Primary aldosteronism: Higher volume load, cardiac output and arterial stiffness than in essential hypertension.

BACKGROUND: The diagnostics of primary aldosteronism (PA) are usually carried out in patients taking antihypertensive medications. We compared haemodynamics between medicated PA, medicated essential hypertension (EH), never-medicated EH and normotensive controls (n = 130 in all groups). METHODS: The hypertensive groups were matched for age (53 years), sex (84 male/46 female) and body mass index (BMI) (30 kg m-2 ); normotensive controls had similar sex distribution (age 48 years, BMI 27 kg m-2 ). Haemodynamics were recorded using whole-body impedance cardiography and radial pulse wave analysis, and the results were adjusted as appropriate. Radial blood pressure recordings were calibrated by brachial blood pressure measurements from the contralateral arm. RESULTS: Radial and aortic systolic and diastolic blood pressure was similar in PA and never-medicated EH, and higher than in medicated EH and normotensive controls (P ≤ 0.001 for all comparisons). Extracellular water balance was ~ 4% higher in PA than in all other groups (P < 0.05 for all), whilst cardiac output was ~ 8% higher in PA than in medicated EH (P = 0.012). Systemic vascular resistance and augmentation index were similarly increased in PA and both EH groups when compared with controls. Pulse wave velocity was higher in PA and never-medicated EH than in medicated EH and normotensive controls (P ≤ 0.033 for all comparisons). CONCLUSIONS: Medicated PA patients presented with corresponding systemic vascular resistance and wave reflection, but higher extracellular water volume, cardiac output and arterial stiffness than medicated EH patients. Whether the systematic evaluation of these features would benefit the clinical diagnostics of PA remains to be studied in future.

Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects.

BACKGROUND: Renewed interest in triglyceride-rich lipoproteins as causative agents in cardiovascular disease mandates further exploration of the integrated metabolism of chylomicrons and very low-density lipoproteins (VLDL). METHODS: Novel tracer techniques and an integrated multi-compartmental model were used to determine the kinetics of apoB48- and apoB100-containing particles in the chylomicron and VLDL density intervals in 15 subjects with a wide range of plasma triglyceride levels. RESULTS: Following a fat-rich meal, apoB48 appeared in the chylomicron, VLDL1 and VLDL2 fractions in all subjects. Chylomicrons cleared rapidly from the circulation but apoB48-containing VLDL accumulated, and over the day were 3-fold higher in those with high versus low plasma triglyceride. ApoB48-containing particles were secreted directly into both the chylomicron and VLDL fractions at rates that were similar across the plasma triglyceride range studied. During fat absorption, whilst most triglyceride entered the circulation in chylomicrons, the majority of apoB48 particles were secreted into the VLDL density range. CONCLUSION: The intestine secretes apoB48-containing particles not only as chylomicrons but also directly into the VLDL1 and VLDL2 density ranges both in the basal state and during dietary lipid absorption. Over the day, apoB48-containing particles appear to comprise about 20-25% of circulating VLDL and, especially in those with elevated triglycerides, form part of a slowly cleared 'remnant' particle population, thereby potentially increasing CHD risk. These findings provide a metabolic understanding of the potential consequences for increased CHD risk when slowed lipolysis leads to the accumulation of remnants, especially in individuals with hypertriglyceridemia.

Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics.

BACKGROUND: Triglyceride-rich lipoproteins and their remnants have emerged as major risk factors for cardiovascular disease. New experimental approaches are required that permit simultaneous investigation of the dynamics of chylomicrons (CM) and apoB48 metabolism and of apoB100 in very low-density lipoproteins (VLDL). METHODS: Mass spectrometric techniques were used to determine the masses and tracer enrichments of apoB48 in the CM, VLDL1 and VLDL2 density intervals. An integrated non-steady-state multicompartmental model was constructed to describe the metabolism of apoB48- and apoB100-containing lipoproteins following a fat-rich meal, as well as during prolonged fasting. RESULTS: The kinetic model described the metabolism of apoB48 in CM, VLDL1 and VLDL2 . It predicted a low level of basal apoB48 secretion and, during fat absorption, an increment in apoB48 release into not only CM but also directly into VLDL1 and VLDL2 . ApoB48 particles with a long residence time were present in VLDL, and in subjects with high plasma triglycerides, these lipoproteins contributed to apoB48 measured during fasting conditions. Basal apoB48 secretion was about 50 mg day-1 , and the increment during absorption was about 230 mg day-1 . The fractional catabolic rates for apoB48 in VLDL1 and VLDL2 were substantially lower than for apoB48 in CM. DISCUSSION: This novel non-steady-state model integrates the metabolic properties of both apoB100 and apoB48 and the kinetics of triglyceride. The model is physiologically relevant and provides insight not only into apoB48 release in the basal and postabsorptive states but also into the contribution of the intestine to VLDL pool size and kinetics.

Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity.

BACKGROUND: Overconsumption of dietary sugars, fructose in particular, is linked to cardiovascular risk factors such as type 2 diabetes, obesity, dyslipidemia and nonalcoholic fatty liver disease. However, clinical studies have to date not clarified whether these adverse cardiometabolic effects are induced directly by dietary sugars, or whether they are secondary to weight gain. OBJECTIVES: To assess the effects of fructose (75 g day-1 ), served with their habitual diet over 12 weeks, on liver fat content and other cardiometabolic risk factors in a large cohort (n = 71) of abdominally obese men. METHODS: We analysed changes in body composition, dietary intake, an extensive panel of cardiometabolic risk markers, hepatic de novo lipogenesis (DNL), liver fat content and postprandial lipid responses after a standardized oral fat tolerance test (OFTT). RESULTS: Fructose consumption had modest adverse effects on cardiometabolic risk factors. However, fructose consumption significantly increased liver fat content and hepatic DNL and decreased ß-hydroxybutyrate (a measure of ß-oxidation). The individual changes in liver fat were highly variable in subjects matched for the same level of weight change. The increase in liver fat content was significantly more pronounced than the weight gain. The increase in DNL correlated positively with triglyceride area under the curve responses after an OFTT. CONCLUSION: Our data demonstrated adverse effects of moderate fructose consumption for 12 weeks on multiple cardiometabolic risk factors in particular on liver fat content despite only relative low increases in weight and waist circumference. Our study also indicates that there are remarkable individual differences in susceptibility to visceral adiposity/liver fat after real-world daily consumption of fructose-sweetened beverages over 12 weeks.

Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men.

BACKGROUND AND AIMS: Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. METHODS AND RESULTS: As many as 66 obese (BMI 26-40 kg/m2) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). CONCLUSION: In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.

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

AIMS/HYPOTHESIS: We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. SUBJECTS, MATERIALS AND METHODS: This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. RESULTS: Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC(0-8h) for total trigyceride by 22+/-11% (p=0.037), the incremental AUC(0-8h) (IAUC(0-8h)) for total triglyceride by 85+/-47% (p=0.065), the AUC(0-8h) for chylomicron triglyceride by 65+/-19% (p=0.001) and the IAUC(0-8h) for chylomicron triglyceride by 91+/-28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC(0-8h), -1.0+/-0.5 mg l(-1) h, p=0.037) and chylomicron cholesterol (AUC(0-8h), -0.14+/-0.07 mmol l(-1) h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA(1c) from a baseline of 6.7% (change, -0.4+/-0.1%, p<0.001), all relative to placebo. CONCLUSIONS/INTERPRETATION: Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

Serum C3 but not plasma acylation-stimulating protein is elevated in Finnish patients with familial combined hyperlipidemia.

A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial combined hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (P<0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially.