Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Les abus commis par ceux qui devraient aider: prévention et post-prévention du Professional Sexual Misconduct grâce à un travail d’information

Durch die Arbeit der Initiative Misbruik door Hulpverleners (MdH, Missbrauch durch Hilfeleistende), die sich hauptsächlich auf den psychotherapeutischen und psychiatrischen Bereich des Gesundheitswesens konzentriert, war es innerhalb der letzten drei Jahre möglich, mehr Einblick in die Problematik des „professional sexual misconduct“ (PSM, berufliches sexuelles Fehlverhalten) zu erwerben. Dieser Artikel nennt die Ziele, die MdH sich gestellt hat, vor allem Aufklärungsarbeit anzubieten, gerichtet auf Prävention und Postprävention von PSM. Weiterhin hat sich MdH zur Aufgabe gemacht, Unterstützung und Begleitung für Opfer von PSM anzubieten. Die Erfahrungen zeigen, dass vor allem fehlende Fachkenntnisse bei Organisationen, die mit Fällen von PSM in Kontakt kommen, der nötigen (Post-)Prävention im Wege stehen. Der Artikel schlägt auch einige Lösungen vor. Darüber hinaus wird deutlich, dass das Bestehen von MdH notwendig ist und dass die Initiative einen positiven Beitrag leistet. Dieser Artikel soll deutschsprachige Länder über unsere Initiative informieren, und er möchte sie einladen, auch einen Beitrag zur Prävention zu leisten.Schlüsselworte (Sexueller) Missbrauch; Hilfeleistende; Prävention; Öffentlichkeit; Disziplinarbehörden; Wissenschaftliche StudienThrough the work carried out by the initiative of Misbruik door Hulpverleners (MdH, abuse by caregivers), which primarily deals with professional sexual misconduct (PSM) within the mental health sector, over the past three years it has been possible to gain further insight into PSM. The article offers insight into the aims formulated by MdH. A primary goal is to offer educational material towards the prevention and aftercare of PSM. A further task of the initiative is to offer support and guidance for victims. From experience gained in the field, it appears that the main problem standing in the way of prevention and intervention concerns a lack of expertise by organizations that deal with PSM. The article offers some solutions to this problem. Furthermore, a number of positive changes and events are described in the article which demonstrate the necessity of MdH and the positive contribution it offers. This article means to inform about our initiative and to encourage the setup of similar initiatives that will inform people about the problem of PSM and help towards the prevention of PSM in the future.Keywords (Sexual) abuse; Helper; Prevention; Public; Institution; Scientific research.Le travail accompli par le groupe « initiative MdH » (misbruik door hulpverleners), concentré essentiellement sur le domaine psychothérapeutique et psychiatrique de la santé publique, a permis ces trois dernières années d'en savoir plus sur le problème du Professional Sexual Misconduct (les abus sexuels commis par des professionnels, PSM). Dans le présent article, nous présentons les objectifs que la MdH s'est fixés ; il s'agit avant tout d'accomplir un travail d'information axé sur la prévention et la post-prévention du PSM. L'initiative s'est en outre donné pour tâche de soutenir et d'accompagner les victimes de PSM.La démarche d'information est menée au niveau de tous les médias. Une aide aux victimes est également offerte. Dans ce sens, les prestations mises en place par la MdH sont aisément accessibles à tous.Les expériences acquises montrent qu'un nombre relativement important de soignants (au sens large) souffrent d'importants troubles psychiques et/ou psychosexuels issus de problèmes narcissiques devant être considérés comme sérieux. En même temps, en règle générale ces personnes se rendent coupables sans que des symptômes spécifiques soient manifestes pour leur environnement. C'est pourquoi il arrive souvent que les institutions sociales évaluent mal le problème. Un bref exemple extrait de la presse belge sert à illustrer cet aspect.Les membres de la MdH ont constaté que les autorités disciplinaires ne disposent souvent pas du savoir spécialisé requis ; ils vont même jusqu'à prétendre que, dans certains cas, ces autorités couvrent les coupables, ce qui provoque bien sûr des problèmes supplémentaires aux personnes qui recherchent de l'aide.Les expériences faites dans le cadre de la MdH au niveau de l'offre d'une thérapie ultérieure montrent que seul un petit nombre de professionnels concernés peuvent en bénéficier.Il    s'avère que c'est surtout le manque de connaissances des organisations confrontées à des cas de PSM qui se pose en obstacle à la démarche de (post-)prévention requise. Nous proposons quelques solutions dans notre article. Il reste que, de toute évidence, il faut que la MdH continue à intervenir et qu'elle apporte une contribution positive. Nous souhaitions diffuser des informations sur ce thème dans les pays de langue allemande et y inviter les responsables à apporter une contribution à la prévention

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Genetic studies of body mass index yield new insights for obesity biology

Note: A full list of authors and affiliations appears at the end of the article. Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.</p