Type 1 diabetes in pregnancy is associated with higher rates of maternal and infant complications. The complications are associated with maternal hyperglycaemia. Thus, the main goal of treatment for these women is to optimise glycaemic control and thereby improve clinical outcomes for themselves and for their baby. This thesis examines glycaemic control in the mothers and infants of pregnancies affected by type 1 diabetes. I present the first home studies of closed-loop insulin delivery in this population. The aim of these studies was to assess the feasibility, efficacy, and utility of overnight and then day-and-night closed-loop insulin delivery in pregnant women with type 1 diabetes. The overnight study, which examined 16 pregnant women (mean age 34.1 years, HbA1c 6.8%, 14.4 weeks gestation), compared overnight use of the closed-loop system with sensor-augmented pump therapy in a 2x4-week randomised crossover design. We found that closed-loop therapy was associated with a 15% improvement in overnight time spent with target glucose concentration (3.5-7.8 mmol/L; 74.7% during closed-loop use vs 59.5% during sensor-augmented pump therapy use). The day-and night study also examined 16 pregnant women (mean age 32.8 years, HbA1c 8.0%, 16.4 weeks’ gestation) using a 2x4-week randomised crossover design to compare continuous day-and-night use of closed-loop insulin delivery with sensor-augmented pump therapy. This study enrolled a more diverse range of participants than the overnight study, but found that closed-loop therapy was associated with comparable glucose control and significantly less hypoglycaemia than sensor-augmented pump therapy. Chapter 4 examines women’s experiences of using the closed-loop system during pregnancy. While the system was generally well-received by participants, individual interactions and perceptions of the system varied markedly, and often did not align with biomedical measures of glycaemic response. After participation in either crossover study, participants could choose to continue using the technology until delivery (overnight study), or until 6 weeks post-partum (day and night study). Those data are presented in Chapters 2 and 3. The combined data from the women who used the closed-loop system during labour and delivery in either study are presented in Chapter 5. Tight glycaemic control during labour and delivery has traditionally been considered important for reducing rates of neonatal hypoglycaemia. However, despite very tight maternal glycaemic control in the women who used closed-loop insulin delivery, rates of neonatal hypoglycaemia were high. In order to better characterise the relationship between maternal glucose control in type 1 diabetes pregnancy and neonatal hypoglycaemia, Chapter 6 details an observational study in which continuous glucose monitoring was used to measure maternal and neonatal glycaemic control in 16 mother-infant pairs. The study found that, while neonatal hypoglycaemia was very frequent, it was generally, but not always, detected and treated effectively. Together, these studies suggest that a novel management tool, closed-loop insulin delivery, can improve overnight glycaemic control, and perhaps reduce hypoglycaemia during type 1 diabetes-affected pregnancies above what is possible with currently available treatments. However, complication rates remain high for these women and their babies. Further research is needed both to further develop treatments that can improve maternal glycaemic control, and to better understand the pathogenesis of diabetes-related pregnancy complications, with the ultimate goal of improving outcomes for women and their children. A definitive trial to assess the clinical efficacy, patient acceptability, and cost effectiveness of closed-loop is now warranted.

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.

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An implantable closed-loop insulin delivery device (INsmart device) containing a glucose responsive gel has been developed within the INsmart research group, over a period of 10 years, to mimic pancreas. In this thesis, the reliability and performance capability of the INsmart device was studied for future clinical use. Investigations into the device material compatibility with insulin solution, assessed by monitoring insulin loss and degradant formation over a period of 31 days using RP-HPLC have shown that stainless steel and titanium are the most compatible materials. Polycarbonate contributes to insulin loss after 11 days, resin might not be the best material and polyurethane is the least compatible for future device designs. To study insulin delivery mechanism and kinetics from the device, fluorescently labelled human insulin (FITC-insulin) was synthesised and characterised using RP-HPLC and MS, to produce a product with predominantly di-labelled conjugate (>75%) with no unreacted FITC or native insulin. Clinically used insulin analogues were also fluorescently labelled to produce predominantly di-labelled FITC-insulin conjugate with potential future biological and in vitro applications. The drug release mechanism from the glucose sensitive gel held in the INsmart device, studied using fluorescein sodium was determined as a Fickian diffusion controlled release mechanism. The diffusion coefficient (D) for FITC-insulin in the non-polymerised dex2M-conA gel (NP gel) determined using mathematical models, QSS and TL slope methods was 1.05 ± 0.02 x 10-11 m2/s and in the cross-linked dex500MA-conAMA gel (CL gel) was 0.75 ± 0.06 x 10-11 m2/s. In response to physiologically relevant glucose triggers in the NP gel, the diffusivity of FITC-insulin increases with increasing glucose concentrations, showing a second order polynomial fit, device thus showing glucose sensitivity and graded response, mimicking pancreas. Rheological measurements further confirmed the gel glucose responsiveness demonstrated by a third order polynomial fit between FITC-insulin D and the NP complex viscosity in response to increasing glucose concentration. The knowledge of FITC-insulin diffusion kinetics in the gel has aided in making some theoretical predictions for the capability and performance of the INsmart device. Alternate device geometry and design optimisation is also explored.