Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

<p>Abstract</p> <p>Background</p> <p>7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, <it>SGNE1 </it>is located. The aim of this study is to analyze associations of <it>SGNE1 </it>genetic variation with obesity and metabolism related quantitative traits.</p> <p>Methods</p> <p>We screened <it>SGNE1 </it>for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort.</p> <p>Results</p> <p>We did not find any association between <it>SGNE1 </it>SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort.</p> <p>Conclusion</p> <p><it>SGNE1 </it>genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.</p

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

Numerical acoustic modelling of a ventilation unit by 3D FEM and application to the design of an ANC feedforward system

Strong insulation in modern buildings and housing requires efficient ventilation systems. A popular solution is a decentralized system with one ventilation unit per room, but the noise emitted by such a unit then has a major impact on the comfort. In this research, it is intended to equip an existing ventilation unit with an active noise control (ANC) system to reduce its low-frequency noise emissions. The ANC system will be hosted in an additional duct deporting the air inlet aperture approximately one meter away from its original position. The one-channel feedforward ANC system has a reference microphone located between the fan and the anti-noise loudspeaker and an error microphone at the duct’s end. The transfer functions have been computed by a 3D FEM solver, between the fan and several reference and error microphone locations. Several combinations of reference/error microphone positions were then tested regarding the possible active attenuation of a white noise emitted by the primary source. Optimal control by the ANC controller was assumed, the optimal filter being computed with the help of the corresponding transfer functions. Theoretical attenuations were obtained and optimal positions were finally defined for the two microphones of the ANC system. The first results are finally discussed in this paper and raise some questions regarding the influence of the noise spectrum on the attenuations obtained.Silenthalpic (C7711

Numerical modelling and characterization of a heat exchanger

Strong insulation in modern building and housing requires efficient ventilation systems. A popular solution is a decentralized set-up with one ventilation unit per room. The noise emitted by a ventilation unit then has a major impact on the room comfort. In order to reduce the heat transfer to the outside, a ventilation unit is typically designed as a double flux-system with a heat exchanger. This exchanger has a noticeable impact on the acoustic behavior of the ventilation unit. It is therefore of interest to study its effect through numerical simulations. The numerical modelling of a realistic heat exchanger is presented in this paper. The exchanger is placed inside its ventilation casing and modelled using a double equivalent fluid homogenization. Unknown homogenization properties are retrieved in two steps. Acoustic transfer functions are first measured experimentally in order to characterize the propagation paths through the heat exchanger. In a second step, an optimization loop is computed with the numerical model of the heat exchanger. This allows to determine the homogenization properties fitting the measured transfer functions for each frequency. Finally the results for the characterized heat exchanger homogenization model are compared against measurement.Silenthalpic (C7711

Constantinople 1453 : des Byzantins aux Ottomans: textes et documents

International audienceÀ l’aube du 29 mai 1453, après un siège spectaculaire de presque deux mois, les troupes du sultan ottoman Mehmed II entraient dans Constantinople, mettant fin à l’empire millénaire de Byzance. Un monde basculait, et Constantinople devint capitale ottomane.L’événement fit à l’époque grande impression et fut par la suite surchargé de significations dans l’histoire universelle : on y voyait notamment, avec la consécration de la puissance ottomane, la fin du Moyen Âge et les débuts de l’époque moderne.Ce livre remet en perspective ce moment catalyseur, et de la façon la plus vivante qui soit : par les textes. Pour la première fois en français, il rassemble les sources grecques, ottomanes et occidentales, mises en contexte et éclairées à la lumière des derniers états de la recherche. Elles témoignent ensemble de la bataille, de ses suites immédiates et de sa postérité à plus long terme, jusque dans ses dimensions légendaires.À partir des points de vue les plus divers, ces textes de ton, de nature et d’origine très différents dévoilent ainsi toute la complexité de l’événement : une invitation à en repenser le sens

Genetic analysis of ADIPOR1 and ADIPOR2 candidate polymorphisms for type 2 diabetes in the Caucasian population.

Adiponectin is a metabolic link between adipose tissue and insulin action, mediating part of obesity-associated insulin resistance and type 2 diabetes. Two adiponectin receptors have been identified, and we investigated whether sequence variations in adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) genes could contribute to the genetic risk for type 2 diabetes in a case-control study of 1,498 Caucasian subjects. We sequenced the putative functional regions of the two genes in 48 subjects and selected single nucleotide polymorphisms (SNPs) from the public database. Five SNPs in ADIPOR1 and 12 in ADIPOR2 were tested for association with type 2 diabetes. No SNP of ADIPOR1 showed association in any of the samples from the French population. In contrast, three SNPs of ADIPOR2 showed nominal evidence for association with type 2 diabetes before correction for multiple testing (odds ratio [OR] 1.29-1.37, P = 0.034-0.014); only rs767870, located in intron 6, was replicated in an additional diabetes dataset (n = 636, OR 1.29, P = 0.020) with significant allelic association from the overall meta-analysis of 2,876 subjects (adjusted OR 1.25 [95% CI 1.07-1.45], P = 0.0051). In conclusion, our data suggest a modest contribution of ADIPOR2 variants in diabetes risk in the French population