Bingley, Penelope Juliet; (1994) Towards prevention of type 1 diabetes: population-based risk assessment in the Oxford region. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Intervention to prevent or delay the clinical onset of Type 1 (insulin- dependent) diabetes now appears a realistic possibility. In this thesis I review a number of preliminary steps that must be completed before a clinical trial of this type can be undertaken. I describe the population-based, prospective Bart's-Oxford study of childhood diabetes and its use to determine the incidence of Type 1 diabetes in the Oxford Regional Health Authority (RHA). Implications of epidemiological studies for understanding the pathogenesis of childhood diabetes are discussed. I review the advantages and difficulties of the family study approach, and show how these were taken into account in the design of the Bart's- Oxford family study. I review the genetic approach to prediction before describing studies I have undertaken to improve risk assessment in family members using (i) immune markers (islet cell antibodies (ICA) alone and in combination with other humoral markers) and (ii) the intravenous glucose tolerance test. I report a comparison of patterns of basal insulin secretion in ICA positive family members and controls to assess their value as potential early metabolic markers. I describe how these findings can be used in the design of a multicentre intervention study in ICA positive relatives. Only 10% of children with newly diagnosed diabetes have an affected first degree relative and identification of high risk subjects with no family history of diabetes is essential if intervention is to have any impact on the frequency of Type 1 diabetes in the population as a whole. I therefore examined the prevalence and prognostic significance of ICA in the general childhood population, comparing 2,925 schoolchildren in the Oxford RHA with 274 age- matched siblings from the family study. This demonstrated that ICA are considerably less predictive of Type 1 diabetes in the general population than in relatives and, on the basis of my findings, I have proposed a possible two-stage strategy for screening in the general population to overcome these limitations.

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