Table 1.

Lessons from the study of genetics of human insulin resistance

• Disorders of insulin signaling only partially phenocopy common insulin resistance

• Monogenic lipodystrophies provide a more complete phenocopy

• Allelic variants underpinning common variation in fasting insulin, triglycerides, and HDL are dominated by genes with high expression in adipose tissue

• These findings are more consistent with the model of impaired adipose tissue expandability and lipotoxicity (cf Vidal-Puig) than with the view that inflammation is the major link between overnutrition and insulin resistance

• Large-scale population genetic studies are now pinpointing specific genes and helping to validate them as therapeutic targets