Closed-loop Insulin Delivery Research Articles

Sleep Quality and Quantity in Caregivers of Children with Type 1 Diabetes Using Closed-Loop Insulin Delivery or a Sensor-Augmented Pump

Introduction. Parents of children living with type 1 diabetes (T1D) often report short and/or poor quality sleep. The development of closed-loop systems promises to transform the management of T1D. This study compared sleep quality and quantity in caregivers of children using a closed-loop system (CL) or sensor-augmented pump (SAP) therapy. Method. Data from sleep diaries, accelerometers, and questionnaires were provided by forty parents (classified as caregiver 1 (main analyses) or 2 (supplementary analyses) based on their contribution towards treatment management) of 21 very young children aged 1 to 7 years living with T1D (mean age: 4.7 (SD = 1.7)). Assessments were made at a single post-randomisation time point when the child was completing either the 16-week CL arm (n = 10) or the 16-week SAP arm (n = 11) of the main study. Results. Overall, there was a mixed pattern of results and group differences were not statistically significant at the p < 0.05 level. However, when we consider the direction of results and results from caregiver 1, sleep diary data showed that parents of the CL (as compared to the SAP) group reported a shorter sleep duration but better sleep quality, fewer awakenings, and less wake after sleep onset (WASO). Actiwatch data showed that caregiver 1 of the CL (as compared to the SAP) group had a shorter sleep latency; greater sleep efficiency; and less wake after sleep onset. Results from the Pittsburgh Sleep Quality Index also showed better sleep quality for caregiver 1 of the CL group as compared to the SAP group. Conclusions. Results from this study suggest that sleep quality and quantity in parents of children using CL were not significantly different to those using SAP. Considering effect sizes and the direction of the non-significant results, CL treatment could be associated with better sleep quality in the primary caregiver. However, further research is needed to confirm these findings. This trial is registered with NCT05158816.

Electro-responsive silk fibroin microneedles for controlled release of insulin

To date, very limited work has been done on convenient and active control of insulin release. Herein, we report an electro-responsive insulin delivery system based on thiolated silk fibroin. The disulfide cross-linking points in TSF were reduced and broken to form sulfhydryl groups under electrification, which led to the increase of microneedle swelling degree and promoted insulin release. After power failure, the sulfhydryl group is oxidised to form disulfide bond crosslinking point again, resulting in the reduction of microneedle swelling degree and thus the reduction of release rate. The insulin loaded in the electro-responsive insulin delivery system showed good reversible electroresponsive release performance. The addition of graphene reduced the microneedle resistance and increased the drug release rate under current conditions. In vivo studies on type 1 diabetic mice show that electro-responsive insulin delivery system effectively controls the blood glucose before and after feeding by switching on and off the power supply, and this blood glucose control can be maintained within the safe range (100–200 mg/dL) for a long time (11h). Such electrically responsive delivery microneedles show potential for integration with glucose signal monitoring and are expected to build closed-loop insulin delivery systems.

Clinical Rounds.

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Time requirements for perioperative glucose management using fully closed-loop versus standard insulin therapy: A proof-of-concept time-motion study.

To compare the time required for perioperative glucose management using fully automated closed-loop versus standard insulin therapy. We performed a time-motion study to quantify the time requirements for perioperative glucose management with fully closed-loop (FCL) and standard insulin therapy applied to theoretical scenarios. Following an analysis of workflows in different periods of perioperative care in elective surgery patients receiving FCL or standard insulin therapy upon hospital admission (pre- and intra-operatively, at the intermediate care unit and general wards), the time of process-specific tasks was measured by shadowing hospital staff. Each task was measured 20 times and its average duration in combination with its frequency according to guidelines was used to calculate the cumulative staff time required for blood glucose management. Cumulative time was calculated for theoretical scenarios consisting of elective minor and major abdominal surgeries (pancreatic surgery and sleeve gastrectomy, respectively) to account for the different care settings and lengths of stay. The FCL insulin therapy reduced the time required for perioperative glucose management compared to standard insulin therapy, across all assessed care periods and for both perioperative pathways (range 2.1-4.5). For a major abdominal surgery, total time required was 248.5 min using FCL versus 753.9 min using standard insulin therapy. For a minor abdominal surgery, total time required was 68.6 min and 133.2 min for FCL and standard insulin therapy, respectively. The use of fully automated closed-loop insulin delivery for inpatient glucose management has the potential to alleviate the workload of diabetes management in an environment with adequately trained staff.

Clinician Experiences With Hybrid Closed Loop Insulin Delivery Systems in Veterans With Type 1 Diabetes: Qualitative Study.

Hybrid closed loop (HCL) insulin pumps adjust insulin delivery based on input from a continuous glucose monitor. Several systems are FDA approved and associated with improved time in range, reduction in hemoglobin A1c, and decreased incidence of hypoglycemia. Major diabetes guidelines differ in their strength of recommendations regarding the use of HCL systems. Overall, limited information about the factors that influence HCL pump clinical decision-making is available, especially among endocrinology clinicians. The study objective is to describe the knowledge and attitudes, network support, and self-efficacy regarding HCL insulin delivery systems among endocrinology clinicians in one Veterans Affairs (VA) Healthcare System in the Midwest. Following a descriptive approach, this qualitative study used semistructured interviews and inductive thematic analysis. All endocrinologists, endocrinology fellows, and nurses in the endocrinology and metabolism department at one VA Healthcare System in the Midwest were invited to participate in one-on-one phone interviews. Thematic analysis explored clinician perspectives on HCL insulin pump systems. Participants (n=11) had experience within VA and university health care system endocrinology clinics. From their experiences, 4 themes were identified involving the evaluation and assessment of insulin pump candidates, prescribing challenges, clinical benefits of HCL pumps, and overall clinician confidence. Findings suggest that clinicians believe HCL systems have significant glycemic benefits but are not appropriate for all patients, especially those with cognitive impairment. HCL pump initiation is a multi-step process requiring an interdisciplinary team of health care clinicians to ensure patient and pump success. Furthermore, HCL systems improve clinician confidence in overall diabetes management.

Implementation of fully closed-loop insulin delivery for inpatients with diabetes: real-world outcomes.

Fully closed-loop insulin delivery has been shown in clinical trials to be safe and improve glucose control compared with standard insulin therapy in the inpatient setting. We investigated the feasibility of implementing the approved CamAPS HX fully closed-loop system in a hospital setting. This implementation project was conducted in a large teaching hospital in Cambridge, UK. Healthcare professional training was multimodal including face-to-face workshops, online learning modules and supported by standard operating procedures. Set-up and maintenance of closed-loop devices was undertaken by the inpatient diabetes team. Selection of suitable patients was multidisciplinary and prioritised those with more challenging diabetes management. Demographic and clinical data were collected from electronic health records and diabetes data management platforms. In the 12 months since the closed-loop system was implemented, 32 inpatients (mean±SD age 61±16 years, 8 females, 24 males) used closed-loop insulin delivery during their admission, across medical and surgical wards in the hospital with a total of 555 days of closed-loop glucose control (median[IQR]: 14[6, 22] days per inpatient). The time spent in target glucose range 3.9-10.0mmol/L was 53.3±18.3%. Mean glucose was 10.7±1.9mmol/L with 46.0±18.2% of time spent with glucose >10.0mmol/L. Time spent with sensor glucose below 3.9mmol/L was low (median[IQR]: 0.38[0.00, 0.85]). There were no episodes of severe hypoglycaemia or diabetic ketoacidosis during closed-loop use. We have demonstrated that the fully closed-loop system can be safely and effectively implemented by a diabetes outreach team in complex medical and surgical inpatients with challenging glycaemic control.

Closed-loop insulin delivery in pregnant women with type 1 diabetes (CRISTAL): a multicentre randomized controlled trial – study protocol

BackgroundDespite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5–7.8 mmol/L or 63–140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy.MethodsIn this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18–45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c (< 53 vs. ≥ 53 mmol/mol or < 7 vs. ≥ 7%), and method of insulin delivery (MDI or CSII). The primary outcome will be the time spent within the pregnancy glucose target range, as measured by the CGM at four time points in pregnancy: 14–17, 20–23, 26–29, and 33–36 weeks. Prespecified secondary outcomes will be overnight TIR, time below range (TBR: <3.5 mmol/L or < 63 mg/dL), and overnight TBR. Other outcomes will be exploratory. The planned sample size is 92 participants. The study will end after postpartum discharge from hospital. Analyses will be performed according to intention-to-treat as well as per protocol.DiscussionThis large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023.Trial registrationClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971

Increasing Use of Diabetes Devices: What Do Health Care Professionals Need?

