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Aim: \ud To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal.\ud \ud Materials and Methods: \ud Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal.\ud \ud Results: \ud Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p

Aims:\ud \ud To investigate how apolipoprotein C‐III (apoC‐III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC‐III, and whether improvement of glycaemic control using the glucagon‐like peptide‐1 analogue liraglutide for 16 weeks modifies apoC‐III dynamics.\ud Materials and Methods:\ud \ud Postprandial apoC‐III kinetics were assessed after a bolus injection of [5,5,5‐2H3]leucine using ultrasensitive mass spectrometry techniques. We compared apoC‐III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non‐diabetic subjects. Liver fat content, subcutaneous abdominal and intra‐abdominal fat were determined using proton magnetic resonance spectroscopy.\ud Results:\ud \ud Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC‐III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC‐III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC‐III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC‐III secretion rate was higher in subjects with type 2 diabetes compared with BMI‐matched non‐diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042).\ud Conclusions:\ud \ud The results reveal that the secretion rate of apoC‐III is associated with elevation of triglyceride‐rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC‐III.

Aims Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or beta-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.

English summary

IF 10.5; International audience; To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

AIMS An independent, powerful coronary heart disease (CHD) predictor is a low level of high-density lipoprotein cholesterol (HDL-C). Discoidal preβ-HDL particles and large HDL2 particles are the primary cholesterol acceptors in reverse cholesterol transport, a key anti-atherogenic HDL mechanism. The quality of HDL subspecies may provide better markers of HDL functionality than does HDL-C alone. We aimed I) to study whether alterations in the HDL subspecies profile exist in low-HDL-C subjects II) to explore the relationship of any changes in HDL subspecies profile in relation to atherosclerosis and metabolic syndrome; III) to elucidate the impact of genetics and acquired obesity on HDL subspecies distribution. SUBJECTS The study consisted of 3 cohorts: A) Finnish families with low HDL-C and premature CHD (Study I: 67 subjects with familial low HDL-C and 64 controls; Study II: 83 subjects with familial low HDL-C, 65 family members with normal HDL-C, and 133 controls); B) a cohort of 113 low- and 133 high-HDL-C subjects from the Health 2000 Health Examination Survey carried out in Finland (Study III); and C) a Finnish cohort of healthy young adult twins (52 monozygotic and 89 dizygotic pairs) (Study IV). RESULTS AND CONCLUSIONS The subjects with familial low HDL-C had a lower preβ-HDL concentration than did controls, and the low-HDL-C subjects displayed a dramatic reduction (50-70%) in the proportion of large HDL2b particles. The subjects with familial low HDL-C had increased carotid atherosclerosis measured as intima-media-thickness (IMT), and HDL2b particles correlated negatively with IMT. The reduction in both key cholesterol acceptors, preβ-HDL and HDL2 particles, supports the concept of impaired reverse cholesterol transport contributing to the higher CHD risk in low-HDL-C subjects. The family members with normal HDL-C and the young adult twins with acquired obesity showed a reduction in large HDL2 particles and an increase in small HDL3 particles, which may be the first changes leading to the lowering of HDL-C. The low-HDL-C subjects had a higher serum apolipoprotein E (apoE) concentration, which correlated positively with the metabolic syndrome components (waist circumference, TG, and