Coming of age: the artificial pancreas for type 1 diabetes.

The artificial pancreas (closed-loop system) addresses the unmet clinical need for improved glucose control whilst reducing the burden of diabetes self-care in type 1 diabetes. Glucose-responsive insulin delivery above and below a preset insulin amount informed by sensor glucose readings differentiates closed-loop systems from conventional, threshold-suspend and predictive-suspend insulin pump therapy. Insulin requirements in type 1 diabetes can vary between one-third-threefold on a daily basis. Closed-loop systems accommodate these variations and mitigate the risk of hypoglycaemia associated with tight glucose control. In this review we focus on the progress being made in the development and evaluation of closed-loop systems in outpatient settings. Randomised transitional studies have shown feasibility and efficacy of closed-loop systems under supervision or remote monitoring. Closed-loop application during free-living, unsupervised conditions by children, adolescents and adults compared with sensor-augmented pumps have shown improved glucose outcomes, reduced hypoglycaemia and positive user acceptance. Innovative approaches to enhance closed-loop performance are discussed and we also present the outlook and strategies used to ease clinical adoption of closed-loop systems.Supported by National Institute of Health Research Cambridge Biomedical Research Centre, Efficacy and Mechanism Evaluation National Institute for Health Research (#14/23/09), The Leona M. & Harry B. Helmsley Charitable Trust (#2016PG-T1D045), JDRF (#2-SRA-2014-256-M-R), National Institute of Diabetes and Digestive and Kidney Diseases (1UC4DK108520-01), and Diabetes UK (#14/0004878).This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00125-016-4022-

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

Closed-loop management of inpatient hyperglycemia.

The prevalence of diabetes in the hospital is increasing and approximately 18-20% of hospital beds are occupied by someone with diabetes [1]. Diabetes disproportionally affects the elderly, with three times greater prevalence in hospitalised people aged over 65 years than in those aged under 45 years [2]. Maintaining near normoglycaemia during hospital admissions can be very challenging. The impact of the current illness, medication changes, alterations to meal timings and intake, and requirement for nutrition support in hospital can all contribute to sub-optimal glucose control. Both hyper- and hypoglycemia in hospital are associated with increased risk of complications, length of stay, admission to the intensive care unit and mortality [3].Diabetes UK (#14/0004878), Swiss National Science Foundation (P1BEP3_165297) and European Foundation for the Study of Diabetes. Additional support for the Artificial Pancreas work by JDRF, National Institute for Health Research Cambridge Biomedical Research Centre and Wellcome Trust Strategic Award (100574/Z/12/Z)

Technology in the management of type 2 diabetes: Present status and future prospects

Funder: This research was funded by the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre and Wellcome Strategic Award (100574/Z/12/Z). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.Abstract: The growing incidence of type 2 diabetes (T2D) is a significant health concern, representing 90% of diabetes cases worldwide. As the disease progresses, resultant insulin deficiency and hyperglycaemia necessitates insulin therapy in many cases. It has been recognized that a significant number of people who have a clinical requirement for insulin therapy, as well as their healthcare professionals, are reluctant to intensify treatment with insulin due to fear of hypoglycaemia, poor understanding of treatment regimens or lack of engagement, and are therefore at higher risk of developing complications from poor glycaemic control. Over the past decade, the rise of diabetes technologies, including dosing advisors, continuous glucose monitoring systems, insulin pumps and automated insulin delivery systems, has led to great improvements in the therapies available, particularly to those requiring insulin. Although the focus has largely been on delivering these therapies to the type 1 diabetes population, it is becoming increasingly recognized that people with T2D face similar challenges to achieve recommended glycaemic standards and also have the potential to benefit from these advances. In this review, we discuss diabetes technologies that are currently available for people with T2D and the evidence supporting their use, as well as future prospects. We conclude that there is a clinical need to extend the use of these technologies to the T2D population to curb the consequences of suboptimal disease management in this group

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)

