Title: Can metformin prevent type 1 diabetes? A mechanistic pilot trial (SETUP FUNDING)
Funder: Juvenile Diabetes Research Foundation

Abstract: The autoimmunity hypothesis for T1D, although intuitively attractive, was based on observation, not experiment. Some 20 or so trials using immunotherapy to prevent T1D have been unsuccessful, and none has brought patient benefit. One reason could be that the original interpretation of events was incorrect, and funding is sought to test an alternative. The accelerator hypothesis relies on new evidence for a fundamentally different interpretation of the same observations. It proposes that stress is the cause of beta cell loss, and autoimmunity the response in people who are genetically susceptible. The fastest diabetes predictably presents in the youngest, and incurs the most intense immune response. The immune response is intrinsically inflammatory, and will accelerate the apoptosis yet more. The immune response is controlled by immune response genes, so the fastest (youngest) diabetic is also likely to carry the most reactive immuno-genotype. If insulin demand is the driver, and autoimmunity the response, it is inappropriate to target the immune system in attempts to prevent T1D. Insulin demand is largely related to insulin resistance, and the present trial will test the ability of metformin, a hypoglycaemic agent, to reduce the insulin resistance of children at risk of type 1 diabetes and, with it, beta cell stress. A successful outcome (fall of insulin resistance) will lead to a larger trial with onset of disease as the outcome measure. Metformin is the only medication approved in children to reduce insulin resistance, and we want to test its effectiveness in children at risk of type 1 diabetes in three stages. Stage 1, under consideration here, is designed to establish whether metformin can reduce insulin demand specifically in children at risk of T1D, before going on to commit a larger number to a definitive trial. We shall contact every family in Scotland who has a child with T1D through the Scottish Study Group for Care of Diabetes in the Young (SSGCYD) and the Scottish Diabetes Research Network (SDRN). Both relate to the National Institute of Health Research which supports trials of this kind in the UK. We shall screen the siblings of type 1 diabetic children for islet-related autoantibodies, and recruit the ~1:20 among them who are double-antibody positive into a four-month RCT of liquid-formula metformin. The outcome measures will be a fall in HOMA-IR, and improvement in the indices of glucose tolerance. The trial will further establish the precision data needed to properly power Stages 2 (surrogate outcome) and 3 (diabetes outcome) that will follow. If Stage 1 is successful, its participants will be joined by a much larger number of similar children from other centres in the UK in a five year study that will test whether metformin can prevent the onset of T1D over a period of five years. A successful outcome will provide a simple, cheap and universally accessible means of preventing diabetes in children. This proposal is to screen individuals for entry into the trial.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: METABOLIC AND ENDOCRINE