Despite evidence of improved diabetes outcomes with diabetes technology such as continuous glucose monitoring (CGM) systems, insulin pumps, and hybrid closed-loop (HCL) insulin delivery systems, these devices are underutilized in clinical practice for the management of insulin-requiring diabetes. This low uptake may be the result of health care providers' (HCPs') lack of confidence or time to prescribe and manage devices for people with diabetes. We administered a survey to HCPs in primary care, pediatric endocrinology, and adult endocrinology practices in the United States. Responding HCPs expressed a need for device-related insurance coverage tools and online data platforms with integration to electronic health record systems to improve diabetes technology uptake in these practice settings across the United States.

Diabetes Technology and Therapy in the Pediatric Age Group.

Diabetes Technology and Therapy in the Pediatric Age Group.

Using Digital Health Technology to Prevent and Treat Diabetes.

Using Digital Health Technology to Prevent and Treat Diabetes.

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.

Fully automated closed-loop insulin delivery in adults with type 2 diabetes: an open-label, single-center, randomized crossover trial

In adults with type 2 diabetes, the benefits of fully closed-loop insulin delivery, which does not require meal bolusing, are unclear. In an open-label, single-center, randomized crossover study, 26 adults with type 2 diabetes (7 women and 19 men; (mean ± s.d.) age, 59 ± 11 years; baseline glycated hemoglobin (HbA1c), 75 ± 15 mmol mol−1 (9.0% ± 1.4%)) underwent two 8-week periods to compare the CamAPS HX fully closed-loop app with standard insulin therapy and a masked glucose sensor (control) in random order, with a 2-week to 4-week washout between periods. The primary endpoint was proportion of time in target glucose range (3.9–10.0 mmol l−1). Analysis was by intention to treat. Thirty participants were recruited between 16 December 2020 and 24 November 2021, of whom 28 were randomized to two groups (14 to closed-loop therapy first and 14 to control therapy first). Proportion of time in target glucose range (mean ± s.d.) was 66.3% ± 14.9% with closed-loop therapy versus 32.3% ± 24.7% with control therapy (mean difference, 35.3 percentage points; 95% confidence interval (CI), 28.0–42.6 percentage points; P < 0.001). Time > 10.0 mmol l−1 was 33.2% ± 14.8% with closed-loop therapy versus 67.0% ± 25.2% with control therapy (mean difference, −35.2 percentage points; 95% CI, −42.8 to −27.5 percentage points; P < 0.001). Mean glucose was lower during the closed-loop therapy period than during the control therapy period (9.2 ± 1.2 mmol l−1 versus 12.6 ± 3.0 mmol l−1, respectively; mean difference, −3.6 mmol l−1; 95% CI, −4.6 to −2.5 mmol l−1; P < 0.001). HbA1c was lower following closed-loop therapy (57 ± 9 mmol mol−1 (7.3% ± 0.8%)) than following control therapy (72 ± 13 mmol mol−1 (8.7% ± 1.2%); mean difference, −15 mmol mol−1; 95% CI, −11 to −20 mmol l−1 (mean difference, −1.4%; 95% CI, −1.0 to −1.8%); P < 0.001). Time < 3.9 mmol l−1 was similar between treatments (a median of 0.44% (interquartile range, 0.19–0.81%) during the closed-loop therapy period versus a median of 0.08% (interquartile range, 0.00–1.05%) during the control therapy period; P = 0.43). No severe hypoglycemia events occurred in either period. One treatment-related serious adverse event occurred during the closed-loop therapy period. Fully closed-loop insulin delivery improved glucose control without increasing hypoglycemia compared with standard insulin therapy and may represent a safe and efficacious method to improve outcomes in adults with type 2 diabetes. This study is registered with ClinicalTrials.gov (NCT04701424).

Commercial hybrid closed-loop systems available for a patient with type 1 diabetes in 2022.

