The accelerator hypothesis: a unifying explanation for type-1 and type-2 diabetes.

Despite 30 years of research, the cause of type-1 diabetes remains unknown. Meanwhile, its incidence has risen three-fold, its clinical features have become increasingly difficult to distinguish from type-2 diabetes and the contribution of genes to its pathogenesis has changed. The accelerator hypothesis argues that type-1 and type-2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds. It identifies three processes which variably accelerate beta cell loss: constitution, insulin resistance and the immune response to it. None of the accelerators leads to diabetes in the absence of weight gain, a trend which the hypothesis deems central to the rising incidence of all diabetes in the industrially developed and developing world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose accelerates beta cell apoptosis (glucotoxicity) and, by increasing beta cell immunogenicity, further accelerates apoptosis in a subset genetically predisposed to an intense immune response. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay--one a subset of the other. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes type 1 from type 2. The control of weight gain, and with it insulin resistance, could be the means of preventing both by slowing their progression.