Improving diagnosis of adult onset Type 1 diabetes using islet autoantibodies. Medical Studies, PhD (GW4 BioMed MRC DTP)

Supervisory team:
Dr Angus Jones, University of Exeter Medical School
Dr Timothy McDonald, University of Exeter Medical School
Dr Kathleen Gillespie, University of Bristol
Dr Alistair Williams, University of Bristol

Misdiagnosis of adult Type 1 diabetes is common, leading to poor treatment. Current available laboratory tests do not allow definitive diagnosis. This clinical research project will improve islet autoantibody testing and inform the best way to use these tests in the NHS, to help patients with Type 1 diabetes get the right diagnosis and treatment.

Background and aim:
Over half of type 1 diabetes (T1D) occurs after age 30, however recognising late onset T1D is difficult, as presentation overlaps with type 2 diabetes. This means over 40% of patients are misdiagnosed as Type 2 diabetes (T2D) and initially treated without insulin. They may become severely unwell as insulin is essential to survival in type 1 diabetes. Islet autoantibodies are inexpensive tests that can identify T1D but a number of issues need addressed to enable their robust use and interpretation in clinical practice:
1. Despite several islet antibodies being available many hospitals only offer tests for antibodies to glutamate decarboxylase (GADA); the clinical utility of additional testing is poorly defined.
2. The cut-off used to define a positive test has not been robustly determined, with the assay limit of detection commonly used. This can result in low test speceficity (19,000 extensively phenotyped participants with islet antibody measurement. These unique cohorts allow assessment of diagnostic performance against robust outcomes including loss of endogenous insulin secretion, treatment response and progression to insulin therapy. They will:
1. Identify the optimal threshold for defining islet autoantibody positivity, and determine what thresholds are currently used in UK clinical laboratories and the associated test performance
2. Determine additional diagnostic utility of ZnT8 and IA2 islet autoantibodies over GADA alone in adult onset T1D
3. Qualitatively characterise islet autoantibodies in antibody positive adult onset diabetes (isoform, level, binding affinity and epitope specificity) and determine whether these characteristics are associated with the characteristics of T1D including rapid progression and severe insulin deficiency
4. Determine whether antibody persistence is associated with characteristics of T1D
5. Examine persistence and characteristics of positive islet antibodies in non-diabetic control populations, to determine if this represents true underlying autoimmunity or analytical false positive results

Outcome: This PhD will give key information for the clinical use of islet antibody in clinical practice and improve diagnostic utility, to improve recognition and care of adult onset T1D.

To apply for this project please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.