The genetics of insulin resistance: Where's Waldo?

The physiologic hallmarks of type 2 diabetes are insulin resistance in hepatic and peripheral tissues and pancreatic β-cell dysfunction. Thus, genetic loci underlying susceptibility to type 2 diabetes are likely to map to one of these endophenotypes. Genome-wide association studies have now identified up to 38 susceptibility loci for type 2 diabetes and a number of other loci underlying variation in type 2 diabetes-related quantitative traits. The majority are of unknown biology or map to pancreatic β-cell dysfunction. A seemingly disproportionate minority map to insulin resistance. We briefly discuss the known insulin resistance loci identified from genome-wide association, and then discuss reasons why additional insulin resistance loci have not been identified. We present alternative views that may partly explain the apparent dearth of insulin resistance loci contributing to genetic susceptibility to type 2 diabetes, rather than focus on traditional issues such as study design and sampling, which have been addressed elsewhere.