Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study.

We previously identified a hormone sensitive lipase (HSL) promoter variant, -60C>G, which in vitro exhibits 40% reduced promoter activity. In this study we examined the effect of the -60C>G on glycemic and lipid measures in the population based Ely study of metabolic function and insulin resistance in 218 middle-aged men and 276 middle-aged women. Adipose tissue HSL is the rate-limiting step in triglyceride lipolysis, generating free fatty acids for energy utilization. HSL is also expressed in pancreatic beta-cells where its activity therefore may affect insulin secretion. In the women, carriers of the HSL -60G allele had significantly lower fasting insulin levels (P=0.0005) and a lower total area under the curve for insulin during the oral glucose tolerance test (P=0.005). There was no demonstrable association in men with these measures of insulin sensitivity but carriers of the -60G allele had significantly lower fasting non-esterified fatty acid (NEFA) levels (P=0.025) and higher low density lipoprotein cholesterol levels (P=0.02) than men who were non-carriers. This study provides additional evidence for a role for HSL in the development of insulin resistance, from which carriers of the -60G allele, associated here with markers of insulin sensitivity in women, and with lower NEFA levels in men, might be protected.