Endocrinology and Diabetes

Understanding progression from asymptomatic type 2 diabetes towards heart failure with preserved ejection fraction through multidimensional phenotyping

Supervisors: Professor Gerry McCann (gpm12@leicester.ac.uk), Dr Emer Brady (emb29@leicester.ac.uk) and Dr Gaurav Gulsin (gg149@leicester.ac.uk)

Type 2 diabetes (T2D) is a major risk factor for heart failure with preserved ejection fraction (HFpEF), with an insidious, progressive and multifactorial pathophysiology. Several imaging studies have

demonstrated early deleterious myocardial alterations that precede HFpEF symptomology (termed stage B HF (SBHF)). We have been awarded £1.387million in funding from the British Heart Foundation to characterise the trajectory of SBHF in T2D towards symptomatic HFpEF and identify specific biological pathways that drive progression.  This work is an extension to our recently completed clinical cohort study the “Prevalence and Determinants of SubclInical Cardiovascular Dysfunction in Adults with Type 2 Diabetes – The PREDICT Study” (NCT03132129). In PREDICT, over 500 people with T2D (stage A and SBHF) were comprehensively phenotyped with advanced multidimensional multi-organ imaging, cardiopulmonary exercise testing and multi-omics. We will be inviting 200 participants back for repeat testing to assess disease progression and central and peripheral drivers of exercise intolerance, the signature and debilitating symptom of HFpEF. 

The successful candidate will contribute to the development of, and have access to, this world-leading bioresource. They will use this rich data for the identification of distinct endotypes in T2D with variable progression of SBHF to inform targeted intervention trials for the prevention of symptomatic HF.

Impact of diabetes technology on rates of hypoglycaemia

Suervisors: Professor Pratik Choudhary (pratik.choudhary@leicester.ac.uk) , Professor Claire Meek (cm881@leicester.ac.uk) and Dr Jonah Thomas (jjct1@leicester.ac.uk)

There have been huge advances in diabetes therapies and technology which have been shown to reduce the risk of hypoglycaemia in randomised clinical trials. However, access to these technologies is variable, and must also be viewed in the context of an ageing population who are often living with multiple long-term conditions.

The ACF will evaluate the impact of novel diabetes technologies and therapies on admissions to hospital with hypoglycaemia at both a local and national level. The project will first utilise local data to explore underlying factors that predict repeat hospital admissions. National databases such as CPRD and HES will then be used to explore national trends in hospital admissions, and the potential impact of diabetes therapies and comorbidities. The overarching aim of this project is to use this information to develop a risk score based on information available in routine databases, possibly using machine learning techniques.

Targeting obesity in type 1 diabetes

Supervisors: Professor Pratik Choudhary (pratik.choudhary@leicester.ac.uk) , Professor Tom Yates (ty20@leicester.ac.uk) and Dr Dimitris Papamargaritis (dp421@leicester.ac.uk)

People living with type 1 diabetes (T1D) continue to have a 2-3 times higher risk of developing premature cardiovascular disease than the general population. This is increasingly exacerbated by comorbidities more typically associated with type 2 diabetes, including living with obesity. People with T1D are also less likely to be active (due to fear of hypoglycaemia). Changes in insulin therapy and risk of hypoglycaemia make weight loss and exercise without hypoglycaemia challenging in this group.

Recent advances in continuous glucose monitoring (CGM) may help to manage this. Furthermore, newer generations of glucose lowering therapies developed primarily for type 2 diabetes have the potential to help with substantial weight loss and improved cardiovascular health. There is an opportunity to explore how such therapies can be used in the management of T1D to help people lose weight, improve their cardiovascular health and adopt a more active lifestyle.

This project aims to work with experts in the field to design new management options and programmes for T1D and pilot them to form the basis for a competitive fellowship. The applicant will also have access to rich clinical data to further explore the phenotype of obesity and cardiovascular risk in T1D.

