The Artificial Pancreas in Children and Adolescents with Type 1 Diabetes: Bringing Closed-Loop Home

Type 1 diabetes is one of the most common chronic conditions in childhood and adolescence. Despite ongoing development of more physiological insulin preparations, recent advancements in insulin pump technology and more accurate blood glucose monitoring, in clinical practice it remains challenging to achieve normoglycaemia whilst reducing the risk of hypoglycaemia, particularly in young people with type 1 diabetes. Closed-loop insulin delivery (the artificial pancreas) is an emerging technology gradually progressing from bench to clinical practice. Closed-loop systems combine glucose sensing with computer-based algorithm informed insulin delivery to provide real-time glucose-responsive insulin administration. The key objective of my thesis is to evaluate the safety, efficacy and utility of closed-loop insulin delivery in children and adolescents with type 1 diabetes outside of the research facility setting. Results of five clinical trials are presented in the main chapters of this thesis. In a mechanistic study, the impact of glucose sensor operation duration on efficacy of overnight closed-loop was investigated comparing closed-loop performance on day 1 of sensor insertion to day 3 to 4 of sensor. Twelve adolescents with type 1 diabetes attended the research facility for two overnight visits. The sequence of the interventions was random. Despite 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. In home settings, overnight closed-loop application was evaluated over three months in 25 children and adolescents with type 1 diabetes aged six to 18 years. The study was conducted at three centres in the UK and adopted a randomised cross-over design. Compared to sensor-augmented pump therapy, overnight home use of closed-loop increased the proportion of time sensor glucose was in target, and reduced mean glucose and hypoglycaemia. Two randomised crossover studies evaluated the safety and efficacy of day-and-night hybrid closed-loop insulin delivery in young people with type 1 diabetes aged 10 to 18 years over seven days, and 21 days, respectively. A total of 24 subjects were enrolled in this single centre trial. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes was safe, and improved glucose control without increasing the risk of hypoglycaemia. Finally, closed-loop technology was assessed in five very young children (aged one to seven years) with type 1 diabetes in a two-period, crossover study. Closed-loop was used during both 3-week intervention periods, either with standard strength insulin (U100), or with diluted insulin (U20). The order of intervention was random. Free-living home use of day-and-night hybrid closed-loop in very young children with type 1 diabetes was feasible and safe. Glucose control was comparable during both intervention periods. Thus, use of diluted insulin during closed-loop insulin delivery might not be of additional benefit in this population. In conclusion, studies conducted as part of my thesis demonstrate that use of hybrid closed-loop insulin delivery systems in children and adolescents aged one to 18 years in free daily living without remote monitoring or supervision is feasible, safe and effective. My work supports the progression of this technology from research to mainstream clinical practice

Understanding the Determinants of Sustained Beta Cell Function in Type 1 Diabetes

