Insulin-secreting beta-cell dysfunction induced by human lipoproteins.

Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDL-induced apoptosis of beta-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.

Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial.

OBJECTIVE: Impaired endothelial function was demonstrated in HIV-infected persons on protease inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. This study determined whether endothelial function improves after switching from other PI to atazanavir. DESIGN: Randomised, observer-blind, treatment-controlled trial. SETTING: Three university-based outpatient clinics. PATIENTS: 39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting low-density lipoprotein (LDL)-cholesterol greater than 3 mmol/l. INTERVENTION: Patients were randomly assigned to continue the current PI or change to unboosted atazanavir. MAIN OUTCOME MEASURES: Endpoints at week 24 were endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery, lipid profiles and serum inflammation and oxidative stress parameters. RESULTS: Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9% (SD 1.8) on atazanavir versus 4.0% (SD 1.5) in controls). After 24 weeks' treatment, FMD decreased to 3.3% (SD 1.4) and 3.4% (SD 1.7), respectively (all p = ns). Total cholesterol improved in both groups (p<0.0001 and p = 0.01, respectively) but changes were more pronounced on atazanavir (p = 0.05, changes between groups). High-density lipoprotein and triglyceride levels improved on atazanavir (p = 0.03 and p = 0.003, respectively) but not in controls. Serum inflammatory and oxidative stress parameters did not change; oxidised LDL improved significantly in the atazanavir group. CONCLUSIONS: The switch from another PI to atazanavir in treatment-experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Atherogenic lipid profiles and direct effects of antiretroviral drugs on the endothelium may affect vascular function. Trial registration number: NCT00447070.

Prevalence, awareness and control of diabetes in the Seychelles and relationship with excess body weight.

BACKGROUND: The evidence for a "diabesity" epidemic is accumulating worldwide but population-based data are still scarce in the African region. We assessed the prevalence, awareness and control of diabetes (DM) in the Seychelles, a rapidly developing country in the African region. We also examined the relationship between body mass index, fasting serum insulin and DM. METHODS: Examination survey in a sample representative of the entire population aged 25-64 of the Seychelles, attended by 1255 persons (participation rate of 80.2%). An oral glucose tolerance test (OGTT) was performed in individuals with fasting blood glucose between 5.6 and 6.9 mmol/l. Diabetes mellitus (DM), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were defined along criteria of the ADA. Prevalence estimates were standardized for age. RESULTS: The prevalence of DM was 11.5% and 54% of persons with DM were aware of having DM. Less than a quarter of all diabetic persons under treatment were well controlled for glycemia (HbA1c), blood pressure or LDL-cholesterol. The prevalence of IGT and IFG were respectively 10.4% and 24.2%. The prevalence of excess weight (BMI > or = 25 kg/m2) and obesity (BMI > or = 30 kg/m2) was respectively 60.1% and 25.0%. Half of all DM cases in the population could be attributed to excess weight. CONCLUSION: We found a high prevalence of DM and pre-diabetes in a rapidly developing country in the African region. The strong association between overweight and DM emphasizes the importance of weight control measures to reduce the incidence of DM in the population. High rates of diabetic persons not aware of having DM in the population and insufficient cardiometabolic control among persons treated for DM stress the need for intensifying health care for diabetes.