Benefits and Challenges of Current Closed-Loop Technologies in Children and Young People With Type 1 Diabetes

Recent advances in diabetes technology have led to the development of closed-loop insulin delivery systems for the management of type 1 diabetes. Several such systems are now commercially available for children and young people. While all available systems have been shown to improve glycaemic control and quality of life in this population, qualitative data also highlights the challenges in using closed-loop systems, which vary among different pediatric age-groups. Very young children require systems that are able to cope with low insulin doses and significant glycaemic variability due to their high insulin sensitivity and unpredictable eating and exercise patterns. Adolescents' compliance is often related to size and number of devices, usability of the systems, need for calibrations, and their ability to interact with the system. Given the speed of innovations, understanding the capabilities and key similarities and differences of current systems can be challenging for healthcare professionals, caregivers and young people with type 1 diabetes alike. The aim of this review is to summarize the key evidence on currently available closed-loop systems for children and young people with type 1 diabetes, as well as commenting on user experience, where real-world data are available. We present findings on a system-basis, as well as identifying specific challenges in different pediatric age-groups and commenting on how current systems might address these. Finally, we identify areas for future research with regards to closed-loop technology tailored for pediatric use and how these might inform reimbursement and alleviate disease burden

Correction to: New closed-loop insulin systems.

A Correction to this paper has been published: 10.1007/s00125-021-05443-1</jats:p

Feasibility of Automated Insulin Delivery Guided by Continuous Glucose Monitoring in preterm infants

Abstract: Objective: Closed-loop systems have been used to optimise insulin delivery in children with diabetes, but they have not been tested in neonatal intensive care. Extremely preterm infants are prone to hyperglycaemia and hypoglycaemia; both of which have been associated with adverse outcomes. Insulin sensitivity is notoriously variable in these babies and glucose control is time-consuming, with management requiring frequent changes of dextrose-containing fluids and careful monitoring of insulin treatment. We aimed to evaluate the feasibility of closed-loop management of glucose control in these infants. Design and Setting: Single centre feasibility study with a randomized parallel design in a neonatal intensive care unit. Eligibility criteria included birth weight <1200g and <48hours of age. All infants had subcutaneous continuous glucose monitoring for the first week of life, with those in the intervention group receiving closed-loop insulin delivery in a pre-specified window, between 48 and 72hours of age during which time the primary outcome was percentage of time in target (sensor glucose 4-8mmol/l). Results: The mean (SD) gestational age and birth weight of intervention and control study arms were 27.0(2.4) weeks, 962(164) g and 27.5(2.8) weeks, 823(282) g respectively, and were not significantly different. The time in target was dramatically increased from median (IQR) 26%(6, 64) with paper guidance to 91%(78, 99) during closed loop (p<0.001). There were no serious adverse events and no difference in total insulin infused. Conclusions: Closed-loop glucose control based on subcutaneous glucose measurements appears feasible as a potential method of optimizing glucose control in extremely preterm infants.Funding was provided by the Evelyn Trust, the National Institute of Health Research EME Program and the National Institute of Health Research Cambridge Biomedical Research Centre. Medtronic provided the continuous glucose monitoring system and sensors. Medtronic had no role in design of the study, the gathering of data, access to data, preparation of the manuscript or decision to publish the results

New closed-loop insulin systems.

Advances in diabetes technologies have enabled the development of automated closed-loop insulin delivery systems. Several hybrid closed-loop systems have been commercialised, reflecting rapid transition of this evolving technology from research into clinical practice, where it is gradually transforming the management of type 1 diabetes in children and adults. In this review we consider the supporting evidence in terms of glucose control and quality of life for presently available closed-loop systems and those in development, including dual-hormone closed-loop systems. We also comment on alternative 'do-it-yourself' closed-loop systems. We remark on issues associated with clinical adoption of these approaches, including training provision, and consider limitations of presently available closed-loop systems and areas for future enhancements to further improve outcomes and reduce the burden of diabetes management