Animal models of GWAS-identified type 2 diabetes genes

Abstract

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.

Figure 1

Electron Micrographs and Optical Projection Tomography (OPT) in ZnT8^+/+ and ZnT8^−/− mice. (a) Transmission electron microscopy images of isolated islets from ZnT8^+/+ and ZnT8^−/− male mice at high magnification (scale bar 1 mm) reveals the appearance of rod-shaped core granules in ZnT8^−/− cells, indicated by red arrows (n = 3 mice). Sections were cut and images were acquired by Dr. Raffaella Carzaniga and Ms. Katrin Kronenberger. (b) Representative three-dimensional OPT projections of whole fixed and permeabilised pancreas from ZnT8^−/− and ZnT8^+/+ mice. In red are the insulin positive structures (β cells). The overall shape of the whole pancreas was visualized as autofluorescence and is apparent as white/grey shading. Scale bar = 1 cm. (c) Relative (right panel) and absolute (left panel) β-cell volume (n = 2 pancreata per genotype).