In a detailed study, the effect of sensitizing tissues to insulin with a thiazolidinedione (pioglitazone) on postprandial lipid metabolism was compared to a group of type 2 diabetic patients treated with sulphonylurea (glibenclamide) in a treatment regime designed to achieve equivalent glycaemic control (HbAlc) in both groups. An oral fat tolerance test was administered after a 6 week treatment with diet and after 20 weeks treatment with glibenclamide or pioglitazone. Glycaemic control in both groups was unchanged by either treatment but in the fasting state, insulin sensitization caused a significant reduction in plasma total triglyceride content due to a significant reduction in total VLDL and, in particular, VLDL-2 present. The overall triglyceride response to the fat test showed a significant improvement to control clearance levels in the pioglitazone group that was not observed in the glibenclamide group. Chylomicron and chylomicron remnant clearance improved with insulin sensitization. IDL and LDL-TG was significantly higher in the diabetic patients than the controls and after treatment with thiazolidinedione the triglyceride content of these lipoproteins was reduced by contrast to glibenclamide treatment. Cholesterol content did not change significantly over the postprandial period either overall or in lipoproteins. There were only small effects on the enzymes of lipoprotein remodelling (LCAT, CETP, PLTP, HL or LPL) by insulin sensitization. Insulin release was reduced over the postprandial period by insulin sensitization and a significant reduction of proinsulin and 32-33 split-proinsulin also occurred. The results of this study show that sensitizing tissues to the action of insulin causes a reduction in insulin resistance (HOMA) and a more rapid clearance of postprandial lipoproteins. In addition there is an apparent beneficial effect on ?-cell function which is manifested by lower levels of incompletely processed insulin species probably caused by a less prolonged period of glycaemia.