OBJECTIVE: To investigate the impact of visceral obesity on cholesterol metabolism in normoglycemic offspring of patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: The proportion of intra-abdominal fat (IAF) was measured by abdominal computer tomography, and serum cholesterol synthesis and absorption markers were determined by gas-liquid chromatography in 109 normoglycemic offspring of patients with type 2 diabetes. Insulin action was measured with the hyperinsulinemic euglycemic clamp. The gene encoding squalene synthase (farnesyl-diphosphate farnesyltransferase 1) was screened with the single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Cholesterol synthesis markers correlated positively with IAF (r = 0.213 to 0.309, p < or = 0.027) and negatively with the rates of insulin-stimulated whole-body glucose uptake (r = -0.372 to -0.248, p < or = 0.010). However, serum squalene, the first measured precursor of cholesterol synthesis, showed a positive correlation with IAF (r = 0.309, p = 0.001) without any association with subcutaneous fat or insulin sensitivity. Variation in the farnesyl-diphosphate farnesyltransferase 1 gene did not explain elevated serum squalene levels in viscerally obese subjects. From the cholesterol absorption markers, cholestanol was associated negatively with IAF and positively with whole-body glucose uptake (p < 0.05). DISCUSSION: High serum squalene levels are associated with visceral obesity but not with subcutaneous obesity. Whether this finding is causally connected to visceral obesity remains to be established.