camp (∼5 hours skiing/day) at three sites: Wintergreen, VA; Kirkwood, and Breckenridge, CO. Study participants were randomized 1:1 at each site. The control group used remote monitored sensor-augmented pump (RM-SAP), and the experimental group used the t: slim X2 with Control-IQ Technology AP system. All subjects were remotely monitored 24 hours per day by study staff. RESULTS: The Control-IQ system improved percent time within range (70-180 mg/dL) over the entire camp duration: 66.4 ± 16.4 vs 53.9 ± 24.8%; P = .01 in both children and adolescents. The AP system was associated with a significantly lower average glucose based on continuous glucose monitor data: 161 ± 29.9 vs 176.8 ± 36.5 mg/dL; P = .023. There were no differences between groups for hypoglycemia exposure or carbohydrate interventions. There were no adverse events. CONCLUSIONS: The use of the Control-IQ AP improved glycemic control and safely reduced exposure to hyperglycemia relative to RM-SAP in pediatric patients with T1D during prolonged intensive winter sport activities.

Continuous Glucose Monitors and Activity Trackers to Inform Insulin Dosing in Type 1 Diabetes: The University of Virginia Contribution.

Objective: Suboptimal insulin dosing in type 1 diabetes (T1D) is frequently associated with time-varying insulin requirements driven by various psycho-behavioral and physiological factors influencing insulin sensitivity (IS). Among these, physical activity has been widely recognized as a trigger of altered IS both during and following the exercise effort, but limited indication is available for the management of structured and (even more) unstructured activity in T1D. In this work, we present two methods to inform insulin dosing with biosignals from wearable sensors to improve glycemic control in individuals with T1D. Research Design and Methods: Continuous glucose monitors (CGM) and activity trackers are leveraged by the methods. The first method uses CGM records to estimate IS in real time and adjust the insulin dose according to a person's insulin needs; the second method uses step count data to inform the bolus calculation with the residual glucose-lowering effects of recently performed (structured or unstructured) physical activity. The methods were tested in silico within the University of Virginia/Padova T1D Simulator. A standard bolus calculator and the proposed "smart" systems were deployed in the control of one meal in presence of increased/decreased IS (Study 1) and following a 1-hour exercise bout (Study 2). Postprandial glycemic control was assessed in terms of time spent in different glycemic ranges and low/high blood glucose indices (LBGI/HBGI), and compared between the dosing strategies. Results: In Study 1, the CGM-informed system allowed to reduce exposure to hypoglycemia in presence of increased IS (percent time < 70 mg/dL: 6.1% versus 9.9%; LBGI: 1.9 versus 3.2) and exposure to hyperglycemia in presence of decreased IS (percent time > 180 mg/dL: 14.6% versus 18.3%; HBGI: 3.0 versus 3.9), tending toward optimal control. In Study 2, the step count-informed system allowed to reduce hypoglycemia (percent time < 70 mg/dL: 3.9% versus 13.4%; LBGI: 1.7 versus 3.2) at the cost of a minor increase in exposure to hyperglycemia (percent time > 180 mg/dL: 11.9% versus 7.5%; HBGI: 2.4 versus 1.5). Conclusions: We presented and validated in silico two methods for the smart dosing of prandial insulin in T1D. If seen within an ensemble, the two algorithms provide alternatives to individuals with T1D for improving insulin dosing accommodating a large variety of treatment options. Future work will be devoted to test the safety and efficacy of the methods in free-living conditions.

Closed-Loop Control with Unannounced Exercise for Adults with Type 1 Diabetes using the Ensemble Model Predictive Control.

