The Hypothesis

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The accelerator hypothesis argues that type-1 and type-2 diabetes are the same disorder of insulin resistance, set against different genetic backgrounds [7]. The first accelerator - a constitutionally (intrinsically) high rate of p cell apoptosis during life [8] - is necessary for diabetes to develop, but seldom in itself sufficient to cause it. It reflects natural variation within the population.

Insulin resistance, the second accelerator, is acquired largely from weight gain and physical inactivity. It further increases the rate of p cell apoptosis through glucotoxicity and lipotoxicity [9, 10]. However, those who develop type-1 diabetes are members of the same population as those who develop type 2, exposed to the same obesogenic environment. A subset with both intrinsic susceptibility and insulin resistance - those with genes that program a particularly intense immune response to the upregulated islets - develops p cell autoimmunity, the third accelerator. The hypothesis views autoimmunity as a response to insulin resistance, rather than the cause of the diabetes - an inflammatory response within the p cells, whose intensity is associated with significant collateral damage. The glucagon-secreting a cells are spared because they are metabolically downregulated in hyperglycemia, rather than upregulated.

The author has argued, like others before him [11], that the immune system evolved originally as a 'housekeeper', programmed to phagocytose the detritus of natural cell death [12]. It retains that primordial function. From this perspective, autoimmunity will be antigen-driven and specific, its intensity responsive to the rate of apoptosis (antigenic load) and modulated by genetic influences. The issues of self-tolerance and its abrogation, which have always made it difficult conceptually to reconcile autoimmunity with a normal immune system, are not at issue where clones expand appropriately to remove apoptotic bodies. Antibodies in this context are classic immunological adaptors. They link the specific subparticulate molecules to be cleared to nonspecific Fc receptors of phagocytic neutrophils, which in turn engulf the complex and dispose of it through the reticuloendothelial system [13].

Insulin dependency is the end stage towards which all diabetes moves, the rate dependent on the accelerators present, and the notions of type 1 and type 2, insulin- and non-insulin-dependent, are consequently artificial. The development of diabetes is just a matter of time, and tempo is the only feature that distinguishes one type from another. Of the three accelerators, the first is intrinsic and others acquired. Insulin resistance, the second accelerator, is associated with visceral fat mass and is widely believed to explain the epidemic rise of type-2 diabetes in the industrially developed world [14]. The accelerator hypothesis argues that visceral weight gain is also central to type-1 diabetes, as much responsible for its rising incidence as for that of type 2, and the environmental factor in type-1 diabetes that has eluded epidemiology for so long.

The concept of an etiological link between the two types of diabetes is not new, and has been suggested before [15], but the evidence is now stronger. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay. Type-1 diabetes is the same as type 2 except for one essential add-on: intense immune response.

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