Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes

A wide range of genetically engineered murine models of type 2 diabetes have been created to try to understand the site of the primary defect in insulin action, and the relationship between insulin resistance and impaired beta-cell function in diabetes. Genetic disruption of various aspects known to be important in diabetes has examined specific facets, including glucose sensing, transcription factors for the insulin gene, the insulin gene itself, insulin and insulin-like growth factor receptors, downstream signaling components and some mutations that increase insulin sensitivity. This article focuses on models that have given insight into insulin resistance and impaired insulin production, especially models that examine molecules involved in the signaling pathway downstream of insulin binding its receptor. These models recapitulate many features of human type 2 diabetes and, although they have emphasized the complexity of this disease, they offer numerous opportunities to characterize particular aspects and eventually fit them together to help delineate the human disease.