This paper presents an individualized Ensemble Model Predictive Control (EnMPC) algorithm for blood glucose (BG) stabilization and hypoglycemia prevention in people with type 1 diabetes (T1D) who exercise regularly. The EnMPC formulation can be regarded as a simplified multi-stage MPC allowing for the consideration of N en scenarios gathered from the patient's recent behavior. The patient's physical activity behavior is characterized by an exercise-specific input signal derived from the deconvolution of the patient's continuous glucose monitor (CGM), accounting for known inputs such as meal, and insulin pump records. The EnMPC controller was tested in a cohort of in silico patients with representative inter-subject and intra-subject variability from the FDA-accepted UVA/Padova simulation platform. Results show a significant improvement on hypoglycemia prevention after 30 min of mild to moderate exercise in comparison to a similarly tuned baseline controller (rMPC); with a reduction in hypoglycemia occurrences (< 70 mg/dL), from 3.08% ± 3.55 with rMPC to 0.78% ± 2.04 with EnMPC (P < 0.05).

Heart rate informed artificial pancreas system enhances glycemic control during exercise in adolescents with T1D.

OBJECTIVE: To evaluate the safety and performance of using a heart rate (HR) monitor to inform an artificial pancreas (AP) system during exercise among adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized, cross-over trial, adolescents with T1D age 13 - 18 years were enrolled to receive on separate days either the unmodified UVa AP (stdAP) or an AP system connected to a portable HR monitor (AP-HR) that triggered an exercise algorithm for blood glucose (BG) control. During admissions participants underwent a structured exercise regimen. Hypoglycemic events and CGM tracings were compared between the two admissions, during exercise and for the full 24-hour period. RESULTS: Eighteen participants completed the trial. While number of hypoglycemic events during exercise and rest was not different between visits (0.39 AP-HR vs 0.50 stdAP), time below 70 mg dL -1 was lower on AP-HR compared to stdAP, 0.5±2.1% vs 7.4±12.5% (P = 0.028). Time with BG within 70-180 mg dL -1 was higher for the AP-HR admission vs stdAP during the exercise portion and overall (96% vs 87%, and 77% vs 74%), but these did not reach statistical significance (P = 0.075 and P = 0.366). CONCLUSIONS: Heart rate signals can safely and efficaciously be integrated in a wireless AP system to inform of physical activity. While exercise contributes to hypoglycemia among adolescents, even when using an AP system, informing the system of exercise via a HR monitor improved time <70 mg dL -1 . Nonetheless, it did not significantly reduce the total number of hypoglycemic events, which were low in both groups.

Use of an artificial pancreas among adolescents for a missed snack bolus and an underestimated meal bolus.

OBJECTIVE: The objective of this study was to evaluate the safety and performance of the artificial pancreas (AP) in adolescents with type 1 diabetes (T1D) following insulin omission for food. RESEARCH DESIGN AND METHODS: In a randomized, cross-over trial, adolescents with T1D aged 13-18 yr were enrolled in a randomized, cross-over trial. On separate days, received either usual care (UC) through their home insulin pump or used an AP system (Diabetes Assistant platform, continuous glucose monitor, and insulin pump). Approximately 1 h after admission, participants in both groups received an unannounced snack of 30 g carbohydrate, and 4 h later they received an 80 g lunch, for which both groups only received 75% of the calculated insulin dose to cover carbohydrates. On the UC day (but not the AP day), they received their full high blood glucose (BG) correction factor at lunch. Each admission lasted approximately 8 h. RESULTS: A total of 16 participants completed the trial. On the AP day (compared to UC), mean BG was lower (197 ± 10 vs. 235 ± 14 mg/dL) and time in range 70-180 mg/dL was higher (43% ± 7 vs. 19% ± 7) (both p < 0.05) overall; these results held in the time following the snack and meal (also p < 0.05). During the trial, there were no differences between groups in the rate of hypoglycemia <70 mg/dL. CONCLUSIONS: The AP provided improvements in short-term glycemic control without increases in hypoglycemia following missed insulin for food in adolescents. Thus, the AP partly compensates for missed insulin boluses for food, a common occurrence in adolescent diabetes care. Further testing is needed in longer-term settings.

