Accelerator Prevention Trial

Autoimmunity has been the accepted explanation for type 1 diabetes (T1D) for the past 40 years, but clinical trials of immunotherapy have proved disappointing, and have not offered a means of prevention. The Accelerator hypothesis proposes a radically different explanation for T1D based on the tempo of progression, and the factors that influence it. The Accelerator Prevention Trial (APT) is a randomised trial, based on the accelerator hypothesis, which is testing whether metformin can slow the tempo of progression sufficiently to lower the incidence of diabetes in children at risk. The trial will report in 2021, is sponsored by the University of Exeter and is conducted in Scotland and the North of England, which have a high incidence of T1D.

Background

Although immune interventions have proved successful in preventing T1D in animal models, the same has not been true for humans. The disparity suggests different mechanisms, and questions whether the autoimmunity paradigm is appropriate in man. The accelerator hypothesis offers an alternative account, needed to explain the rise in childhood diabetes over the past 40 years, and the inability of immune-based interventions to have prevented it. It views T1D and type 2 diabetes (T2D) as the same disorder of beta cell stress, set against different genetic backgrounds. Stress shortens the lifespan of beta cells, and the accelerator hypothesis is built, not on differences in type of diabetes, but on differences in tempo of beta cell loss. The rise in insulin demand associated with contemporary living is considered to be The Primary accelerator, and the immune response to it a secondary accelerator that can propel a critical loss into childhood. Where the conventional explanation for T1D has invoked an immune attack on the insulin-producing beta cells by a faulty immune system, the accelerator hypothesis sees ‘autoimmunity’ as a normal, albeit inflammatory, response to beta cell stress confined to the small minority of the population with reactive immune response (HLA) genes. If insulin demand is the primary driver, and ‘autoimmunity’ the response, logic dictates that interventions to prevent childhood diabetes should seek to reduce insulin demand.

Design

APT is a classic randomised placebo-controlled trial of metformin in children and young people at risk of T1D. Metformin is a widely used medication that lowers blood glucose levels, reduces insulin demand and thereby tempers beta cell stress. Diabetes is a state in which the homeostatic control of glucose is lost as a result of beta cell failure, and APT seeks to prevent diabetes in children at risk by slowing beta cell loss. The trial is divided into three stages, each seeking evidence of beta cell preservation:

Stage 1 to establish whether metformin reduces demand on the beta cell specifically in children at risk of type 1 diabetes as it does in other patient groups (duration four months). Measures will include indices from continuous glucose monitoring, fasting insulin, HOMA-IR, and the behaviour of glucose, insulin and C-peptide and the insulinogenic index during the course of a mixed meal tolerance test.

Stage 2 to assess the long-term impact of reducing beta cell stress on surrogate markers of glucose control in children at risk of T1D (36 months). Measures will be those in Stage 1 repeated at six-monthly intervals to explore trends in beta cell function and glucose control.

Stage 3 to determine the impact of beta cell preservation on the incidence of diabetes incidence (60 months).

Recruitment

APT will identify from the Scottish national record system (SCI-diabetes) all families in which a member developed T1D below the age of 25y, and will screen their siblings aged 5–16y for the presence of two or more beta-cell antibodies. Double antibody positivity in such siblings predicts a high risk of diabetes (~40% over five years). If numbers require it, the offspring aged 5–16y of parents who themselves developed T1D below the age of 25y will provide a second pool.

Study Sites

APT involves 11 study sites: Borders, Dumfries & Galloway, Fife, Forth Valley, Greater Glasgow (and Western Isles), Grampian (and Orkney, Shetland), Highlands (and Hebrides), Kilmarnock, Northumbria, Tayside, Wishaw.

Sponsorship and Funding

The trial is sponsored by the University of Exeter, funded by the Juvenile Diabetes Research Foundation (JDRF), and conducted by the Tayside Clinical Trials Unit based at Ninewells Hospital, Dundee, Scotland. It is directed by Prof Terry Wilkin (Chief Investigator, University of Exeter) and Prof Steve Greene (Principal Investigator, University of Dundee).

Implications

Clinical trials are needed to provide experimental evidence and explain mechanisms. They are the machinery of 'translational medicine', whereby hypothesis and observation from the laboratory or the natural world are rigorously tested and, if appropriate, translated into human benefit. Trials of immunological therapies based on the autoimmunity paradigm have not so far brought human benefit so, if successful, the Accelerator Prevention Trial and its different mechanism may be the first to bring the benefits of evidence-based science to the prevention of childhood diabetes. Insulin re-sensitisation, whether through weight loss, physical activity or simple medication such as metformin, is universally available, commercially unexploitable, and not toxic.