Rosiglitazone Improves Postprandial Triglyceride and Free Fatty Acid Metabolism in Type 2 Diabetes

Abstract

OBJECTIVE -Increased postprandial lipemia is part of diabetic dyslipidemia and is associated with accelerated atherosclerosis. We investigated the effects of the peroxisome proliferatoractivated receptor-␥ agonist rosiglitazone on postprandial lipemia in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS-A randomized, 8-week, crossover, placebocontrolled, double-blind trial was performed in which rosiglitazone at 4 mg was administrated twice daily in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. Postprandial curves were calculated as the total area under the curve (AUC) and the incremental area under the curve (dAUC).RESULTS -Rosiglitazone did not change fasting plasma triglycerides compared with placebo (1.97 Ϯ 0.22 vs. 1.88 Ϯ 0.20 mmol/l, respectively) but decreased postprandial triglyceride levels, leading to significantly lower triglyceride dAUC (Ϫ37%, P Ͻ 0.05), without changing total triglyceride AUC. Significant postprandial triglyceride reductions in the chylomicron fraction (Svedberg flotation rate [Sf] Ͼ400) were achieved with rosiglitazone, which resulted in a significant lower triglyceride AUC (Ϫ22%) in this fraction. The postprandial triglyceride increase in VLDL1 (Sf 60 -400) was also lower after rosiglitazone (Ϫ27%), but this did not result in a significant lower triglyceride AUC. In VLDL2 (Sf 20 -60), there were no significant differences in triglyceride AUC and triglyceride dAUC between rosiglitazone and placebo. Rosiglitazone decreased free fatty acid (FFA) AUC (Ϫ12%) and FFA dAUC (Ϫ18%) compared with placebo.CONCLUSIONS -Rosiglitazone improves the metabolism of large triglyceride-rich lipoproteins and decreases postprandial FFA concentrations in type 2 diabetes. This may have clinical implications, as these effects may contribute to cardiovascular risk reduction. Diabetes Care 28:844 -849, 2005D yslipidemia is one of the main cardiovascular risk factors in type 2 diabetes (1). An increased hepatic free fatty acid (FFA) flux has been postulated as a major contributor of diabetic dyslipidemia because it could lead to hepatic overproduction of triglyceride-rich lipoproteins (TRLs) (1). It is important to realize that humans are nonfasting most of the day and that nonfasting triglycerides are also predictors of atherosclerosis (2). Exaggerated and prolonged postprandial hyperlipidemia is an important characteristic of diabetic dyslipidemia (1-3). Several studies have shown that, even in fasting normolipidemic subjects, impaired clearance of TRL and their remnants is linked to atherosclerosis (4 -9). Therefore, therapeutic modulation of postprandial lipemia may convey increased protection from atherosclerosis.Thiazolidinediones (TZDs) are oral antihyperglycemic agents that reduce insulin resistance in peripheral tissues and decrease hepatic glucose production (10). TZDs are potent synthetic ligands for peroxisome proliferator-activated receptor-␥ (PPAR-␥) activation, thereby directly influencing the transcription of gen...

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

“…Insulin sensitisation with pioglitazone partially corrected the delayed decrease in postprandial NEFA levels seen in diabetic patients, suggesting an effect of insulin sensitisation on the inhibition of adipocyte NEFA release [44,45]. In our study, pioglitazone reduced fasting triglyceride levels; however, this does not seem to be the case with rosiglitazone, which has been shown to enhance postprandial triglyceride disposal, with this effect being attributed to an improvement in the lipolysis of intact chylomicrons [46]. The reason for the differences in action of these two TZDs is not known, but may lie in the fact that pioglitazone reportedly has a greater potential than rosiglitazone to react with the PPAR-α receptor, but other differences in their pleiotropic effects or actions not involving nuclear genes cannot be ruled out [47][48][49][50].…”

Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes

“…One important observation of our present work is that the administration of rosiglitazone to insulin-resistant rats induced an increase in glyceroneogenesis, which was accompanied by an improvement in dyslipidaemia, as shown by the large decrease in plasma triacylglycerol. Similar observations were previously reported in humans, in whom thiazolidinediones induced a reduction in postprandial plasma triacylglycerol [8,35]. As expected, a strong correlation was also shown between the glyceroneogenic flux of the tissue and the release of NEFA in the incubation medium.…”

Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes

“…Thiazolidinediones have been reported to exert beneficial effects on postprandial TG metabolism [17][18][19][20], but these are unlikely to be mediated by reduced NEFA flux to the liver, a mechanism that is largely independent of improved glycaemia. Both metformin [21,22] and glipizide [23] can improve postprandial lipaemia in poorly controlled patients with type 2 diabetes.…”