Integration of a Safety Module to Prevent Rebound Hypoglycemia in Closed-Loop Artificial Pancreas Systems.

BACKGROUND: With automated insulin delivery (AID) systems becoming widely adopted in the management of type 1 diabetes, we have seen an increase in occurrences of rebound hypoglycemia or generated hypoglycemia induced by the controller's response to rapid glucose rises following rescue carbohydrates. Furthermore, as AID systems aim to enable complete automation of prandial control, algorithms are designed to react even more strongly to glycemic rises. This work introduces a rebound hypoglycemia prevention layer (HypoSafe) that can be easily integrated into any AID system. METHODS: HypoSafe constrains the maximum permissible insulin delivery dose based on the minimum glucose reading from the previous hour and the current glucose level. To demonstrate its efficacy, we integrated HypoSafe into the latest University of Virginia (UVA) AID system and simulated two scenarios using the 100-adult cohort of the UVA/Padova T1D simulator: a nominal case including three unannounced meals, and another case where hypoglycemia was purposely induced by an overestimated manual bolus. RESULTS: In both simulation scenarios, rebound hypoglycemia events were reduced with HypoSafe (nominal: from 39 to 0, hypo-induced: from 55 to 7) by attenuating the commanded basal (nominal: 0.27U vs. 0.04U, hypo-induced: 0.27U vs. 0.03U) and bolus (nominal: 1.02U vs. 0.05U, hypo-induced: 0.43U vs. 0.02U) within the 30-minute interval after treating a hypoglycemia event. No clinically significant changes resulted for time in the range of 70 to 180 mg/dL or above 180 mg/dL. CONCLUSION: HypoSafe was shown to be effective in reducing rebound hypoglycemia events without affecting achieved time in range when combined with an advanced AID system.

Artificial Intelligence and Machine Learning for Improving Glycemic Control in Diabetes: Best Practices, Pitfalls, and Opportunities.

OBJECTIVE: Artificial intelligence and machine learning are transforming many fields including medicine. In diabetes, robust biosensing technologies and automated insulin delivery therapies have created a substantial opportunity to improve health. While the number of manuscripts addressing the topic of applying machine learning to diabetes has grown in recent years, there has been a lack of consistency in the methods, metrics, and data used to train and evaluate these algorithms. This manuscript provides consensus guidelines for machine learning practitioners in the field of diabetes, including best practice recommended approaches and warnings about pitfalls to avoid. METHODS: Algorithmic approaches are reviewed and benefits of different algorithms are discussed including importance of clinical accuracy, explainability, interpretability, and personalization. We review the most common features used in machine learning applications in diabetes glucose control and provide an open-source library of functions for calculating features, as well as a framework for specifying data sets using data sheets. A review of current data sets available for training algorithms is provided as well as an online repository of data sources. SIGNIFICANCE: These consensus guidelines are designed to improve performance and translatability of new machine learning algorithms developed in the field of diabetes for engineers and data scientists.

Sustained 3-Year Improvement of Glucose Control With Hybrid Closed Loop in Children With Type 1 Diabetes While Going Through Puberty.

