More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics. 1. Introduction The estimated global prevalence for diabetes in 2011 was 366 million, and the disease is expected to affect 552 million people by 2030 (Diabetes U.K. figures; [1] accessed 09/01/13). Type 2 diabetes (T2D) is a complex and multifactorial disease characterised by impaired insulin secretion and insulin resistance. Disease risk/progression is determined by a combination of genetic and environmental factors. It has been consistently demonstrated that lifestyle factors are associated with risk of T2D across populations [2–8], with increased adiposity being the greatest modifiable risk factor for the disease [9, 10]. Inactivity [3, 11], “bad” diet [2, 6, 8, 12–14], smoking, and other vices [8, 15, 16] and the nutritional environment during pre- and postnatal life [17] also contribute to the risk for developing diabetes. It has been estimated that 30–70% of？？T2D risk may be due to genetics [18]. Whilst pedigree-based linkage analysis and the candidate gene approach led to the discovery of highly penetrant genetic defects which account for the development of diabetes [19–24], it is the advent of large scale genome-wide association studies (GWAS) which have led to the accelerated discovery of risk-variants associated with T2D [25–34]. Currently, over 60 common risk variants have been identified [30–34], with a combined disease risk of 5–10% [34, 35], suggesting the existence of many more as yet undiscovered loci [34, 36, 37]. Most of the GWAS-identified associations for T2D have high linkage disequilibrium with a causal variant with a small effect size; the largest common variant-signal identified to date is that for TCF7L2, which has a per allelle odds ratio of 1.35 [27–29]. Most of the common variant signals identified by GWAS are associated with defective pancreatic islet function, indicating that this is the primary driver for the
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