Insights into insulin resistance and type 2 diabetes from knockout mouse models.

The pathogenesis of type 2 diabetes is characterized by two major features: peripheral insulin resistance and impaired insulin secretion from pancreatic β cells (1, 2). The application of transgenic mouse technology to the study of diabetes has been extensively reviewed (3). Here, I review the application of a complementary approach, gene knockout technology, to the problem of understanding insulin resistance and its sequelae. After reviewing the phenotypes of animals with individual targeted mutations in homozygous or heterozygous form, I turn to the effects of double mutations and show that interactions between mediators of insulin signaling can account for the development of overt diabetes. Gene knockout technology allows the investigator to generate homozygous null mutant mice and to examine the effects of a total lack of a particular gene product. Resultant phenotypes are expected to reflect physiological functions of the specific gene in vivo. The effects of gene dosage can be studied by focusing on heterozygous null mutants. Moreover, crossing of various heterozygous and/or homozygous knockout animals can be used to reconstitute alterations in multiple genes. Conditional (i.e., tissue-specific or inducible) knockouts can also be created using the Cre/loxP system (4). This tool expands the application of the knockout approach to allow the study of mutations that would be lethal if expressed systemically, and it allows the study of specific effects of mutations in a particular tissue without influences from the other tissues.

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