Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity.

Dairy products and the metabolic syndrome in a prospective study, DESIR.

Objective: In previous cross-sectional analyses of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, we have found inverse associations between dairy product consumption and metabolic syndrome (MetS) traits. We have now analyzed in a prospective way the influence of dairy product and calcium consumption at inclusion on the 9-year cumulative incidence of the MetS and associated traits in the French prospective study with a 9-year follow-up, DESIR.

Methods: After exclusion of diabetic subjects and those being on a diet at inclusion, 3417 men and women who completed a food frequency at baseline could be studied.

New gene functions in megakaryopoiesis and platelet formation.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment.

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

Influence of hyperinsulinemia and insulin resistance on in vivo β-cell function: their role in human β-cell dysfunction.

Objective: Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR).

Research Design And Methods: Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study.

[Age and sex variations of HbA(1C) in a French population without known diabetes aged 6 to 79 years].

HbA(1C) is being used for screening and diagnosing diabetes. We determined mean values of HbA(1C) according to age and sex in a large population without known diabetes, in a wide age range 6-79  years. 5,138 men and women without known diabetes aged 6-79  years participated in a routine health examination provided by their medical insurance.

Low water intake and risk for new-onset hyperglycemia.

Objective: Water intake alters vasopressin secretion. Recent findings reveal an independent association between plasma copeptin, a surrogate for vasopressin, and risk of diabetes.

Research Design And Methods: Participants were 3,615 middle-aged men and women, with normal baseline fasting glycemia (FG), who were recruited in a 9-year follow-up study.

Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept.

Aims/hypothesis: Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population.

Methods: Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.

Effects of genetic susceptibility for type 2 diabetes on the evolution of glucose homeostasis traits before and after diabetes diagnosis: data from the D.E.S.I.R. Study.

Objective: To assess the impact of genetic susceptibility on evolution toward type 2 diabetes (T2D) by analyzing time trajectories of fasting glucose, glycated hemoglobin (HbA(1c)), insulin sensitivity (homeostasis model assessment [HOMA2%S]), and β-cell secretion (HOMA2%B) in a large nondiabetic cohort. We also examined whether baseline HbA(1c) modified the effect of genetic predisposition on the time trajectories.

Research Design And Methods: Time trajectories were drawn in 4,744 participants from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.

Gender-specific differences in carotid intima-media thickness and its progression over three years: a multicenter European study.

Background And Aims: This multicentre European study evaluated, in a young-to-middle-aged healthy population without carotid atherosclerosis, the gender-related differences in carotid intima-media thickness (IMT) and its short-term (3-year) progression, and whether these differences are related to different vascular ageing rate, cardiovascular risk profile or different susceptibility to family predisposition to cardiovascular diseases (CVD).

Methods And Results: 366 men and 422 women (age between 30 and 60 years) underwent B-mode carotid ultrasound at baseline and after 3-year follow-up period. IMT in 3 carotid segments was higher in men than in women (p < 0.

Comparing incident diabetes as defined by fasting plasma glucose or by HbA(1c). The AusDiab, Inter99 and DESIR studies.

Aim: We examined the ability of fasting plasma glucose and HbA(1c) to predict 5-year incident diabetes for an Australian cohort and a Danish cohort and 6-year incident diabetes for a French cohort, as defined by the corresponding criteria.

Methods: We studied 6025 men and women from AusDiab (Australian), 4703 from Inter99 (Danish) and 3784 from DESIR (French), not treated for diabetes and with fasting plasma glucose < 7.0 mmol/l and HbA(1c) < 48 mmol/mol (6.

Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort.

It was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.

Association of sirtuin 1 (SIRT1) gene SNPs and transcript expression levels with severe obesity.

Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI >40 kg/m(2) and 637 children, BMI >97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians.

Factors influencing endothelial function in healthy pre- and post-menopausal women of the EU-RISC study.