glucose), highlighting the need for a better understanding of apoE metabolism in human atherosclerosis. In the twin study, the increase in small HDL3b particles was associated with obesity independent of genetic effects. The heritability estimate, of 73% for HDL-C and 46 to 63% for HDL subspecies, however, demonstrated a strong genetic influence. These results suggest that the relationship between obesity and lipoproteins depends on different elements in each subject. Finally, instead of merely elevating HDL-C, large HDL2 particles and discoidal preβ-HDL particles may provide beneficial targets for HDL-targeted therapy. Pieni HDL-kolesterolin määrä on sepelvaltimotaudin vaaratekijä. Monimuotoiset HDL-hiukkaset suojaavat verisuonia mm. kuljettaen ylimääräistä kolesterolia soluista maksaan. HDL-hiukkasten jakauma ja laatu saattavat vaikuttaa siihen, miten hyvin HDL-hiukkaset suojaavat sepelvaltimotaudilta. Tämän tutkimuksen tavoitteet olivat selvittää I) onko henkilöillä, joilla on matala HDL-kolesterolin pitoisuus, muutoksia HDL-hiukkasten jakaumassa, II) liittyvätkö mahdolliset muutokset valtimonkovettumatautiin ja metaboliseen oireyhtymään, III) perimän ja ylipainon vaikutus HDL-hiukkasten jakaumaan. Tutkimus koostui kolmesta kohortista: A) suomalaisista perheistä, joissa esiintyy matalaa HDL-kolesterolin pitoisuutta ja sepelvaltimotautia varhaisella iällä (osatutkimus I: 67 perheenjäsentä, joilla on matala HDL-kolesterolin pitoisuus sekä 64 tervettä verrokkia, osatutkimus II: 83 perheenjäsentä, joilla on matala HDL-kolesterolin pitoisuus, 65 perheenjäsentä, joilla on normaali HDL-kolesterolin pitoisuus, sekä 133 tervettä verrokkia), B) suomalaisesta Terveys 2000 tutkimuksesta (113 henkilöä, joilla on matala HDL-kolesterolin pitoisuus ja 133 henkilöä, joilla on korkea HDL-kolesterolin pitoisuus), C) suomalaisista, nuorista aikuisista kaksosista (52 identtistä ja 89 epäidenttistä paria). Tutkimuksessa todettiin, että henkilöillä, joilla on perinnöllinen matala HDL-kolesterolin pitoisuus, on verrokkeihin nähden pienempi kiekkomaisten preβ-HDL-hiukkasten pitoisuus. Isojen, pyöreiden HDL2b-hiukkasten suhteellinen määrä oli huomattavasti pienentynyt (50-70%) ja pienten HDL3-hiukkasten osuus suurentunut henkilöillä, joilla on matala HDL-kolesterolin pitoisuus. Henkilöillä, joilla on perinnöllinen matala HDL-kolesterolin pitoisuus, kaulavaltimoiden seinämät olivat paksuuntuneet heijastaen heidän sepelvaltimotautiriskiään. HDL2b-hiukkasten osuus oli käänteisesti yhteydessä kaulavaltimoiden seinämäpaksuuteen. HDL2b- ja preβ-HDL-hiukkaset ovat ensisijaisia kolesterolin vastaanottajia soluista maksaan. Tulos niiden vähentymisestä tukee käsitystä siitä, että henkilöillä, joilla on matala HDL-kolesterolin pitoisuus, kolesterolin kuljetus soluista maksaan on heikentynyt johtaen suurentuneeseen sepelvaltimotaudin riskiin. Myös perheenjäsenillä, joilla HDL-kolesterolin pitoisuus oli normaali, HDL2b-hiukkasten osuus oli pienentynyt ja HDL3-hiukkasten osuus suurentunut verrokkeihin nähden. Samanlainen muutos HDL-hiukkasten jakaumassa nähtiin ylipainoisilla, nuorilla aikuisilla kaksosilla normaalipainoisiin kaksosiin nähden. HDL2-hiukkasten osuuden vähenemä saattaakin olla ensimmäinen muutos, joka johtaa HDL-kolesterolin pitoisuuden pienenemiseen. Kaksostutkimuksessa havaittiin, että sekä ylipaino että perinnölliset tekijät vaikuttavat HDL-hiukkasten jakaumaan. Terveys 2000 tutkimuksessa matalan HDL-kolesterolin pitoisuuden henkilöillä seerumin kohonnut apolipoproteiini E:n (apoE) pitoisuus oli yhteydessä metabolisen oireyhtymään (suurentuneeseen vyötärönympäryyteen, triglyseridipitoisuuteen ja verensokeriin). Lisäksi HDL-hiukkasten apoE-jakauma oli heillä muuntunut. Tulos valotti aiemmin niukasti tunnettua apoE:n roolia HDL:n aineenvaihdunnassa. Tutkimuksen tulokset viittaavat siihen, että uusia HDL-kolesteroliin vaikuttavia lääkehoitoja kehitettäessä on tärkeää ottaa huomioon niiden vaikutus HDL-hiukkasten jakaumaan.