Type 1 diabetes is a disease defined by the inexorable autoimmune destruction of pancreatic beta cells, leading to endogenous insulin deficiency. C-peptide, a 31 amino acid protein that joins the alpha and beta chains of insulin in the proinsulin molecule, is well established as a marker of endogenous insulin secretion. Circulating levels within people with type 1 diabetes demonstrate persistence of insulin secretion, in some cases, for many years after diagnosis. Additionally, histological analyses of donor pancreata have provided evidence for persistent immunoreactive insulin-positive beta cells. These findings have challenged the dogma that all beta cells are destroyed at, or soon after, onset of type 1 diabetes. Although it is clear there is some relationship between residual C-peptide and preserved beta cell mass, residual C-peptide alone cannot distinguish between loss of beta cell mass and reduced functionality. As such, C-peptide level remains a contested surrogate for the aetiopathological definition of type 1 diabetes, which is used across disease classification and as the end point in many intervention trials designed to preserve beta cell function. A fundamental difference between type 1 diabetes and type 2 diabetes is that the former is characterised by rapid progression to endogenous insulin deficiency due to autoimmune beta-cell destruction. Since histological classification is impossible in living humans with type 1 diabetes, C-peptide-defined type 1 and type 2 diabetes have been used as the endpoint in the development and validation of classification models which combine clinical features and biomarkers to improve classification of disease at diagnosis. In Chapter 2, I aimed to I validate a classification model that was previously developed on a C-peptide outcome in a clinical cohort, against a histological definition of type 1 diabetes. This classification model combined age, body mass index (BMI), autoantibody status and type 1 diabetes genetic risk score (T1D GRS), with its predictive performance tested on samples defined histologically as having type 1 diabetes and non-type 1 diabetes from the Network for Pancreatic Organ Donors with Diabetes (nPOD) biobank. Strong predictive performance of the model in this setting demonstrated that the C-peptide outcome, used in its development, is representative of histologically defined disease, confirming that C-peptide is a robust, appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible. In the 1970s it was crystallised that type 1 diabetes is a disease mediated by the autoimmune destruction of insulin producing beta cells. Since then, the centrepiece of many disease modifying intervention trials has been to augment the survival of functional beta cells, assessed via measures of preserved C-peptide secretion. However, there are clear differences in disease progression between children and adults with recent suggestions that, even within children, differences are driven by underlying endotypes. In Chapter 3, across disease duration, I compared the trends of decline of C-peptide in a cohort of living children from the UK Genetic Resource Investigating Diabetes, to the trends of decline of pancreatic beta cells in organ donors from the combined nPOD and Exeter Archival Diabetes Biobank (EADB), through stratifying by newly described age at diagnosis associated endotypes. I demonstrated that C-peptide loss and beta cell loss, in all age at diagnoses studied, mirror one another across duration of disease. I demonstrated that proportionally fewer children diagnosed <7 retained C-peptide after one year of diagnosis, with the levels of retained C-peptide being lower at diagnosis that those diagnosed at older ages. I showed these trends of loss are almost identical in pancreas donors, with proportionally fewer children retaining islets containing insulin positive beta cells after one year of diagnosis, with fewer insulin positive beta cells at diagnosis as compared to donors diagnosed at older ages. The results in this chapter are indicative of the differences in disease progression in children. The rapid depletion of C-peptide and beta cells in children diagnosed < 7 years is suggestive that early intervention close to or before diagnosis may be most time critical, and should additionally be considered in planning and interpretation of intervention trials. Preserving C-peptide is unequivocally beneficial to a person diagnosed with type 1 diabetes, associating with reduced frequency and severity of self-reported hypoglycaemia and fewer long term microvascular complications, as evidenced originally from DCCT. In Chapter 4, using insights from continuous glucose monitoring (CGM) technology, I demonstrated that higher levels of endogenous insulin secretion around the time of diagnosis impact glycaemic variability, but are not associated with hypoglycaemia. The work in this chapter adds to findings from previous studies of longer duration diabetes to offer a more complete picture of the impact that variation in C-peptide levels have on glucose control in people with type 1 diabetes. Increased use of flash and continuous glucose monitoring has enabled more detailed, daily insights into glycaemic control within type 1 diabetes, the relationships of such with C-peptide have been explored within this thesis. This technology however offers a wealth of opportunity for exploring the lived experience type 1 diabetes, in relation to daily glucose control. In Chapter 5 I developed upon the skills I had refined in CGM data analysis, exploring the impact that free-lived high and moderate intensity exercise have on glycaemic control in type 1 diabetes, as compared to an individual’s non-exercise “normal”. I compare monitored glucose traces from 10 adults with type 1 diabetes that each completed three, 14-day intervention periods of: home-based high intensity interval exercise, home-based moderate intensity continuous exercise and a free-living non-exercise control period. A key part of this analysis was the careful comparison of the glucose traces in each exercise intervention period to the glucose traces within the non-exercise of control period, in order to understand how much exercise perturbed an individual from their “normal” . In this analysis I found that the exercise modes assessed increase glycaemic variability and hypoglycaemia in the 4 hours after exercise, had a modest effect on glycaemic variability overnight, but increased glycaemic variability and hypoglycaemia the day after exercise. The findings in this chapter suggest that developing focused clinical guidance around time periods post-exercise, and accounting for “everyday life”, may improve the management of blood glucose in type 1 diabetes and ultimately reduce barriers to exercise. In the majority of endocrine conditions, the hormone in question is measured as part of routine usual care. In diabetes this is not yet the case. In this thesis I provide evidence that C-peptide is a robust surrogate marker of functional beta cells in clinical settings and demonstrate how an estimate of a patients C-peptide reserve could benefit clinical management. In addition to C-peptide level, I explore how exercise is another influential factor on glucose control in type 1 diabetes. Throughout this thesis I aim to place findings within the context of the lived experience of type 1 diabetes. After all, it is the people living with type 1 diabetes that are the reason we continue our research

