The accelerator hypothesis offers a new explanation for type 1 diabetes, and a new approach to its prevention.
What is diabetes?
Diabetes is caused by a high blood sugar, due to failure of the body’s beta cells to make enough insulin.
Insulin regulates blood sugar levels, and type 1 diabetes needs to be treated with injections of insulin because there is none left in the body. It is important to keep blood sugar levels as even as possible with the right amount of insulin. When sugar levels go too high, you will feel tired and thirsty. When they drop too low, you may feel light-headed, shaky and sweaty. Diabetes can be managed, and life can be good. Lots of men and women have won Olympic medals despite type 1 diabetes. Life has to be disciplined, but the highs and lows can often be avoided and complications prevented.
Why is type 1 diabetes special?
Type 1 diabetes is distinctive because its genetic component is random. As a result, the disease usually turns up unexpectedly in families who have never known diabetes before. Parents wonder why their child, and not the boy next door? Is it my fault? No, it’s because of the genes. The type 1 diabetes genes are distributed randomly throughout the population, but it needs a double dose (one dose from each parent) to be fully active, so it strikes indiscriminately.
The accelerator hypothesis
The beta cell is central to type 1 diabetes – it is only when the majority of beta cells stop working that type 1 diabetes develops, and treatment with insulin is needed. We believe that the destruction of beta cells speeds up when beta cells are made to work too hard (a state called beta cell stress), and that this is critical to the development of type 1 diabetes . This is known as the accelerator hypothesis. We want to protect beta cells from this destruction, by reducing beta cell stress. Metformin is a drug which can reduce beta cell stress, and is safe in children. We want to find out if using this drug in children at high risk of type 1 diabetes can protect their beta cells, prevent the diabetes, and avoid the need for insulin.
Most diseases are clear cut – you either have them, or you don’t. Diabetes is different. We are born with a large reserve of beta cells, but gradually lose them over a lifetime. We are all, in a sense, moving towards diabetes. Most people get by with plenty to spare but, if the loss is accelerated for any reason, diabetes will appear. Beta cell loss is accelerated by making them work too hard, a risk for everyone in our modern environment. Stressed beta cells may also produce signals that healthy beta cells do not, and these signals may be important in driving the immune response that destroys beta cells in type 1 diabetes.
We believe that the combination of beta cell stress and ‘type 1’ genes may be central to type 1 diabetes. The genes – wildcards if you like – play a key role because they greatly accelerate the loss of beta cells, yet are unavoidable and random. So random that only one or two families out of every ten in which type 1 diabetes appears will have known type 1 diabetes before. Those who don’t carry the genes (the large majority of people) are unlikely to get diabetes while they’re young – they simply take their lifetime chance along with the rest of us.
The reasoning behind the hypothesis is backed up by a lot of published observations, but needs to be formally tested. The approach we will take is to protect the beta cells from stress in the hope that they will not ‘switch on’ the immune reaction.