Background: We studied the impact of lifestyle, body composition, different insulin sensitivity indices and the first insulin response in healthy pre- and post-menopausal women with a low cardiovascular risk profile (the EU-RISC study, 'Relationship between Insulin Sensitivity and Cardiovascular Disease' (n = 51, 47 ± 4 years, body mass index 23.6 ± 3.7 kg/m(2), waist girth 79.

HbA1c, fasting plasma glucose and the prediction of diabetes: Inter99, AusDiab and D.E.S.I.R.

Introduction: With diabetes defined by HbA1c≥6.5% and/or FPG≥7.0mmol/l and/or diabetes treatment, we investigated HbA1c and fasting plasma glucose (FPG) thresholds/change-points above which the incidence of diabetes increases.

High blood pressure and obesity: disparities among four French Overseas Territories.

Background And Purpose: The epidemiological characteristics of hypertension and obesity in French Overseas Territories (FOTs) have never been compared.

Methods: This cross-sectional survey included representative population-based samples of 602, 601, 620 and 605 men and women aged more than 15 years, respectively, from four FOTs of Guadeloupe, Martinique, French Guiana, and French Polynesia. Hypertension was defined as blood pressure (BP) at least 140/90 mmHg or the current use of antihypertensive treatment.

Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study.

Aims/hypothesis: Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes.

Number of children and change in markers of metabolic health over 9-years in men and women. Data from the DESIR study.

Aim: Parity is associated with an increased risk of coronary heart disease and type 2 diabetes, possibly mediated by long-term modification of metabolic health. Studying associations between the number of children with health and disease in men in addition to women allows for differentiation between the social and lifestyle influences of child-rearing, and the biological influences of childbearing. We sought to determine whether the number of children is associated with the incidence of raised fasting glucose (fasting plasma glucose≥6.

Liver iron overload is associated with elevated SHBG concentration and moderate hypogonadotrophic hypogonadism in dysmetabolic men without genetic haemochromatosis.

Aims: To assess the relation between moderate iron overload on sex hormone binding globulin (SHBG) levels and gonadotroph function in men with dysmetabolic iron overload syndrome and the effects of phlebotomy.

Methods: The relationship between magnetic resonance imaging assessed liver iron concentration (LIC) and plasma ferritin levels with total testosterone, bioavailable testosterone (BT), SHBG and LH levels, were studied in 50 men with moderate dysmetabolic iron excess, in the absence of genetic haemochromatosis, who were randomised to phlebotomy therapy or to normal care.

Results: Four patients (8%) had low total testosterone (<10.

Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study.

Objective: Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes.

Research Design And Methods: In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose).

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study.

Context: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-γ (PPARγ) is known to modulate body mass index (BMI) and T2D risk.

Objective: Our aim was to study the interaction effect between PPARγ gene (PPARG) polymorphisms Pro12Ala and 1431C>T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.

Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women.

Objective: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration.

Research Design And Methods: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals.

Predicting CHD risk in France: a pooled analysis of the D.E.S.I.R., Three City, PRIME, and SU.VI.MAX studies.

Background: We aimed to develop and validate a simple coronary heart disease (CHD) risk algorithm applicable to asymptomatic men and women in France, and to compare its accuracy with that of the last published version of the Framingham risk function for cardiovascular disease.

Design: A pooled analysis of four French prospective general-population studies.

Methods: The baseline and follow-up data from D.

Dairy consumption and the incidence of hyperglycemia and the metabolic syndrome: results from a french prospective study, Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR).

Objective: In the French Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, cross-sectional analyses have shown that a higher consumption of dairy products and calcium are associated with a lower prevalence of the metabolic syndrome (MetS). We assess the influence of dairy products on 9-year incident MetS and on impaired fasting glycemia and/or type 2 diabetes (IFG/T2D).

Research Design And Methods: Men and women who completed a food frequency questionnaire at baseline and after 3 years were studied (n = 3,435).