OBJECTIVE: To evaluate the impact of prolonged hybrid closed loop (HCL) use in children with type 1 diabetes (T1D) on glucose control and BMI throughout pubertal progression. RESEARCH DESIGN AND METHODS: We used a prospective multicenter extension study following the Free-Life Kid AP (FLKAP) HCL trial. The 9-month previously reported FLKAP trial included 119 prepubertal children (aged 6-12 years). During the extension study, participants could continue to use HCL for 30 months (M9 to M39). HbA1c values were collected every 3 months up to M39, while continuous glucose monitoring metrics, BMI Z scores, and Tanner stages were collected up to M24. Noninferiority tests were performed to assess parameter sustainability over time. RESULTS: One hundred seventeen children completed the extension study, with mean age 10.1 years (min-max 6.8-14.0) at the beginning. Improvement of HbA1c obtained in the FLKAP trial was significantly sustained during extension (median [interquartile range], M9: 7.0% [6.8-7.4], and M39: 7.0% [6.6-7.4], P < 0.0001 for noninferiority test) and did not differ between children who entered puberty at M24 (Tanner ≥ stage 2; 54% of the patients) and patients who remained prepubertal. BMI Z score also remained stable (M9: 0.41 [-0.29 to 1.13] and M24: 0.48 [-0.11 to 1.13], P < 0.0001, for noninferiority test). No severe hypoglycemia and one ketoacidosis episode not related to the HCL system occurred. CONCLUSIONS: Prolonged use of HCL can safely and effectively mitigate impairment of glucose control usually associated with pubertal progression without impact on BMI in children with T1D.

Patient reported outcomes (PROs) and user experiences of young children with type 1 diabetes using t:slim X2 insulin pump with control-IQ technology.

OBJECTIVE: Examine patient-reported outcomes (PROs) after the use of t:slim X2 insulin pump with Control-IQ technology (CIQ) in young children with type 1 diabetes. METHODS: Children with type 1 diabetes, ages 2 to < 6 years (n = 102), were randomly assigned 2:1 to either CIQ or standard care (SC) with pump or multiple daily injections (MDI) plus continuous glucose monitoring (CGM) for 13 weeks. Both groups were offered to use CIQ for an additional 13 weeks after the randomized control trial's (RCT) completion. Guardians completed PRO questionnaires at baseline, 13-, and 26-weeks examining hypoglycemia concerns, quality of life, parenting stress, and sleep. At 26 weeks, 28 families participated in user-experience interviews. Repeated measures analyses compared PRO scores between systems used. RESULT: Comparing CIQ vs SC, responses on all 5 PRO surveys favored the CIQ group, showing that CIQ was superior to SC at 26 weeks (p values < 0.05). User-experience interviews indicated significant benefits in optimized glycemic control overall and nighttime control (28 of 28 families endorsed). All but 2/28 families noted substantial reduction in management burden resulting in less mental burden and all but 4 stated that they wanted their children to continue using CIQ. CONCLUSIONS: Families utilizing CIQ experienced glycemic benefits coupled with substantial benefits in PROs, documented in surveys and interviews. Families utilizing CIQ had reduced hypoglycemia concerns and parenting stress, and improved quality of life and sleep. These findings demonstrate the benefit of CIQ in young children with type 1 diabetes that goes beyond documented glycemic benefit.

Therapy Settings Associated with Optimal Outcomes for t:slim X2 with Control-IQ Technology in Real-World Clinical Care.

Objective: To determine insulin dosing parameters that are associated with and predict optimal outcomes for people using t:slim X2 with Control-IQ technology (CIQ). Methods: Retrospective deidentified data from CIQ users were analyzed to determine the effect of Correction Factor, Carbohydrate-to-Insulin (C:I) Ratio, and basal rate settings (standardized by total daily insulin [TDI]) on glycemic control. We performed an associative analysis followed by linear regressions to determine the relative importance of the settings and confounding variables (e.g., age or number of user-initiated boluses) in predicting consensus glycemic outcomes. Results: Data from 20,764 individuals were analyzed (median age 39 years [interquartile range 19, 59], 55% female, TDI 46.4 U [33-65.2]). More aggressive Correction Factor settings, C:I ratio settings, and basal programs were all strongly associated with higher time in range (TIR, 70-180 mg/dL) and to a lesser degree to higher time <70 mg/dL. In linear regression, more aggressive Correction Factor predicted higher TIR, lower coefficient of variation, and importantly had only negligible impact on time below range. Higher basal rate settings and lower C:I ratio predicted increased TIR as well as increased hypoglycemia. The most important predictor in all glycemic outcomes was the average number of user-given boluses per day. Conclusion: Basal rates, C:I ratios, and Correction Factor settings all impact glycemic outcomes in CIQ users in usual clinical care. The correction Factor setting may be the most impactful "lever to pull" for clinicians and CIQ users to optimize TIR while not increasing hypoglycemia.

