The accelerator hypothesis: insulin resistance as the central cause of type 1 and type 2 diabetes

I read with interest the review by Wilkin1 discussing the ‘accelerator’ hypothesis. I commend the author for bravely attempting to unite the type 1 and type 2 disease classifications and advance the theory of diabetes pathogenesis; however, one must play devil's advocate when necessary. The author proposes that in type 1 diabetes ‘the driver, according to accelerator hypothesis, is insulin resistance’, much as in type 2 diabetes. I urge the consideration of two cases, which, although hypothetical, I think we can agree are characteristic of many individuals who develop diabetes. One is a child of normal weight from a middle-class family of European ethnicity. Viral infection in this child results in the infection of pancreatic β cells (as has been observed previously2), and a natural immune response ensues. Depending on the child's genetic background,3, 4, 5 this may include autoimmune responses that ultimately cause β-cell destruction. In the face of compromised insulin production capacity, whether this child develops elevated blood glucose will depend on how effective the remaining insulin functions. When this scenario is played out across a population of genetically high-risk individuals, those with greater insulin resistance are more likely to develop diabetes, as has been observed in a number of studies (for example, see Bingley et al.6) and cited by the author. The true causative agent, however, is the initial interplay of the virus–immune system, which creates the insult to β cell survival. In this circumstance, insulin resistance is not the driver of the development of disease, but a covariate. This is not to say that interventions to improve insulin sensitivity in high-risk individuals are misguided—providing some kind of alleviation of the insulin production burden facing β cells at this critical time may offer some hope of avoiding diabetes. This is a vastly different theoretical underpinning from that proposed by the author, however, whereby insulin resistance is in fact the primary insult, and subsequent inflammation and autoimmune β-cell destruction arise from insulin-resistance-induced upregulation of the β-cell. The other case is an individual with a low level of autoimmunity who survives until their late forties before developing diabetes, at which point they are overweight and insulin resistant. They have been continually exposed across the course of their lifetime to environmental agents, such as air pollution, pesticides, xenoestrogens and components of plastics, such as phthalates and bisphenol A, all of which impair metabolic signalling and are so ubiquitous as to be nearly unavoidable in modern society. The extent to which their weight status, insulin resistance and development of diabetes can be attributed to their conscious lifestyle choices, unwitting exposure to endocrine disruptors or genetic factors cannot possibly be untangled because of the complexity of the inter-relationships and interactions of each; the disease end point of diabetes no doubt results from the combined effects of all these factors. Insulin resistance is certainly a feature, but can it be said to be the cause of their diabetes? The author declares no conflict of interest. I am supported by a scholarship from the National Heart Foundation of New Zealand.