Exploring the use of novel technology in type 2 diabetes management

Supervisors: Professor Pratik Choudhary (pratik.choudhary@leicester.ac.uk), Professor Claire Meek (cm881@leicester.ac.uk) and Professor David Webb (drw17@leicester.ac.uk)

Diabetes technology has revolutionised the lives and care of people living with type 1 diabetes, and there is considerable growing interest in digital health as a means of delivering care and providing support for individuals with type 2 diabetes. The success of flash glucose monitoring on improving glycaemic control and patient-reported outcome measures in type 1 diabetes is notable at this point, though the evidence-base that wearable technology facilitates behaviour change in other types of diabetes is sparse. This project will explore the use of novel technologies within type 2 diabetes management.

The ACF will experience a range of clinical trials, and have the opportunity to support and participate in a number of academic and commercial trials around the use of technology in diabetes. We will provide training in data analysis and experimental medicine techniques, such as insulin clamps and other detailed physiological assessments.

Physical activity, chronotype and multiple long-term conditions: The Step In Time Project

Supervisors: Professor Melanie Davies (mjd34@leicester.ac.uk) , Professor Shahrad Taheri (st607@leicester.ac.uk) , Dr Andrew Hall (ah747@leicester.ac.uk) , and Dr Joseph Henson (jjh18@leicester.ac.uk)

Although physical activity is a cornerstone treatment for the management of type 2 diabetes (T2DM) and obesity, its application is often based on a one-size-fits-all approach. Moreover, there is considerable variability in how individuals respond. It is hypothesised that the intra-individual variability is partly driven by chronotype, which is closely related to the circadian system, controlling 24-hour cycles of behaviour and physiology.  Indeed, those living with T2DM demonstrate signs indicative of clock disruption, which can lead to impaired glucose control. Although light is the most important time cue to realign the circadian system, physical activity may also act as a potent environmental cue to foster chrono-biological homeostasis which is constantly being challenged by modern 24/7 society. Despite holding great translational potential, the impact of such an approach in those living with diabetes and obesity is unknown. Therefore, the aim of this project is to evaluate whether the timing of physical activity, in accordance with the circadian rhythm effects health outcomes in individuals living with T2DM and obesity.

Preventing early-onset type 2 diabetes (EOT2D) after gestational diabetes mellitus (GDM): improving risk stratification in multi-ethnic populations

Supervisors: Professor Claire Meek (cm881@leicester.ac.uk)  & Dr Claire Gillies (clg13@leicester.ac.uk)

Background: A previous diagnosis of gestational diabetes mellitus (GDM) is one of the strongest risk factors for the development of early-onset type 2 diabetes (EOT2D), a disease characterised by severe and early macrovascular and microvascular complications. Although preventing EOT2D is crucial for individual and population health, very little research has focussed on risk stratification or interventions for women with previous GDM.

GDM is typically diagnosed at 24-28 weeks of pregnancy using an oral glucose tolerance test. However, some women meet the criteria for gestational diabetes earlier in pregnancy, with evidence of hyperglycaemia from the first trimester (Early GDM). Previous work in Prof Meek’s group in the Leicester Diabetes Centre using a secondary analysis of the DiGest clinical trial population suggests that women with Early GDM have increased risk of prediabetes or type 2 diabetes postnatally, suggesting that they could be prioritised for early intervention efforts. However, this has not been assessed in a large multi-ethnic clinical population.

Aims: This project will assess if Early GDM is associated with increased risk of prediabetes or early-onset type 2 diabetes in clinical practice, using assessment of real-world data, systematic review and clinical trial data.

Impact: Improved risk stratification could support tailored intervention strategies to reduce risk of EOT2D after GDM.

