Diabetes results from the loss or malfunction of the beta cells in the pancreas that make insulin. Autoimmunity has been the accepted explanation for type 1 diabetes (T1D) for 40 years, but clinical trials of immunotherapy have proved disappointing, and have not provided a means of prevention. The accelerator hypothesis proposes a different explanation for T1D, based on the tempo of beta cell loss and the environmental factors that drive it. The autoimmune diabetes Accelerator Prevention Trial (adAPT) is testing the accelerator hypothesis, by seeking to establish whether a drug which protects the beta cell metformin can slow the tempo of loss sufficiently to reduce the incidence of diabetes in children at risk. The trial is sponsored by the University of Exeter, conducted in Scotland by the Tayside Clinical Trials Unit and funded by JDRF. It will report finally in 2022.
Contents
Background
Although immune interventions have been successful in preventing T1D in animal models, the same has not so far proved true for humans. The disparity suggests that the mechanisms may be different, and questions whether the autoimmunity paradigm, in the way it is currently configured, is appropriate for T1D in man. The accelerator hypothesis offers an alternative account, which is needed to explain the rise in childhood diabetes over the past 40 years, and the inability so far of immune-based interventions to prevent it. It views T1D and type 2 diabetes (T2D) as disorders of beta cell stress, set against different genetic backgrounds. Stress shortens the life of beta cells, and the accelerator hypothesis is built, not on difference in type of diabetes, but on variation 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 or human leukocyte antigen (HLA) genes. If insulin demand is the primary driver, and ‘autoimmunity’ the response, logic suggests that interventions to prevent childhood diabetes should aim at reduction of insulin demand rather than suppression of the immune system.
Design
adAPT 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 protects the beta cell from stress. Diabetes is a state in which the homeostatic control of glucose is lost as a result of beta cell failure, and adAPT 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 in children at risk of type 1 diabetes as it does in others. Measures will include fasting insulin, HOMA2-IR, indices from continuous glucose monitoring and the behaviour of glucose, insulin, C-peptide and the insulinogenic index during the course of a mixed meal tolerance test(duration four months).
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. Measures will be those used in Stage 1 repeated at six-monthly intervals to explore differences and trends in beta cell function and glucose control between and within the active and placebo arms of the trial (36 months).
Stage 3 to determine the impact of beta cell preservation on the incidence of cumulative diabetes incidence (60 months).
Recruitment
adAPT will identify from the Scottish national register (SCI-diabetes), and from diabetes clinics in the North of England, all families in which a member developed T1D below the age of 25y, and will screen their siblings and/or offspring 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 for recruitment.
Study Sites
adAPT involves 10 study sites based on the Scottish Health Boards: Ayrshire & Arran (Kilmarnock), Borders (Melrose), Dumfries & Galloway (Dumfries), Fife (Kirkcaldy), Forth Valley (Larbert), Central Glasgow & Clyde (Glasgow), Grampian with Orkney and Shetland (Aberdeen), Highlands & Argyll with the Western Isles (Inverness), Lanarkshire (Wishaw) and Tayside (Dundee). Discussions are currently ongoing to incorporate families in the North of England.
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 (Co-CI, University of Dundee).
Implications
Clinical trials are needed to provide experimental evidence and to 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 that, if successful, adAPT may change the paradigm on which T1D is based, and offer a means of prevention which is cheap, universally available, commercially unexploitable, and safe.