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SummaryAims To study whether changes in endogenous insulin secretion at the same glycaemic control affect the plasma concentrations of lipoproteins in patients with Type 2 diabetes mellitus. Methods Fifteen patients, age 59 ± 2 years (mean ± sem), body weight 86.3 ± 3.0 kg, body mass index 29.6 ± 0.9 kg/m2 were treated with sulphonylurea and insulin in combination or with insulin alone in a randomized, double-blind, crossover study. All patients were treated with a multiple daily injection regimen with the addition of glibenclamide 10.5 mg daily or placebo tablets. Results During combination therapy, the dose of insulin was 25% less (P < 0.002) and there was a 29% increase in plasma C-peptide concentration (P = 0.01). Plasma levels of free insulin were not changed. Plasma levels of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein (IGFBP)-1 were lowered. There were no differences in the 24-h blood glucose profiles or HbA1c (6.0 ± 0.2 vs. 6.3 ± 0.2%; P = 0.16). Body weight was similar. There was a significant decrease in plasma LDL cholesterol (3.04 ± 0.24 vs. 3.41 ± 0.21 mmol/l; P = 0.04), apolipoprotein A1 and of lipoprotein(a) but an increase in VLDL-triglycerides (1.36 ± 0.31 vs. 0.96 ± 0.16 mmol/l; P = 0.02) during combination therapy. The ratio between LDL cholesterol and apolipoprotein B concentrations was significantly lower during combination therapy (P < 0.01). Conclusions Combination therapy with insulin and sulphonylureas increases portal insulin supply and thereby alters liver lipoprotein metabolism when compared with insulin therapy alone. [ABSTRACT FROM AUTHOR]