Strategies and prospects for finding insulin resistance genes

In this paper I review the evidence that human sensitivity to insulin is influenced by heredity, in particular by one or more genes with relatively large effects. Even granting the existence of such genes, however, the best route toward identifying them — and the related genes that are presumed to affect an individual’s risk of obesity or type 2 diabetes — remains unclear. Thus, the phenotype of insulin resistance can be assessed either directly, with techniques such as the euglycemic hyperinsulinemic clamp, or indirectly, using various proxy measures such as serum insulin concentrations. In addition, several different genotyping strategies might be employed. These alternatives raise both practical and theoretical questions: Which of the available phenotypic traits offers the most promising approach to identifying insulin resistance genes? Which methodologies are most powerful, and which best exploit the anticipated continued successes of the Human Genome Project? Finally, is it more realistic to search for genes influencing “intermediate” phenotypes such as insulin sensitivity, or to seek the related disease genes directly?