Objective-Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). Approach and Results-We performed an in vivo kinetic study with stable isotopes (D 8 -valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d).We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron.

Our study showed that apelin concentrations were increased in diabetic patients. This rise, which was greater in type 1 than in type 2 diabetic patients, suggests that obesity is not the main determinant of plasma apelin levels. The negative correlation with glycosylated haemoglobin in patients with type 2 diabetes could indicate that apelin plays a role in glycaemic balance and even insulin sensitivity.

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Catabolism of HDL particles is accelerated in type 2 diabetes, leading to a reduction in plasma residence time, which may be detrimental. Rosuvastatin is the most powerful statin to reduce LDL-cholesterol, but its effects on HDL metabolism in type 2 diabetes remain unknown. We performed a randomized double-blind cross-over trial of 6-week treatment period with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes. An in vivo kinetic study of HDL-apolipoprotein A-I (apoA-I) with 13 C leucine was performed at the end of each treatment period. Moreover, a similar kinetic study was carried out in eight nondiabetic normolipidemic controls. Rosuvastatin significantly reduced plasma LDL-cholesterol (251%), triglycerides (TGs) (238%), and HDL-TG (223%). HDL-apoA-I fractional catabolic rate (FCR) was decreased by rosuvastatin (0.25 6 0.06 vs. 0.32 6 0.07 pool/day, P 5 0.011), leading to an increase in plasma HDL-apoA-I residence time (4.21 6 1.02 vs. 3.30 6 0.73 day, P 5 0.011). Treatment with rosuvastatin was associated with a concomitant reduction of HDL-apoA-I production rate. The decrease in HDL-apoA-I FCR, induced by rosuvastatin, was correlated with the reduction of plasma TGs and HDL-TG. HDL apoA-I FCR and production rate values in diabetic patients on rosuvastatin were not different from those found in controls. Rosuvastatin is responsible for a 22% reduction of HDL-apoA-I FCR and restores to normal the increased HDL turnover observed in type 2 diabetes. These kinetic modifications may have beneficial effects by increasing HDL plasma residence time. Cardiovascular disease is the major cause of morbidity and mortality in patients with type 2 diabetes, and cardiovascular disease risk is 2-to 4-fold increased over nondiabetic subjects (1-4). Abnormalities of lipid metabolism, observed in type 2 diabetes, are one of the major factors contributing to vascular risk (5, 6). Diabetic dyslipidemia includes increased plasma triglycerides (TGs), decreased HDL-cholesterol levels, and qualitative lipoprotein abnormalities, such as TG enrichment of LDL and HDL particles (7, 8). Low HDL-cholesterol level, in patients with type 2 diabetes, has been shown to be due to increased catabolism of HDL lipoproteins by in vivo kinetic studies using radioisotopes (9) or stable isotopes (10). This increased catabolism of HDL particles leads automatically to significantly decrease their plasma residence time. The cardiovascular protective role of HDL is thought to be mainly due to its role in reverse cholesterol transport (11) and potentially to the antioxidative, anti-inflammatory, antithrombotic, and endothelium-dependent vasorelaxant effects of HDL particles (12). The increased catabolism of HDL lipoproteins is likely to reduce the cardioprotective effects of HDLs in patients with type 2 diabetes.Rosuvastatin is a statin that has been shown to reduce LDL-cholesterol more than the other statins at an equivalent dose (13). In addition, rosuvastatin significantly decreases plasma TG level with larger effect than prav...

OBJECTIVE Dyslipidemia observed in type 2 diabetes (T2D) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles, which all have apolipoprotein B100 (apoB100) as a major apolipoprotein. This prompted us to study the effect of the GLP-1 agonist liraglutide on the metabolism of apoB100-containing lipoproteins. RESEARCH DESIGN AND METHODS We performed an in vivo kinetic study with stable isotopes (L-[1-13C]leucine) in 10 patients with T2D before and after 6 months of treatment with liraglutide (1.2 mg/day). We also evaluated in mice the effect of liraglutide on the expression of genes involved in apoB100-containing lipoprotein clearance. RESULTS In patients with T2D, liraglutide treatment significantly reduced plasma apoB100 (0.93 ± 0.13 vs. 1.09 ± 0.11 g/L, P = 0.011) and fasting triglycerides (1.76 ± 0.37 vs. 2.48 ± 0.69 mmol/L, P = 0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL1-apoB100 (4.11 ± 1.91 vs. 2.96 ± 1.61 pools/day, P = 0.005), VLDL2-apoB100 (5.17 ± 2.53 vs. 2.84 ± 1.65 pools/day, P = 0.008), and IDL-apoB100 (5.27 ± 2.77 vs. 3.74 ± 1.85 pools/day, P = 0.017) and in catabolism of LDL-apoB100 (0.72 ± 0.22 vs. 0.56 ± 0.22 pools/day, P = 0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced proprotein convertase subtilisin/kexin type 9 (PCSK9), retinol-binding protein 4 (RBP4), and tumor necrosis factor-α (TNF-α) gene expression in adipose tissue and decreased PCSK9 mRNA and increased LDL receptor protein expression in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver. CONCLUSIONS Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100-containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2D.