Type 1 and type 2 diabetes—chalk and cheese?

Abstract

The conventional wisdom is that the two major subtypes of diabetes, type 1 and type 2, represent distinct conditions with widely different pathophysiologies. However, the growing recognition that a substantial proportion of people with diabetes have features of both type 1 and type 2 diabetes [1] indicates that it may not always be possible to assign each patient to a neat diagnostic box. Instead, we should probably be thinking more in terms of a spectrum of disease, with ‘typical’ type 1 diabetes at one extreme and ‘typical’ type 2 diabetes at the other. Indeed, some go further and try to explain the clinical overlap, together with the growing incidence of all types of diabetes, by proposing that both major forms of diabetes share common aetiological factors. One widely cited example is the ‘accelerator hypothesis’ [2], which holds that increasing rates of obesity and insulin resistance contribute to the development of type 1 and type 2 diabetes by driving a more rapid decline in beta cell function, irrespective of the nature of the original islet insult. By defining fundamental pathophysiological processes underlying individual susceptibility to disease, genetic analyses have the potential to inform debates such as these. With the recent crop of genome-wide association studies taking the tally of loci confidently implicated in the pathogenesis of multifactorial forms of diabetes [3– 5] to more than 60, it has become possible to use these to explore the ‘aetiological architecture’ of diabetes. A number of recent papers describe attempts to do just this [6–14]. In this issue of Diabetologia, Raj and colleagues take a panel of variants known to influence individual risk of type 2 diabetes and examine their effects on predisposition to type 1 diabetes [12]. Since the effects of these variants on type 2 diabetes risk are quite modest (odds ratios of 1.1 to 1.4 per allele), an important feature of this study was the use of large sample collections (more than 25,000 individuals). This allowed the authors to be confident that they had not missed small, but nonetheless informative, effects of these variants on risk of type 1 diabetes. Apart from a modest association between the Pro12Ala variant in the PPARG gene and type 1 diabetes, there was no evidence that these type 2 diabetes risk variants impact on susceptibility to type 1 diabetes. The authors conclude that this argues strongly against pathophysiological mechanisms common to both major forms of diabetes. K. R. Owen :M. I. McCarthy (*) Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK e-mail: mark.mccarthy@drl.ox.ac.uk