Endocrine Abstracts

Some 40 years ago, diabetes was re-classified from a single disorder into autoimmune (T1D) and metabolic (T2D) on the interpretation of observation rather than the outcome of experiment. The 20 or so experiments carried out since to test the autoimmune hypothesis (largely randomised trials of immunotherapy) have proved disappointing, and none has translated into patient benefit. There is arguably reason to question the autoimmunity paradigm. The accelerator hypothesis argues that T1D and T2D are the same disorder of insulin resistance, set against different genetic backgrounds. Humans are born with a substantial reserve of β cells, which is gradually lost throughout life. For most, the rate of loss is slow and inconsequential. When accelerated, however, the loss becomes critical within a lifetime, and diabetes results at an age (adulthood or childhood) determined by the tempo of loss. The accelerator hypothesis makes no fundamental distinction between ‘no diabetes’ (the majority), ‘slow diabetes’ (adult onset) and ‘fast diabetes’ (childhood onset). What matters to prevention is proper identification of the accelerator responsible. Insulin demand (insulin resistance) is the primary accelerator, and autoimmunity the response to stressed beta cells in the few with reactive HLA genes which further accelerates their loss. Evidence will be presented that pre-type one diabetic children are insulin resistant, that autoantibodies (the hallmark of T1D) are common in T2D and that the age at presentation of T1D in children is inversely related to their BMI – true acceleration. A series of trials to test the accelerator hypothesis are planned.