Pharmacist interventions to improve cardiovascular disease risk factors in diabetes: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This systematic review and meta-analysis of randomized controlled trials (RCTs) assesses the effect of pharmacist care on cardiovascular disease (CVD) risk factors among outpatients with diabetes. RESEARCH DESIGN AND METHODS: MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched. Pharmacist interventions were classified, and a meta-analysis of mean changes of blood pressure (BP), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BMI was performed using random-effects models. RESULTS: The meta-analysis included 15 RCTs (9,111 outpatients) in which interventions were conducted exclusively by pharmacists in 8 studies and in collaboration with physicians, nurses, dietitians, or physical therapists in 7 studies. Pharmacist interventions included medication management, educational interventions, feedback to physicians, measurement of CVD risk factors, or patient-reminder systems. Compared with usual care, pharmacist care was associated with significant reductions for systolic BP (12 studies with 1,894 patients; -6.2 mmHg [95% CI -7.8 to -4.6]); diastolic BP (9 studies with 1,496 patients; -4.5 mmHg [-6.2 to -2.8]); TC (8 studies with 1,280 patients; -15.2 mg/dL [-24.7 to -5.7]); LDL cholesterol (9 studies with 8,084 patients; -11.7 mg/dL [-15.8 to -7.6]); and BMI (5 studies with 751 patients; -0.9 kg/m(2) [-1.7 to -0.1]). Pharmacist care was not associated with a significant change in HDL cholesterol (6 studies with 826 patients; 0.2 mg/dL [-1.9 to 2.4]). CONCLUSIONS: This meta-analysis supports pharmacist interventions-alone or in collaboration with other health care professionals-to improve major CVD risk factors among outpatients with diabetes.

Diabetes and pre-diabetes are associated with cardiovascular risk factors and carotid/femoral intima-media thickness independently of markers of insuline resistance and adiposity

Background Impaired glucose regulation (IGR) is associated with detrimental cardiovascular outcomes such as cardiovascular disease risk factors (CVD risk factors) or intima-media thickness (IMT). Our aim was to examine whether these associations are mediated by body mass index (BMI), waist circumference (waist) or fasting serum insulin (insulin) in a population in the African region. Methods Major CVD risk factors (systolic blood pressure, smoking, LDL-cholesterol, HDL-cholesterol,) were measured in a random sample of adults aged 25-64 in the Seychelles (n=1255, participation rate: 80.2%). According to the criteria of the American Diabetes Association, IGR was divided in four ordered categories: 1) normal fasting glucose (NFG), 2) impaired fasting glucose (IFG) and normal glucose tolerance (IFG/NGT), 3) IFG and impaired glucose tolerance (IFG/IGT), and 4) diabetes mellitus (DM). Carotid and femoral IMT was assessed by ultrasound (n=496). Results Age-adjusted levels of the major CVD risk factors worsened gradually across IGR categories (NFG < IFG/NGT < IFG/IGT < DM), particularly HDL-cholesterol and blood pressure (p for trend <0.001). These relationships were marginally attenuated upon further adjustment for waist, BMI or insulin (whether considered alone or combined) and most of these relationships remained significant. With regards to IMT, the association was null with IFG/NGT, weak with IFG/IGT and stronger with DM (all more markedly at femoral than carotid levels). The associations between IMT and IFG/IGT or DM (adjusted by age and major CVD risk factors) decreased only marginally upon further adjustment for BMI, waist or insulin. Further adjustment for family history of diabetes did not alter the results. Conclusions We found graded relationships between IGR categories and both major CVD risk factors and carotid/femoral IMT. These relationships were only partly accounted for by BMI, waist and insulin. This suggests that increased CVD-risk associated with IGR is also mediated by factors other than the considered markers of adiposity and insulin resistance. The results also imply that IGR and associated major CVD risk factors should be systematically screened and appropriately managed.

Mécanismes moléculaires de l'homodimérisation de la protéine Scaffold IB1 et son implication dans la sécrétion d'insuline

