Predictors of progression to Type 1 diabetes: preparing for immune interventions in the preclinical disease phase

Abstract

Type 1 diabetes is an incurable disease associated with risk of serious acute and chronic complications. It is caused by a marked loss in insulin-producing beta cells. Immune intervention at clinical onset can transiently suppress a further decline in residual functional beta cell mass, particularly in young patients with a higher residual insulin producing capacity at start of treatment. It might achieve a higher effect during the preclinical phase when the beta cell mass is not yet severely affected. Such prevention trials can be prepared by identifying individuals at very high risk to develop diabetes within 3 years and presenting signs of declining, yet relatively preserved, functional beta cell mass. This article reviews biomarker screening strategies to select these participants and discusses developments that can facilitate rapid and straightforward conclusions from novel clinical studies.

Keywords::

• anti-CD3
• autoantibodies
• C-peptide
• HLA
• hyperglycemic clamp
• OGTT
• prediction
• prevention
• proinsulin
• Type 1 diabetes

Financial & competing interests disclosure

The work of the authors is supported by grants from the Juvenile Diabetes Research Foundation (JDRF Center Grant 4-2005-1327 to DG Pipeleers and project 17-2012-615 to FK Gorus), the European Union (FP-7 project 241883), the Belgian Fund for Scientific Research (FWO-Vlaanderen), the Flemish Ministry of Innovation, the Research Council of the Brussels Free University (OZR-VUB) and the Willy Gepts Fund of the University Hospital Brussels (UZ Brussel). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • In the absence of a lasting cure or prevention of Type 1 diabetes, the global burden of devastating disease complications is likely to grow further in view of the persistent increase in incidence combined with drop in age at diagnosis.

• • To date, immune interventions have been able to transiently preserve residual functional beta cell mass, particularly in patients with relatively preserved beta cell function, young age at diagnosis and short duration of clinical disease.

• • Future trials should attempt to increase and prolong efficacy of beta cell preservation by designing protocols with optimally dosed (combination) therapies and should plan interventions in the late preclinical disease stage during which residual function is even better preserved than at onset.

• • Individuals with a high 3-year risk of Type 1 diabetes are the candidates of choice to participate in such novel trials; their selection is likely to reduce the numbers needed to treat and the time to reach significant conclusions.

• • Their identification requires large-scale cost-effective screening, preferably for a limited number of biomarkers. A restricted antibody panel (islet antigen-2 [IA-2A] and zinc transporter 8 [ZnT8A] autoantibodies) combined with a functional marker (e.g., proinsulin: C-peptide ratio) is proposed to give the highest sensitivity of screening in the relevant age category.

• • Hyperglycemic clamp testing – the gold standard of beta cell function – is proposed as the final inclusion criterion and an important secondary outcome measure of choice for such trials in addition to development of 2 h oral glucose tolerance test (OGTT) diabetes. Future biomarker development should focus on the validation of circulating biomarkers of ongoing beta cell destruction and predictors of good therapeutic response.

Notes