Nicotinic acid effects on insulin sensitivity and hepatic lipid metabolism: an in vivo to in vitro study.

Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan(®) on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan(®) (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan(®) treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri-glyceride production rate was markedly reduced after Niaspan(®) (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05) in the Niaspan(®) condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan(®) treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.

Kinetics of prebeta1 HDL and alphaHDL in type II diabetic patients.

BACKGROUND: The aim of this study was to analyze the recycling of high density lipoprotein (HDL) in six type II diabetic patients compared with six control subjects by endogenous labelling of apolipoprotein A-I (Apo A-I) with stable isotope Apo A. MATERIALS AND METHODS: The -I-HDL kinetics were performed by infusion of (5.5.5-(2)H3)-leucine for 14 h. The prebeta1 and alphaHDL were separated by gel filtration fast protein liquid chromatrography system (FPLC). Kinetics of isotopic enrichment of Apo A-I were analyzed with a multi-compartmental model software (SAAM II, SAAM Institute, Seattle, WA). RESULTS: Plasma Apo A-I concentration was decreased in patients with type II diabetes as a result of a decrease in Apo A-I-alphaHDL (P < 0.05). Diabetic patients were also characterized by an increased relative contribution of Apo A-I in prebeta1 HDL (18.3 +/- 2.8% vs 11.9 +/- 3.7%, P < 0.01). The synthetic rate of prebeta1 HDL was slightly increased in diabetic patients compared with control (NS) and an increase of recycling rate of alpha to prebeta1 HDL was observed (11.67 +/- 3.14 d(-1) vs 7.09 +/- 4.51 d(-1), P < 0.05). The clearance rate of Apo A-I was higher in diabetic patients (P < 0.05 for Apo A-I-prebeta1 HDL and P < 0.005 for Apo A-I-alphaHDL). CONCLUSION: This study suggests that the usual increase in prebeta1 HDL in type II diabetic patients is mainly related to an increased conversion rate of alpha to prebeta1 HDL.

New model for kinetic studies of HDL metabolism in humans.

BACKGROUND: The aim of the study was to develop a new model for kinetic studies of Apolipoprotein A-I of HDL (Apo A-I-HDL) labelled with stable isotope by using HDL subclasses isolated with fast protein liquid chromatography (FPLC). MATERIALS AND METHODS: Apo A-I-HDL kinetics were studied by infusing [5.5.5-(2)H(3)]-leucine for 14 h in six healthy subjects. Prebeta(1) and alphaHDL were separated by FPLC and total HDL by ultracentrifugation (HDL-UC). RESULTS: The tracer-to-tracee ratios were higher in prebeta(1) HDL than in HDL-UC or alphaHDL. Leucine enrichments found in HDL-UC were higher compared with alphaHDL, suggesting that HDL-UC were composed of a mixture of Apo A-I-alphaHDL and Apo A-I-prebeta(1) HDL. Kinetic analysis of data obtained from FPLC was achieved using a multicompartmental model, including a conversion between prebeta(1) and alphaHDL compartments. The production rate of prebeta(1) HDL was 7.72 +/- 2.86 mg kg(-1) d(-1) (mean +/- SD). Prebeta(1) HDL were converted to alphaHDL at a rate of 96.24 +/- 42.99 pool d(-1), and the synthesis rate of prebeta(1) HDL from alphaHDL was 10-fold slower: 7.09 +/- 4.51 pool d(-1). Apo A-I-FCR of HDL-UC was estimated using a one-compartment model (0.165 +/- 0.074 pool d(-1)), and was higher but not significantly compared with FCR of Apo A-I-alphaHDL (0.112 +/- 0.026 pool d(-1)) calculated with the new model. CONCLUSIONS: This study reports for the first time a model involving enrichments of Apo A-I in prebeta(1) and alphaHDL which allowed the measure of Apo A-I cycling within HDL fraction and will aid better understanding of kinetics of HDL in humans.