RÉSUMÉ Les kinases activées par des mitogènes (MAPKs) constituent une importante famille d'enzymes conservée dans l'évolution. Elles forment un réseau de signalisation qui permet à la cellule de réguler spécifiquement divers processus impliqués dans la différenciation, la survie ou l'apoptose. Les kinases formant le module MAPK sont typiquement disposées en cascades de trois partenaires qui s'activent séquentiellement par phosphorylation. Le module minimum est constitué d'une MAPK kinase kinase (MAPKKK), d'une MAPK kinase (MAPKK) et d'une MAPK. Une fois activée, la MAPK phosphoryle différents substrats tels que des facteurs de transcription ou d'autres protéines. Chez les mammifères, trois groupes principaux de MAPKs ont été identifiés. Il s'agit du groupe des kinases régulées par des signaux extracellulaires du type «mitogènes » (ERK), ainsi que des groupes p38 et cJun NH2-terminal kinase (JNK), ou SAPK pour stress activated protein kinase, plutôt activées par des stimuli de type «stress ». De nombreuses études ont impliqué JNK dans la régulation de différents processus physiologiques et pathologiques, comme le diabète, les arthrites rhumatoïdes, l'athérosclérose, l'attaque cérébrale, les maladies de Parkinson et d'Alzheimer. JNK, en particulier joue un rôle dans la mort des cellules sécrétrices d'insuline induite par l'interleukine (IL)-1 β, lors du développement du diabète de type 1. IB1 est une protéine scaffold (échafaud) qui participe à l'organisation du module de JNK. IB1 est fortement exprimée dans les neurones et les cellules β du pancréas. Elle a été impliquée dans la survie des cellules, la régulation de l'expression du transporteur du glucose de type 2 (Glut-2) et dans le processus de sécrétion d'insuline glucose-dépendante. IBl est caractérisée par plusieurs domaines d'interaction protéine-protéine : un domaine de liaison à JNK (JBD), un domaine homologue au domaine 3 de Src (SH3) et un domaine d'interaction avec des tyrosines phosphorylées (PID). Des partenaires d'IB1, incluant les membres de la familles des kinases de lignée mélangée (MLKs), la MAPKK MKK7, la phosphatase 7 des MAPKs (MKP-7) ainsi que la chaîne légère de la kinésine, ont été isolés. Tous ces facteurs, sauf les MLKs et MKK7 interagissent avec le domaine PID ou l'extrême partie C-terminale d'IBl (la chaîne légère de la kinésine). Comme d'autres protéines scaffolds déjà décrites, IBl et un autre membre de la famille, IB2, sont capables d'homo- et d'hétérodimériser. L'interaction a lieu par l'intermédiaire de leur région C-terminale, contenant les domaines SH3 et PID. Mais ni le mécanisme moléculaire, ni la fonction de la dimérisation n'ont été caractérisés. Le domaine SH3 joue un rôle central lors de l'assemblage de complexes de macromolécules impliquées dans la signalisation intracellulaire. Il reconnaît de préférence des ligands contenant un motif riche en proline de type PxxP et s'y lie. Jusqu'à maintenant, tous les ligands isolés se liant à un domaine SH3 sont linéaires. Bien que le domaine SH3 soit un domaine important de la transmission des signaux, aucun partenaire interagissant spécifiquement avec le domaine SH3 d'IB1 n'a été identifié. Nous avons démontré qu'IBl homodimérisait par un nouveau set unique d'interaction domaine SH3 - domaine SH3. Les études de cristallisation ont démontré que l'interface recouvrait une région généralement impliquée dans la reconnaissance classique d'un motif riche en proline de type PxxP, bien que le domaine SH3 d'IB1 ne contienne aucun motif PxxP. L'homodimère d'IB1 semble extrêmement stable. Il peut cependant être déstabilisé par trois mutations ponctuelles dirigées contre des résidus clés impliqués dans la dimérisation. Chaque mutation réduit l'activation basale de JNK dépendante d'IB 1 dans des cellules 293T. La déstabilisation de la dimérisation induite par la sur-expression du domaine SH3, provoque une diminution de la sécrétion d'insuline glucose dépendant. SUMMARY Mitogen activated kinases (MAPK) are an important and conserved enzyme family. They form a signaling network required to specifically regulate process involved in cell differentiation, proliferation or death. A MAPK module is typically organized in a threekinase cascade which are activated by sequential phosphorylation. The MAPK kinase kinase (MAPKKK), the MAPK kinase (MAPKK) and the MAPK constitute the minimal module. Once activated, the MAPK phosphorylates its targets like transcription factors or other proteins. In mammals, three major groups of MAPKs have been identified : the group of extra-cellular regulated kinase (ERK) which is activated by mitogens and the group of p38 and cJun NH2-terminal kinase (JNK) or SAPK for stress activated protein kinase, which are activated by stresses. Many studies implicated JNK in many physiological or pathological process regulations, like diabetes, rheumatoid arthritis, arteriosclerosis, strokes or Parkinson and Alzheimer disease. In particular, JNK plays a crucial role in pancreatic β cell death induced by Interleukin (IL)-1 β in type 1 diabetes. Islet-brain 1 (IB 1) is a scaffold protein that interacts with components of the JNK signal-transduction pathway. IB 1 is expressed at high levels in neurons and in pancreatic β-cells, where it has been implicated in cell survival, in regulating expression of the glucose transporter type 2 (Glut-2) and in glucose-induced insulin secretion. It contains several protein-protein interaction domains, including a JNK-binding domain (JBD), a Src homology 3 domain (SH3) and a phosphotyrosine interaction domain (PID). Proteins that have been shown to associate with IB 1 include members of the Mixed lineage kinase family (MLKs), the MAPKK MKK7, the MAPK phosphatase-7 MKP7, as well as several other ligands including kinesin light chain, LDL receptor related family members and the amyloid precursor protein APP. All these factors, except MLK3 and MKK7 have been shown to interact with the PID domain or the extreme C-terminal part (Kinesin light chain) of IB 1. As some scaffold already described, IB 1 and another member of the family, IB2, have previously been shown to engage in oligomerization through their respective C-terminal regions that include the SH3 and PID domains. But neither the molecular mechanisms nor the function of dimerization have yet been characterized. SH3 domains are central in the assembly of macromolecular complexes involved in many intracellular signaling pathways. SH3 domains are usually characterized by their preferred recognition of and association with canonical PxxP motif. In all these cases, a single linear sequence is sufficient for binding to the SH3 domain. However, although SH3 domains are important elements of signal transduction, no protein that interacts specifically with the SH3 domain of IB 1 has been identified so far. Here, we show that IB 1 homodimerizes through a navel and unique set of SH3-SH3 interactions. X-ray crystallography studies indicate that the dieter interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB 1 SH3 domain lacks this motif. The highly stable IB 1 homodimer can be significantly destabilized in vitro by individual point-mutations directed against key residues involved in dimerization. Each mutation reduces IB 1-dependent basal JNK activity in 293T cells. Impaired dimerization induced by over-expression of the SH3 domain also results in a significant reduction in glucose-dependent insulin secretion in pancreatic β-cells.

Expected impact of applying new 2013 AHA/ACC cholesterol guidelines criteria on the recommended lipid target achievement after acute coronary syndromes.

BACKGROUND: 2013 AHA/ACC guidelines on the treatment of cholesterol advised to tailor high-intensity statin after ACS, while previous ATP-III recommended titration of statin to reach low-density lipoprotein cholesterol (LDL-C) targets. We simulated the impact of this change of paradigm on the achievement of recommended targets. METHODS: Among a prospective cohort study of consecutive patients hospitalized for ACS from 2009 to 2012 at four Swiss university hospitals, we analyzed 1602 patients who survived one year after recruitment. Targets based on the previous guidelines approach was defined as (1) achievement of LDL-C target < 1.8 mmol/l, (2) reduction of LDL-C ≥ 50% or (3) intensification of statin in patients who did not reach LDL-C targets. Targets based on the 2013 AHA/ACC guidelines approach was defined as the maximization of statin therapy at high-intensity in patients aged ≤75 years and moderate- or high-intensity statin in patients >75 years. RESULTS: 1578 (99%) patients were prescribed statin at discharge, with 1120 (70%) at high-intensity. 1507 patients (94%) reported taking statin at one year, with 909 (57%) at high-intensity. Among 482 patients discharged with sub-maximal statin, intensification of statin was only observed in 109 patients (23%). 773 (47%) patients reached the previous LDL-C targets, while 1014 (63%) reached the 2013 AHA/ACC guidelines targetsone year after ACS (p value < 0.001). CONCLUSION: The application of the new 2013 AHA/ACC guidelines criteria would substantially increase the proportion of patients achieving recommended lipid targets one year after ACS. Clinical trial number, NCT01075868.

Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets.

BACKGROUND: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. METHODS: We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). FINDINGS: HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman's correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=-0.59, p=0.0065) insulin sensitivity. CONCLUSIONS: Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Referral from primary care to a physical activity programme: establishing long-term adherence? A randomized controlled trial. Rationale and study design

Background: Declining physical activity is associated with a rising burden of global disease. There is little evidence about effective ways to increase adherence to physical activity. Therefore, interventions are needed that produce sustained increases in adherence to physical activity and are cost-effective. The purpose is to assess the effectiveness of a primary care physical activity intervention in increasing adherence to physical activity in the general population seen in primary care. Method and design: Randomized controlled trial with systematic random sampling. A total of 424 subjects of both sexes will participate; all will be over the age of 18 with a low level of physical activity (according to the International Physical Activity Questionnaire, IPAQ), self-employed and from 9 Primary Healthcare Centres (PHC). They will volunteer to participate in a physical activity programme during 3 months (24 sessions; 2 sessions a week, 60 minutes per session). Participants from each PHC will be randomly allocated to an intervention (IG) and control group (CG). The following parameters will be assessed pre and post intervention in both groups: (1) health-related quality of life (SF-12), (2) physical activity stage of change (Prochaska's stages of change), (3) level of physical activity (IPAQ-short version), (4) change in perception of health (vignettes from the Cooperative World Organization of National Colleges, Academies, and Academic Associations of Family Physicians, COOP/WONCA), (5) level of social support for the physical activity practice (Social Support for Physical Activity Scale, SSPAS), and (6) control based on analysis (HDL, LDL and glycated haemoglobin).Participants' frequency of visits to the PHC will be registered over the six months before and after the programme. There will be a follow up in a face to face interview three, six and twelve months after the programme, with the reduced version of IPAQ, SF-12, SSPAS, and Prochaska's stages. Discussion: The pilot study showed the effectiveness of an enhanced low-cost, evidence-based intervention in increased physical activity and improved social support. If successful in demonstrating long-term improvements, this randomised controlled trial will be the first sustainable physical activity intervention based in primary care in our country to demonstrate longterm adherence to physical activity. Trial Registration: A service of the U.S. National Institutes of Health. Developed by the National Library of Medicine. ClinicalTrials.gov ID: NCT00714831.

Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes.

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

Prise en charge du cholestérol pour prévenir le risque cardiovasculaire:recommandations américaines 2013.Prise de position du Groupe de travail Suisse Lipides et Athérosclérose (GSLA).

Les dernières recommandations américaines de l'American College of Cardiology et de l'American Heart Association proposent d'abaisser le seuil de prescription de statines pour la prévention cardiovasculaire primaire, et d'abandonner les cibles de LDL-cholestérol pour utiliser le plus souvent des statines de haute intensité. Le Groupe de travail Suisse Lipides et Athérosclérose (GSLA) pense que ces recommandations ne devraient pas être appliquées en Suisse, car elles augmenteraient très fortement le nombre de personnes à bas risque sous statines, chez qui le rapport bénéfice/risque au long cours est incertain, et pourraient diminuer l'importance du style de vie, première priorité dans la prévention cardiovasculaire primaire. En outre, l'abandon des cibles de LDL-cholestérol limite l'individualisation de la prise en charge quant au choix du type et du dosage de la statine, et pourrait diminuer l'adhérence thérapeutique. Pour ces raisons, le GSLA recommande de poursuivre avec les stratégies de prévention bien établies en Suisse et résumées dans les recommandations du GSLA 2012.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Rapid Improvement and Maintenance of the Lipid Profile After Roux-en-Y Gastric Bypass (RYGBP)