Experiences of young people and their caregivers of using technology to manage type 1 diabetes mellitus: Systematic literature review and narrative synthesis

Background: In the last decade, diabetes management has begun to transition to technology-based care, with young people being the focus of many technological advances. Yet, detailed insights into the experiences of young people and their caregivers of using technology to manage type 1 diabetes mellitus are lacking.Objective: The objective of our study was to describe the breadth of experiences and perspectives on diabetes technology use among children and adolescents with type 1 diabetes mellitus and their caregivers.Methods: This systematic literature review used integrated thematic analysis to guide a narrative synthesis of the included studies. We analyzed the perspectives and experiences of young people with type 1 diabetes mellitus and their caregivers reported in qualitative studies, quantitative descriptive studies, and studies with a mixed methods design.Results:Seventeen articles met the inclusion criteria, and they included studies on insulin pump, glucose sensors, and remote monitoring systems. The following eight themes were derived from the analysis: (1) expectations of the technology prior to use, (2) perceived impact on sleep and overnight experiences, (3) experiences with alarms, (4) impact on independence and relationships, (5) perceived usage impact on blood glucose control, (6) device design and features, (7) financial cost, and (8) user satisfaction. While many advantages of using diabetes technology were reported, several challenges for its use were also reported, such as cost, the size and visibility of devices, and the intrusiveness of alarms, which drew attention to the fact that the user had type 1 diabetes mellitus. Continued use of diabetes technology was underpinned by its benefits outweighing its challenges, especially among younger people.Conclusions: Diabetes technologies have improved the quality of life of many young people with type 1 diabetes mellitus and their caregivers. Future design needs to consider the impact of these technologies on relationships between young people and their caregivers, and the impact of device features and characteristics such as size, ease of use, and cost.</p

Fasted High-Intensity Interval and Moderate-Intensity Exercise do not Lead to Detrimental 24-Hour Blood Glucose Profiles.

Aims: To compare the effect of a bout of high-intensity interval training (HIT) with a bout of moderate-intensity continuous training (MICT) on glucose concentrations over the subsequent 24h period. METHODS: Fourteen people with type 1 diabetes (duration of type 1 diabetes 8.2±1.4 years), all on basal-bolus regimen, completed a randomised, counterbalanced, crossover study. Continuous glucose monitoring was used to assess glycaemic control following a single bout of HIT (6 x 1min intervals) and 30 mins of moderate-intensity continuous training (MICT) on separate days, compared to a non-exercise control day (CON). Exercise was undertaken following an overnight fast with omission of short-acting insulin. Capillary blood glucose samples were recorded pre and post-exercise to assess the acute changes in glycaemia during HIT and MICT. RESULTS: There was no difference in the incidence of or percentage time spent in hypoglycaemia, hyperglycaemia or target glucose range over the 24h and nocturnal period (24:00-06:00h) between CON, HIT and MICT (P>0.05). Blood glucose concentrations were not significantly (P=0.49) different from pre to post-exercise with HIT (+0.39±0.42 mmol/L) or MICT (-0.39±0.66 mmol/L), with no difference between exercise modes (P=1.00). CONCLUSIONS: HIT or 30 mins of MICT can be carried out after an overnight fast with no increased risk of hypoglycaemia or hyperglycaemia, and provided the pre-exercise glucose concentration is 7-14 mmol/L, no additional carbohydrate ingestion is necessary to undertake these exercises. As HIT is a time-efficient form of exercise, the efficacy and safety of long-term HIT should now be explored

A nonparametric approach for model individualization in an artificial pancreas

The identification of patient-tailored linear time invariant glucose-insulin models is investigated for type 1 diabetic patients, that are characterized by a substantial inter-subject variability. The individualized linear models are identified by considering a novel kernel-based nonparametric approach and are compared with a linear time invariant average model in terms of prediction performance by means of the coefficient of determination, fit, positive and negative max errors, and root mean squared error. Model identification and validation are based on in-silico data collected from the adult virtual population of the UVA/Padova simulator. The data generation involves a protocol designed to produce a sufficient input excitation without compromising patient safety, compatible also with real life scenarios. The identified models are exploited to synthesize an individualized Model Predictive Controller (MPC) for each patient, which is used in an Artificial Pancreas to maintain the blood glucose concentration within an euglycemic range. The MPC used in several clinical studies, synthesized on the basis of a non-individualized average linear time invariant model, is also considered as reference. The closed-loop control performance is evaluated in an in-silico study on the adult virtual population of the UVA/Padova simulator in a perturbed scenario, in which the MPC is blind to random variations of insulin sensitivity in each virtual patient. © 2015, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved

Minimizing hypoglycemia while maintaining glycemic control in diabetes

In the accompanying Perspective, Cryer identifies a number of different areas where therapeutic interventions have the potential to reduce hypoglycemia without compromising glycemic control. Some approaches provide well defined clinical benefits, a few offer dramatic reductions in hypoglycemia but remain out of reach for most people while others, although promising have yet to be properly evaluated. (Table 1) In this Perspective, I examine the evidence which underpins these interventions. It is beyond the scope of this article to review the data for each potential intervention in detail but the reader is directed to the appropriate source where appropriate. The Perspective focuses on treatment of Type 1 diabetes as most of the potential specific therapies have been evaluated in this group although I have commented in relation to recent trials of intensive therapy in Type 2 diabetes

Dose-response between frequency of breaks in sedentary time and glucose control in type 2 diabetes: a proof of concept study

Objectives This study aimed to investigate dose-response between frequency of breaks in sedentary time and glucose control.DesignRandomised three-treatment, two-period balanced incomplete block trial.MethodsTwelve adults with type 2 diabetes (age, 60 ± 11 years; body mass index, 30.2 ± 4.7 kg/m2) participated in two of the following treatment conditions: sitting for 7 h interrupted by 3 min light-intensity walking breaks every (1) 60 min (Condition 1), (2) 30 min (Condition 2), and (3) 15 min (Condition 3). Postprandial glucose incremental area under the curves (iAUCs) and 21-h glucose total area under the curve (AUC) were measured using continuous glucose monitoring. Standardised meals were provided. Results Compared with Condition 1 (6.7 ± 0.8 mmol L−1 × 3.5 h−1), post-breakfast glucose iAUC was reduced for Condition 3 (3.5 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.04). Post-lunch glucose iAUC was lower in Condition 3 (1.3 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.03) and Condition 2 (2.1 ± 0.7 mmol L−1 × 3.5 h−1, p ˂ 0.05) relative to Condition 1 (4.6 ± 0.8 mmol L−1 × 3.5 h−1). Condition 3 (1.0 ± 0.7 mmol L−1 × 3.5 h−1, p = 0.02) and Condition 2 (1.6 ± 0.6 mmol L−1 × 3.5 h−1, p ˂ 0.04) attenuated post-dinner glucose iAUC compared with Condition 1 (4.0 ± 0.7 mmol L−1 × 3.5 h−1). Cumulative 10.5-h postprandial glucose iAUC was lower in Condition 3 than Condition 1 (p = 0.02). Condition 3 reduced 21-h glucose AUC compared with Condition 1 (p < 0.001) and Condition 2 (p = 0.002). However, post-breakfast glucose iAUC, cumulative 10.5-h postprandial glucose iAUC and 21-h glucose AUC were not different between Condition 2 and Condition 1 (p ˃ 0.05).Conclusions There could be dose-response between frequency of breaks in sedentary time and glucose. Interrupting sedentary time every 15 min could produce better glucose control

Targeting acute hyperglycaemia in clinical practice

The UKPDS established the benefit of tight glycaemic control in preventing microvascular disease but was unable to demonstrate an effect on cardiovascular disease. This may have been due to the limitation of traditional agents which were unable to maintain particularly tight glycaemic control in the participants. A number of new oral agents and insulins are now available and show promise in achieving better glycaemic control which is maintained for longer. Side effects of weight gain and hypoglycaemia may also be less frequent and some of the new therapies have direct effects on post-prandial glucose. However the precise clinical benefit of new treatments has yet to be established, particularly in terms of relevant clinical outcomes such as death or cardiovascular disease. Many of the existing data are derived from regulatory studies which establish safety and equivalence and do not often define clinical benefit or value for money. However, some trials which do measure relevant endpoints are in progress and are due to report in the next few years. It seems likely that many of the new treatments will supplant existing therapy and the hope is that this will result in better glycaemic control and less micro and macrovascular disease