Biological prediction of rapid progression to type 1 diabetes: preparing for immune intervention trials in the preclinical disease phase.

Scriptie/masterproef: Doctoral Thesis


Observations from immune intervention studies at clinical onset of patients with type 1 diabetes (T1D) suggest that a better therapeutic response is obtained in subgroups characterized by young age and relatively preserved functional beta cell mass. One can therefore reasonably hypothesize that the preclinical disease phase, where the beta cell function is even better preserved, could offer a window of opportunity for the launch of secondary prevention trials. However, starting such trials in asymptomatic individuals will require: 1) the identification of a limited number of biological markers that are suitable for large scale screening in order to minimize the costs for rapidly identifying individuals with a subclinical disease process and 2) the selection of participants at sufficiently high risk of progression to clinically overt disease short-term to justify exposure to the potential adverse events related to the intervention.
To comply with these requirements, we aimed to develop a cost-effective and efficient screening strategy to identify such high risk individuals among offspring and siblings of patients with T1D at increased risk on the basis of the persistent presence of islet autoantibodies.
We explored if testing for autoantibodies against insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) is as efficient as screening for the four main molecularly defined diabetes autoantibodies (insulin autoantibodies [IAA], glutamate decarboxylase autoantibodies [GADA], IA-2A and ZnT8A) in identifying individuals at high risk of T1D. We found that the progression rate to T1D was higher in the presence if IA-2A and/or ZnT8A irrespective of age. In relatives above age 10, the target group for immune intervention trials, testing for IA-2A and ZnT8A identified relatives with about 50% risk of T1D within 5 years with the same efficiency as screening for all four autoantibody types. However, in relatives younger than 10 years, testing for additional autoantibodies (such as IAA) would be needed for maximal screening efficiency.
Next, we investigated the predictive ability of functional and metabolic parameters derived from hyperglycemic clamp in comparison to oral glucose tolerance test (OGTT)-derived markers for prediction of rapid progression to overt diabetes. Using both univariate and multivariate survival analysis, we observed that low first- and/or second-phase C-peptide release during hyperglycemic clamp were associated with rapid progression to T1D and outperformed OGTT-derived parameters in this respect. Among all prediction models tested, the combination of first-phase C-peptide release during clamp and fasting blood glucose provided the best prediction of impending T1D as judged from the highest area under the receiver operating characteristic curve and the lowest Akaike information criterion. Performing a short hyperglycemic clamp (first-phase release only) in persistently islet autoantibody positive relatives allowed to identify individuals with 50-70% risk of developing T1D within 3 years.
Our findings offer a rationale for a cost-effective and age-independent stepwise approach for identifying individuals at sufficiently high risk of impending diabetes short-term for enrolment in immune intervention trials at the preclinical disease phase.
Datum Prijs30 jun 2015
Toekennende instantie
  • Vrije Universiteit Brussel
BegeleiderFrans Gorus (Promotor), Ilse Weets (Co-promotor), Bart Keymeulen (Co-promotor), Pieter In 'T Veld (Jury), Jean De Schepper (Jury), Bert Bravenboer (Jury), Marie-Christine Vantyghem (Jury), A. Scheen (Jury) & Bruno Lapauw (Jury)

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