Contraception, ethnicity and pre-pregnancy planning in women with early onset type 2 diabetes (EOT2D)

Supervisors:Professor Claire Meek (cm881@leicester.ac.uk), Professor Melanie Davies (mjd34@leicester.ac.uk) and Dr Michelle Hadjiconstantinou (mh333@leicester.ac.uk)

Background: Pregnancy in women with early onset type 2 diabetes (EOT2D) is increasingly common, but clinical outcomes are often suboptimal. Around 30% of affected women have a miscarriage and if glucose levels are high at conception, a further 10% experience a late stillbirth or neonatal death. Diabetes and obesity are also both risk factors for maternal death in pregnancy, a rare but catastrophic outcome for the whole family. Tragically, maternal and perinatal deaths occur more commonly in people in low-income families or from Black or Asian backgrounds.

Despite the high risks of having a pregnancy with EOT2D, many women do not choose to take contraception. Contraception can be used to prevent pregnancy entirely, or to provide time for optimisation of glycaemia and weight, in order to have a safer, planned pregnancy later. We hypothesise that different attitudes towards contraception may contribute to inequalities in pregnancy outcomes in women from different ethnic and socioeconomic groups.

Aims: This project will assess attitudes towards family size, contraception and pregnancy planning in women with EOT2D using assessment of real-world data, systematic review and qualitative interviewing.

Impact: A more nuanced, culturally-sensitive understanding of barriers to contraception in women with EOT2D will allow clinicians to provide relevant health information and more equitable care in future.

Continuous glucose monitoring and neonatal complications in women with type 1 diabetes in pregnancy

Supervisors: Professor Claire Meek (cm881@leicester.ac.uk) , Professor Elaine Boyle (eb124@leicester.ac.uk)  and Professor Tilly Pillay (tp170@leicester.ac.uk)

Background: Women with type 1 diabetes (T1D) in pregnancy are at increased risk of suboptimal perinatal outcomes. Affected neonates are more likely to develop neonatal hypoglycaemia, a common cause of admission to the neonatal intensive care unit (NICU). The accurate diagnosis and management of neonatal hypoglycaemia is essential, as untreated, it is associated with metabolic sequelae and neurocognitive dysfunction in later life.

In the NHS, infants of mothers with diabetes are screened for neonatal hypoglycaemia three times in the first 24 hours after birth, using heel-prick capillary glucose testing. However, recent work in Prof Meek’s team in the Leicester Diabetes Centre suggested that this strategy may miss episodes of hypoglycaemia. The team identified that continuous glucose monitoring (CGM), a novel technology, could improve the identification of neonatal hypoglycaemia. Indeed, CGM could also have a role in prevention of hypoglycaemia in the highest-risk infants.

The aim of this project is to identify if CGM could be used to prevent neonatal hypoglycaemia after a pregnancy affected by T1D. In partnership with the department of neonatology, the study will involve qualitative work to ascertain if CGM is acceptable to parents and HCPs involved in neonatal care, and a pilot randomised, controlled trial using CGM to prevent neonatal hypoglycaemia.

Pharmacotherapy and lifestyle interventions, alone or in combination, for the management of obesity

Supervisors: Dr Dimitris Papamargaritis (dp421@le.ac.uk) , Professor David Webb (david.webb@uhl-tr.nhs.uk) , Professor Melanie Davies (melanie.davies@uhl-tr.nhs.uk) and Professor Shahrad Taheri (st607@leicester.ac.uk)

The prevalence of obesity – a major risk factor for several long-term conditions such diabetes and cardiovascular disease – is increasing rapidly. Lifestyle interventions such as physical activity and low energy diets are considered first-line obesity management strategies, although weight loss is often less than expected and can be challenging to maintain. Newer generations of weight loss therapies are emerging and are achieving weight loss which rivals surgical approaches, but with potential for much greater scalability. However, their impact on a range of wider health outcomes such as vascular health, cardiac function, obstructive sleep apnoea, and fertility requires investigation. Furthermore, the effectiveness of these therapies alone and in combination with lifestyle interventions across diverse populations that vary in age, ethnicity, and disease status remain unclear. This project will include a range of research methodologies including evidence synthesis/systematic reviews, analysis of existing datasets (from real-world evidence and previous clinical trials), and experimental medicine through existing clinical trials, including the OPAL trial.