Through the establishment of a number of large and detailed cohort studies, the Department of Paediatrics provides unique opportunities for translational studies relating to the prenatal and early post-natal determinants of future disease risk, with a particular emphasis on the understanding of key endocrine pathways and potential effects of environmental exposures, including endocrine disrupting chemicals.
Disorders of sexual development (DSD), including detailed clinical, genetic and functional studies of patients with androgen receptor defects, have been a long-standing interest of the University Department of Paediatrics led by Professor Ieuan Hughes and Dr Carlo Acerini. The Department has a unique collection of clinical, biochemical, genetic and histological data and samples, which has been used to further the scientific understanding of DSD. These data have been integral in securing EU funding for a European-wide DSD register and for the scientific exploration of the causes of DSD and its management. The suggestion that some types of DSD, such as undescended testes and hypospadias, may be related to exposure to environmental chemicals acting as endocrine disruptors also led to the establishment of the Cambridge Baby Growth Study (CBGS) in 2001. The CBGS has recruited over 2600 mothers during pregnancy for the study of their children.
The scope of the CBGS was expanded at its outset to look at the influence of other prenatal exposures, such maternal blood glucose levels, on the growth and development of offspring. This work includes the study of genetic factors, nutrition, postnatal biomarkers, and prenatal / early postnatal epigenetic changes on infant growth and body composition and the future risk of adult onset metabolic disease. In conjunction with Dr Ken Ong (MRC Epidemiology Unit, Cambridge), the Department of Paediatrics (Dr Clive Petry and Professor David Dunger) collaborate with a number of other research groups in this area including those lead by Dr Miguel Constancia, Dr Sue Ozanne (Institute of Metabolic Science) and Professor Nabeel Affara (Department of Pathology) at the University of Cambridge. International collaborations with Professor Shane Norris (“Birth to Twenty” cohort in South Africa) and Professor Andrew Prentice (MRC Gambia cohorts) have allowed exploration of the relevance of the findings in the CBGS to transitional societies where pregnancy and very early postnatal exposures may underlie the very rapid increases in prevalence of diseases such as type 2 diabetes.
The University Department of Paediatrics has a strong interest in the developmental origins of health and diseases, such as obesity and type 2 diabetes, and Professor David Dunger and Dr Ken Ong have worked with the Avon Longitudinal Study of Parents and Children, in Bristol, and other cohort studies to delineate effects of low birth weight, rapid early postnatal growth and weight gain, and early pubertal maturation on the risk for subsequent obesity and its related co-morbidities, such as type 2 diabetes and cardiovascular disease. These studies have included epidemiological, genetic and physiological studies involving birth cohort studies, adult cohort studies and patients with conditions such as precocious pubarche and polycystic ovary disease (PCOS). An evolving theme for many of these studies has been the potential role of the growth hormone/insulin-like growth factor-1 axis in regulating developmental changes in insulin sensitivity and insulin secretion. The physiology of these interactions has been studied using the model of type 1 diabetes, and have led to clinical trials of the use of insulin-like growth factor-1 in the treatment of type 1 diabetes, led by Dr Carlo Acerini, and exciting preliminary insulin replacement studies in newborn infants, led by Dr Kathy Beardsall. These studies have also led to the realisation that recombinant human IGF-1, through its insulin sensitising actions, may be the only effective treatment for some children and adolescents with very severe insulin resistance. In collaboration with Professor Steve O’Rahilly and Dr Robert Semple (Institute of Metabolic Science), Cambridge University Hospitals Foundation Trust is the national commissioning centre for the treatment of young people with severe insulin resistance with this service led by Dr Rachel Williams.
Type 1 diabetes research at Addenbrooke’s Hospital has been a major strength of the University Department of Paediatrics. Collaboration with Professor John Todd (Cambridge Institute for Medical Research) has facilitated the establishment of a unique bio-resource, the “Genetic Resource Investigating Diabetes” (GRID), which comprises over 10,500 DNA samples from young people with diabetes across the UK. These DNA samples underpinned the identification of several novel type 1 diabetes susceptibility genes. These studies continue with further collaborations with Professor Todd’s group and Professor Mark Peakman at Guy’s Hospital (London) that aim to explore the links between type 1 diabetes susceptibility genes and disorders of the immune system that could lead to targeted disease prevention strategies.
Professor Dunger’s work over the last 20 years into the natural history of microalbuminuria, a marker of future cardiovascular and microvascular complications of diabetes, has formed a major part of the research activity within the Department of Paediatrics. The identification of the young type 1 diabetes patients at highest risk of such complications has led to the first multicentre international clinical trial testing the effects of blood pressure (ACE inhibitors) and lipid lowering agents (Statins) in adolescents with type 1 diabetes. The group are also closely involved in the evaluation of genetic and other biochemical biomarkers of early risk for complications and the data from these studies will be utilised in further long-term clinical trials to improve the prognosis of young people with type 1 diabetes.
The Department of Paediatrics also has extensive expertise in the physiological evaluation of glucose and insulin metabolism and has been involved in the development of new therapeutic strategies for young people with type 1 diabetes. This includes the exploration of potential adjuvant treatments, such as recombinant human insulin-like growth factor-1, led by Dr Carlo Acerini and Dr Rachel Williams, as well as contributing to the evaluation and development of new insulin analogues.
Professor David Dunger is also the clinical sample collection network coordinator of INNODIA , the Innovative Medicines Initiative or IMI-supported European consortium that aims to improve the understanding of type 1 diabetes and is paving the way to novel therapeutic options to prevent and cure this disease. INNODIA will collect throughout Europe blood samples and data from newly diagnosed patients with type 1 diabetes and first degree relatives of people with type 1 diabetes and study the evolution of the disease in these individuals. INNODIA has accomplished its first major milestone welcoming the first patient to be included into the INNODIA European sample collection system on World Diabetes Day (14th November 2016). ‘These are exciting times’ says Professor David Dunger. ‘In close collaboration with patients, we have developed protocols for follow up, information brochures, informed consents and materials necessary for this collection and will be creating a living biobank’. INNODIA joins forces between academic and industry researchers, but also involves patients and their families.
Following the recruitment of Dr Roman Hovorka, an expert in metabolic modelling of glucose homeostasis, the Department of Paediatrics has subsequently led the world in the development of closed loop subcutaneous insulin delivery systems (the “artificial pancreas”). In the last year the Department of Paediatrics has delivered the first home pilot study of the artificial pancreas in young people with type 1 diabetes with a larger multicentre trial expected during 2014/15.
For clinically related issues please visit Addenbrooke’s Children’s Endocrinology site