The rise in incidence of diabetes in 'westernized' countries over recent time has occurred over a period too brief for changes in the gene pool to exert an influence. Similarly, there is no evidence of falling birth weight over the same period to suggest a deterioration in fetal quality and attendant risk of insulin resistance, as the fetal origins hypothesis proposes - indeed, birth weights have risen. More likely, it is the progressive increase in body weight after birth, with the rising prevalence of obesity at all ages over the past 30 or more years, which is responsible. Most importantly, epidemiological observation suggests that the progressive rise in type-1 diabetes only began in the middle of the 20th century, the time after the end of the Second World War when modern wealth and lifestyles started to involve populations rather than merely individuals .
The accelerator hypothesis at its simplest can be reduced to the unfavorable interplay of two phenomena: insulin resistance and accelerated p cell apoptosis. Apoptosis occurs throughout life at a variable rate, but is intrinsically higher in those who are susceptible to diabetes. Many people of normal body mass, despite intrinsically more rapid p cell apoptosis, never develop glucose intolerance because insulin secretory reserve remains sufficient in such circumstances to maintain control of blood glucose concentrations. However, insulin resistance - whether present at birth or acquired through the accumulation of visceral fat during life - makes demands on insulin secretion that in some cannot be met.
Immune damage of the p cells is an additional accelerator, restricted by genotype to small and independent minorities of the intrinsically diabetes-susceptible and nonsusceptible populations alike. At its most aggressive, the so-called autoimmunity might be sufficient to cause diabetes of itself, though an accelerator different from insulin resistance would be needed to account for the increase in apoptosis which provokes it. The hypothesis predicts that in older patients, where p cell autoreactivity is less aggressive, those with islet cell autoimmunity most likely to develop diabetes will already have the diabetic phenotype - a low p cell mass and high insulin resistance. Those who do not might be expected to remain seropositive but healthy, to succumb only as and when the intrinsic p cell mass wanes and/or insulin resistance rises with the corpulence of advancing age.
Tempo, and tempo alone, it is argued, distinguishes what in the past have been viewed as two separate types of diabetes. The three phases in the progression to overt diabetes - prediabetes, chemical diabetes and clinical diabetes can all be identified in both types, differing only (though sometimes substantially) in their relative duration. Not to take account of these phases and their differences in tempo will make it conceptually difficult to regard as equivalent two diabetic states where insulin is needed from the outset in one, but only (if ever) after a long period of clinical diabetes in the other. The requirement for insulin in both cases is nevertheless reached at exactly corresponding points in the progression of prediabetes . All people with diabetes move towards this point of insulin dependence - some very quickly, others perhaps not in a lifetime.
A hypothesis postulating body mass as a primary risk factor in the etiology of type-1, as well as type-2, diabetes is novel, but eminently testable. Ultimately, it will be necessary to establish whether strategies to reduce the second accelerator (insulin resistance) in those at risk from type-1 diabetes, through weight loss, metformin, or one of the new thiazolidinediones , is paralleled by a deceleration in the third - autoimmune damage to the p cells. The notion that type 1 could represent merely the accelerated development of type-2 diabetes is important if it implies that strategies currently on trial to suppress the immunological accelerator of type-1 diabetes (e.g. anti-CD3 [52, 53]) leave unchanged the insulin resistance which provoked it. The control of weight gain, and with it insulin resistance, could be the fundamental means of averting both.
Was this article helpful?