Technological advances offer the opportunity to improve glycemic control and reduce the risk of complications and burden of type 1 diabetes while improving patient quality of life. Closed-loop insulin delivery systems take the technology to alarger scale by integrating CGM systems with an insulin pump and an algorithm that automates insulin delivery (HCL systems). Several systems using hybrid closed loop technology are currently offered in the global marketplace: the MiniMed™ 670G and MiniMed™ 780G (SmartGuard™) system from Medtronic; the T slim x2 Control IQ from Tandem; the Omnipod5 automated mode (HypoProtect™)5 from Insulet; and the CamAPS FX DanaRS or Ypso pump. Insulet's Omnipod5 automated mode (HypoProtect™) is currently in clinical trials. As technology moves forward, advanced systems are being developed that include an elaborate algorithm with individualization of major target points, automated correction bolus functionality, and increased stability of the automated mode (Advanced Hybrid Closed-Loop - AHCL systems). The AHCL systems include: MiniMed™ 780G (SmartGuard™); Tandem's T slim x2 Control IQ; Insulet's Omnipod5-Automated mode (HypoProtect™); and CamAPS FX. The purpose of this paper is to present commercial devices using HCL and AHCL in 2022, also from ascientific point of view. It is an undeniable fact that "auto-mode" systems represent anew stage that can be confidently called arevolution in diabetology.

Application of Automated Insulin Delivery in Korean Clinical Practice

In contrast to Europe and the United States (US), conventional insulin pumps have not been widely used in East Asia, even among people with type 1 diabetes. Clinical experiences in Europe and the US indicate that automated insulin delivery (AID) can successfully improve the quality of glucose control even in people with type 1 diabetes who do not have experience with conventional insulin pumps. Therefore, prior use of a conventional insulin pump was not a requirement for successful introduction of AID. However, use of AID still requires full understanding of conventional insulin pump management, and AID-specific education as well. Besides basic information on continuous glucose monitoring and conventional insulin pumps, people with type 1 diabetes starting AID should understand the difference between closed-loop and open-loop insulin delivery, should have reasonable expectations for AID, and should be motivated to engage in clinical follow-up to prevent discontinuation of the use of AID devices. Failure to provide AID-specific education before and after the introduction of AID would result in discontinuation of the use of AID devices, which would in turn result in suboptimal glucose control. In this review, I summarize lessons from clinical experience where AID is already in clinical use, and discuss what preparations should be made for successful introduction of AID in Korean clinical practice.

Experiences of Patients Adopting and Adapting to Closed-Loop Insulin Delivery Systems (CLIDS).

The purpose of the study was to explore the perspectives and experiences of adults with type 1 diabetes (T1DM) who are currently using the closed-loop insulin delivery system (CLIDS). Eleven adults with T1DM who used closed-loop insulin pumps for at least 6 months participated in this qualitative descriptive study. Four themes emerged from the rich descriptions: (1) striving for improvement, (2) missing a magic wand effect, (3) seeking support, and (4) barriers to adaptation. These themes represent both process-based and psychosocial implications for nursing practice and patient education. To optimize CLIDS use and outcome, the antecedent conditions that contribute to patients' decision to adopt it must be understood. Then, interventions that focus on setting realistic expectations must be created. Patients need support as they incorporate CLIDS into their T1DM self-management. Training health care providers on the idiosyncrasies of adapting to CLIDS is critical. Patients must learn to relinquish control and trust the machine and manage the anxiety the system's intrusive alarms cause them so they can be better supported cognitively and psychosocially.

Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs

Insulin and glucagon secreted from the pancreas with dynamic balance play a vital role in regulating blood glucose levels. Although distinct glucose-responsive insulin delivery systems have been developed, the lack of a self-regulated glucagon release module limits their clinical applications due to the potential risk of hypoglycemia. Here, we describe a transdermal polymeric microneedle patch for glucose-responsive closed-loop insulin and glucagon delivery to achieve glycemic regulation with minimized risk of hypoglycemia. The glucose-responsive phenylboronic acid units can bind to glucose to reversibly shift the net charge (from positive to negative) of the entire polymeric matrix within microneedles. Therefore, the release ratio of the negatively charged insulin and the positively charged glucagon analog from the patch can be dynamically tuned upon the fluctuation of blood glucose levels to realize glycemic homeostasis. In both chemically induced type 1 diabetic mouse and minipig models, this glucose-responsive dual-hormone microneedle patch demonstrated tight long-term regulation in blood glucose levels (>24 hours in minipigs).

Study protocol: a randomised controlled proof-of-concept real-world study – does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes?

IntroductionPeople with type 1 diabetes (T1D) develop an impaired glucagon response to hypoglycaemia within 5 years of diagnosis, increasing their risk of severe hypoglycaemia. It is not known whether eliminating...

Carbohydrate Intake and Closed-Loop Insulin Delivery System during Two Subsequent Pregnancies in Type 1 Diabetes.

Carbohydrate intake is one of the main determinants of glycemic control. In pregnancy, achievement of tight glycemic control is of utmost importance; however, data on the role of hybrid closed-loop systems (HCLs) in pregnancy are scarce. Therefore, we aimed to assess glycemic control achieved through the use of HCLs, and its association with carbohydrate intake in type 1 diabetes pregnancy. We included data from women with a sensor-augmented pump (SAP) during their first pregnancy and HCL use during the subsequent pregnancy. Student's paired t-test was used to compare data between both pregnancies. Six women were identified, with age 30.2 ± 3.6 vs. 33.0 ± 3.6 years, diabetes duration 23 ± 5 vs. 26 ± 5 years, and baseline HbA1c 6.7 ± 0.7% (50.1 ± 7.7 mmol/mol) vs. 6.3 ± 0.6% (45.2 ± 6.5 mmol/moll) in the first and second pregnancies, respectively. Time with glucose in the range 3.5-7.8 mmol/L was 69.1 ± 6.7 vs. 78.6 ± 7.4%, p = 0.045, with the HCLs compared to SAP. Higher meal frequency, but not the amount of carbohydrate consumption, was associated with more time spent in the target range and lower glycemic variability. HCLs and meal frequency were associated with better glycemic control in a small series of pregnant women with type 1 diabetes. Whether this translates to better perinatal outcomes remains to be seen.

Variation of glucose time in range in type 1 diabetes.

The aim of the study was to assess the variation of glucose time in range (TIR) for persons with type 1 diabetes who perform intermittently scanned continuous glucose monitoring (isCGM). Glucose data for 8 weeks were analysed for 166 persons. TIR was calculated over four consecutive 2 weeks periods. Sixty-one of the persons had two downloads with an interval of >3months. A total of 140 individuals (84%) used multiple daily injection, and 26 (16%) used continuous insulin infusion. The within-individual standard deviation (SD) for TIR was 6.3% corresponding to 95% limits of agreement for the difference between two TIR values of ±17.6%. Mean TIR calculated from the first and last 2 weeks was 52.2 ± 17.1% and 53.7 ± 16.4%, respectively (difference 1.5%, SD of the difference 10.4%, p=.07). For persons with two downloads separated by months, the SD of the difference in TIR was 12.6%. The 95% limit of agreement for TIR is vast for persons using isCGM. It is difficult to draw firm conclusions regarding systematic differences when individual TIR from 2 weeks are compared. This may not be valid for users of insulin pumps with closed-loop insulin delivery.

Insulin infusion rate control using information theoretic–based nonlinear model predictive control for type 1 diabetes patients

It has been proven that model predictive control (MPC) is an efficient method for closed-loop insulin delivery in clinical studies. This paper aims to design an observer-based fractional-order nonlinear MPC for type 1 diabetes mellitus (T1DM) patients. It is assumed that the proposed model is nonlinear and contains parametric uncertainty. To estimate unknown states, optimal non-fragile H∞ observer is designed for Lipschitz nonlinear fractional-order systems including parametric uncertainty and the existence of input disturbance. The min–max optimization-based robust fractional model predictive control (RFMPC) has been presented in the following for insulin delivery. Since sensor noise of continuous monitoring of interstitial glucose concentration is considered non-Gaussian, the performance of the proposed controller is improved under non-Gaussian measurement noise by selecting a proper cost function based on generalized correntropy, and as a contrast, the performance of the mean square error (MSE)-based controller is simulated. According to the results, not only is the performance of the proposed controller better under non-Gaussian situations but also effectively reaches the set point in the case of disturbance and uncertainty and provides higher control accuracy and robustness compared with the MSE-based MPC.