Genetic analysis of type 1 diabetes: embryonic stem cells as new tools to unlock biological mechanisms in type 1 diabetes

Abstract

The nonobese diabetic (NOD) mouse has provided an important animal model for studying the mechanism and genetics of type 1 diabetes over the past 30 years. Arguably, the bio-breeding (BB) rat model may be an even closer phenotypic mimic of the typical human disease. A large number of distinct genetic traits which influence diabetes development have been defined through an extraordinary effort, most conspicuously in the mouse model. However, in both NOD and BB models the lack of availability of robust means for experimental genetic manipulation has restricted our understanding of the mechanisms underlying this spontaneous autoimmune disease. Recent developments in the derivation of embryonic stem (ES) cells have the potential to transform this picture. We argue here that targeting of NOD strain ES cells can bring much needed certainty to our present understanding of the genetics of type 1 diabetes in the NOD mouse. In addition, ES cells can play important roles in the future, in both the NOD mouse and BB rat models, through the generation of new tools to investigate the mechanisms by which genetic variation acts to promote diabetes.

Figure 1. Suggested fruitful strategies for the use of NOD strain ES cells

Three general avenues are indicated in the figure. A. NOD ES cells provide a rapid means of confirming or disproving hypothetical candidate genes and causative variants altering diabetes onset by 'knockin' gene targeting. B. Larger scale gene swap technology could be used to refine currently large or unattributed susceptibility regions; the process should be iterative when successful. C. Reporter strains, for example enabling in vivo imaging of beta cells or their progenitors should also be valuable. Cre-expressing strains for lineage-specific modification may also aid mechanistic studies aimed at understanding the biology of diabetes development and generating models for testing interventions. Second generation ES cells derived from gene targeted NOD mice might also be valuable.