A decreased plasma concentration of high-density lipoprotein (HDL) cholesterol is associated with a higher incidence of coronary artery disease in populations. Therefore, there is intense investigation into the mechanisms responsible for the regulation of HDL cholesterol concentration in plasma. Insulin has a potent effect on HDL cholesterol, but it is unclear whether this is mediated by the primary effect insulin has on plasma triglycerides (TG). In this study, the question of the relationship between glucose, insulin, and HDL cholesterol has been addressed by investigating a cohort of nondiabetic normolipidemic men living in the Venice, Italy, area. One hundred twenty-eight men aged 30 to 69 years were initially recruited. The following parameters were measured: fasting plasma cholesterol, TG, HDL cholesterol, glucose, and insulin. One hundred seventeen of these subjects underwent an oral glucose tolerance test (OGTT), and the glucose and insulin responses were assessed. The final statistical analysis was performed on 98 nondiabetic individuals with plasma lipid levels within the 75th percentile for cholesterol and TG concentrations of the general population of the same age. The insulin response was a positive independent variable for plasma TG (P < .005) and HDL cholesterol (P < .005). On the other hand, HDL cholesterol was negatively associated with plasma TG. This relationship remained significant (P < .0001) also after controlling for age, body mass index (BMI), and glucose- and insulin-related measurements. Consistent with these results, both a stepwise variable selection analysis and a stratification analysis of the data indicated that the plasma TG concentration is the major determinant of HDL cholesterol level.(ABSTRACT TRUNCATED AT 250 WORDS)