Maximizing Glycemic Benefits of Using Faster Insulin Formulations in Type 1 Diabetes: In Silico Analysis Under Open- and Closed-Loop Conditions.

Background: Ultrarapid-acting insulin analogs that could improve or even prevent postprandial hyperglycemia are now available for both research and clinical care. However, clear glycemic benefits remain elusive, especially when combined with automated insulin delivery (AID) systems. In this work, we study two insulin formulations in silico and highlight adjustments of both open-loop and closed-loop insulin delivery therapies as a critical step to achieve clinically meaningful improvements. Methods: Subcutaneous insulin transport models for two faster analogs, Fiasp (Novo Nordisk, Bagsværd, Denmark) and AT247 (Arecor, Saffron Walden, United Kingdom), were identified using data collected from prior clamp experiments, and integrated into the UVA/Padova type 1 diabetes simulator (adult cohort, N = 100). Pump therapy parameters and the aggressiveness of our full closed-loop algorithm were adapted to the new insulin pharmacokinetic and pharmacodynamic profiles through a sequence of in silico studies. Finally, we assessed these analogs' glycemic impact with and without modified therapy parameters in simulated conditions designed to match clinical trial data. Results: Simply switching to faster insulin analogs shows limited improvements in glycemic outcomes. However, when insulin acceleration is accompanied by therapy adaptation, clinical significance is found comparing time-in-range (70-180 mg/dL) with Aspart versus AT247 in open-loop (+5.1%); and Aspart versus Fiasp (+5.4%) or AT247 (+10.6%) in full closed-loop with no clinically significant differences in the exposure to hypoglycemia. Conclusion: In silico results suggest that properly adjusting intensive insulin therapy profiles, or AID tuning, to faster insulin analogs is necessary to obtain clinically significant improvements in glucose control.

Performance Effect of Adjusting Insulin Sensitivity for Model-Based Automated Insulin Delivery Systems.

BACKGROUND: Model predictive control (MPC) has become one of the most popular control strategies for automated insulin delivery (AID) in type 1 diabetes (T1D). These algorithms rely on a prediction model to determine the best insulin dosing every sampling time. Although these algorithms have been shown to be safe and effective for glucose management through clinical trials, managing the ever-fluctuating relationship between insulin delivery and resulting glucose uptake (aka insulin sensitivity, IS) remains a challenge. We aim to evaluate the effect of informing an AID system with IS on the performance of the system. METHOD: The University of Virginia (UVA) MPC control-based hybrid closed-loop (HCL) and fully closed-loop (FCL) system was used. One-day simulations at varying levels of IS were run with the UVA/Padova T1D Simulator. The AID system was informed with an estimated value of IS obtained through a mixed meal glucose tolerance test. Relevant controller parameters are updated to inform insulin dosing of IS. Performance of the HCL/FCL system with and without information of the changing IS was assessed using a novel performance metric penalizing the time outside the target glucose range. RESULTS: Feedback in AID systems provides a certain degree tolerance to changes in IS. However, IS-informed bolus and basal dosing improve glycemic outcomes, providing increased protection against hyperglycemia and hypoglycemia according to the individual's physiological state. CONCLUSIONS: The proof-of-concept analysis presented here shows the potentially beneficial effects on system performance of informing the AID system with accurate estimates of IS. In particular, when considering reduced IS, the informed controller provides increased protection against hyperglycemia compared with the naïve controller. Similarly, reduced hypoglycemia is obtained for situations with increased IS. Further tailoring of the adaptation schemes proposed in this work is needed to overcome the increased hypoglycemia observed in the more resistant cases and to optimize the performance of the adaptation method.