Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal

Free fatty acids released during triglyceride lipolysis play an important r ole in obesity-associated insulin resistance of glucose disposal. Individua l sensitivity of lipolysis to the suppressive effect of insulin varies grea tly among healthy subjects. It is possible that genetic factors contribute to this variation. Among the many proteins involved in the regulation of li polysis, hormone-sensitive lipase (HSL) represents a prime candidate for ge netic variants contributing to the biological variation of insulin sensitiv ity of lipolysis. We determined the insulin sensitivity of lipolysis (suppr ession of isotopically [primed-continuous infusion of d(5) glycerol] measur ed glycerol rate of appearance) and of glucose disposal, using a three-step (n = 20) or standard (n = 53) hyperinsulinemic euglycemic clamp in 73 heal thy, unrelated subjects. To assess the possible role of genetic polymorphis ms, we directly sequenced the coding region of the HSL gene and the noncodi ng exon B from these subjects. We identified two silent mutations and three amino acid polymorphisms: Arg262Met (prevalence, 5%), Glu620Asp (prevalenc e, 31%) and Ser681Ile (prevalence, 22%). The latter two are located in the regulatory domain of HSL but neither had a significant impact on insulin se nsitivity of lipolysis or glucose disposal (with and without adjustment for obesity and age as covariates; all P values > 0.20). We conclude that a nu mber of genetic polymorphisms in HSL exist, some of which are highly preval ent. Neither of the polymorphisms we identified in the coding region, howev er, contributed measurably to the biological variation of insulin sensitivi ty in our lean, healthy population.