To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.