Background: Dyslipidemia, a major component of the metabolic syndrome and an important cardiovascular risk factor, is one of the commonest comorbidity associated with morbid obesity. The aim of this paper is to show that RYGBP markedly improves dyslipidemia and that this improvement maintains over time. Patients and Methods: Prospectively updated databank for bariatric patients. Patients undergoing RYGBP have yearly blood tests during follow-up. The results for lipids at one to five years were compared with preoperative values. Results: The mean excess BMI loss after one and five years was 77,9 % and 72,3%respectively. After one year, there was a significant reduction of the mean total cholesterol, LDL-cholesterol, total cholesterol/HDL ratio and triglyceride values, which maintained up to five years, and an increase of the HDL fraction, which progressed until five years. The proportion of patients with abnormal values decreased from 24,3 to 6,2% for total cholesterol, from 45,1 to 11,7 %for HDL, from 53,3 to 21,9 for LDL, and from 40,5 to 10 % for triglycerides, with no significant change between three and five years, despite some weight regain. Conclusions: RYGBP rapidly improves all components of dyslipidemia, and thereby reduces the overall cardiovascular risk in operated patients.

Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers.

24S- and 27-hydroxycholesterol are obligatory intermediates of cholesterol catabolism and play an important role in the maintenance of whole-body cholesterol homeostasis. Using an HPLC-MS method for oxysterol quantification, the distribution of esterified and unesterified oxysterols in lipoprotein subfractions as well as the influence of daytime, food intake and menstrual cycle on oxysterol concentrations were investigated in healthy volunteers. Moreover, reference intervals for 24S- and 27-hydroxycholesterol in plasma as well as the corresponding levels for 27-hydroxycholesterol in the HDL subfraction were established in 100 healthy volunteers. Both circulating oxysterols are mainly transported in association with HDL and LDL--primarily in the esterified form. No significant diurnal changes and no variations during menstrual cycle of either absolute or cholesterol-related plasma levels were detected. In contrast to 24S-hydroxycholesterol in plasma and 27-hydroxycholesterol in the HDL subfraction, the 95% reference intervals of 27-hydroxycholesterol both in plasma and the non-HDL subfraction were higher in males than in females. The concentrations of 27-hydroxycholesterol in plasma and the non-HDL subfraction showed strong positive correlations with the concentrations of cholesterol, non-HDL cholesterol and triglycerides. Our data on the lipoprotein distribution of oxysterols as well as on their intra- and inter-individual variation set the stage for future clinical studies.

A first population-based cohort study of risk factors of stroke mortality in Africa

Background: We are not aware of any population-based cohort study of risk factors of stroke in the African region. We conducted a longitudinal study in the Seychelles (Indian Ocean, east of Kenya), a middle-income island state with majority of the population of African descent. Data in Africa are important for international comparison and for advocacy in the region. Methods: Three population-based examination surveys were performed in 1989, 1994 and 2004 (n_1081, 1067, and 1255, respectively). Baseline data were linked with cause-specific mortality from vital statistics up to May 2007. We considered stroke (any type) as a cause of death if the diagnosis was reported in any of the 4 fields for underlying and concomitant causes of death. Results. Among the 3317 different persons aged 25-64 at baseline, 291 died including 58 with stroke during follow up (mean: 10.2 years). The prevalence of high blood pressure (BP _140/90 mmHg) was 38%. In multivariate Cox regression, stroke mortality was increased by 18% and 35% for a 10-mmHg increase in systolic, respectively diastolic BP (p_0.001). The hazard ratios were 2.4 (95% CI: 1.7-3.3) for a 10-year age increase, 0.32 (0.15- 0.67) for a 1-mmol HDL-cholesterol increase, 2.2 (1.1- 4.2) for smoking _5 cigarettes vs. no smoking and 1.7 for diabetes (0.93-3.3; p_0.08). No significant association was found for sex, LDL-cholesterol, alcohol intake, and occupation. Conclusion. This first populationbased cohort study in the African region demonstrates high mortality rates from stroke in middle-aged adults and confirms the important role of high BP. This emphasizes the critical importance of reducing BP and other modifiable risk factors in this population.