New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

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

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Yarrowia lipolytica Extracellular Lipase Lip2 as Biocatalyst for the Ring-Opening Polymerization of ε-Caprolactone

Yarrowia lipolytica (YL) is a “non-conventional” yeast that is capable of producing important metabolites. One of the most important products that is secreted by this microorganism is lipase, a ubiquitous enzyme that has considerable industrial potential and can be used as a biocatalyst in the pharmaceutical, food, and environmental industries. In this work, Yarrowia lipolytica lipase (YLL) was immobilized on Lewatit and Amberlite beads and is used in the enzymatic ring-opening polymerization (ROP) of cyclic esters in the presence of different organic solvents. YLL immobilized on Amberlite XAD7HP had the higher protein adsorption (96%) and a lipolytic activity of 35 U/g. Lewatit VPOC K2629 has the higher lipolytic activity (805 U/g) and 92% of protein adsorption. The highest molecular weight (Mn 10,685 Da) was achieved at 90 °C using YLL that was immobilized on Lewatit 1026 with decane as solvent after 60 h and 100% of monomer conversion

Chemo-Enzymatic Syntheses of Polyester-Urethanes

9 páginas.-- Editores: H. N. Cheng y Richard A. Gross.The enzymatic synthesis of α-ω-telechelic polycaprolactone diols (HOPCLOH) and triblock copolymers was studied. Synthesis of α-ω-telechelic PCL diols was achieved by enzymatic ring opening polymerization with Yarrowia lipolytica lipase immobilized on a macroporous resin Lewatit VP OC 1026, and using diethylene glycol and poly(ethylene glycol) as initiators. Biodegradable linear polyester-urethanes were prepared from synthesized PCL diols and hexamethylenediisocyanate (HDI). Depending on the length of PCL in HOPCLOH, the polymers were amorphous or semicrystalline. Measured mechanical properties strongly depend upon the degree of crystallinity of HOPCLOH.Peer reviewe

Enzymatic ring-opening polymerization of ε-caprolactone by Yarrowia lipolytica lipase in ionic liquids

12 páginas, 17 figuras, 1 esquema, 2 tablas.Yarrowia lipolytica (YLL), Candida rugosa (CRL), and porcine pancreatic lipase (PPL) were employed successfully as catalysts in the enzymatic ring-opening polymerization (ROP) of ε-caprolactone in the presence of 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4]), 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), 1-butylpyridinium tetrafluoroborate ([BuPy][BF4]), 1-butylpyridinium trifluoroacetate ([BuPy][CF3COO]), 1-ethyl-3-methylimidazolium nitrate ([EMIM][NO3]) ionic liquids. Poly(ε-caprolactone)s (PCLs) with molecular weights (Mn) in the range of 300–9000 Da were obtained. 1H- and 13C-NMR analyses on PCLs formed by YLL, CRL, and PPL showed asymmetric telechelic -hydroxy-ω-carboxylic acid end groups. Differences between CP-MAS and MAS spectra are observed and discussed in terms of morphology. MALDI-TOF spectra show the formation of at least seven species. Differential scanning calorimetry (DSC) and Wide Angle X-Ray Scattering (WAXS) results demonstrate the high degree of crystallinity present in all the polyesters.Contract grant sponsor: Consejo Nacional de Ciencia y Tecnología (CONACyT); contract grant number: SEP-2004- C01-47173E. Contract grant sponsor: Consejo de Ciencia y Tecnología del Estado de Guanajuato (CONCYTEG). Contract grant sponsor: Universidad de Guanajuatato.Peer reviewe

Synthesis, characterization and hydrolytic degradation of polyester-urethanes obtained by lipase biocatalysis

The enzymatic synthesis of ¿¿¿-telechelic polycaprolactone diols (HOPCLOH) and block copolymers was studied. Synthesis of ¿¿¿-telechelic PCL diols was carried out by enzymatic ring opening polymerization with Yarrowia lipolytica lipase immobilized on Lewatit VP OC K2629 and Amberlyst 15, and using ethylene glycol, diethylene glycol and polyethylene glycol as initiators. Biodegradable linear polyester-urethanes were prepared from synthesized PCL diols and hexamethylenediisocyanate (HDI). Polyester-urethanes degradation was studied using thermogravimetric analysis (TGA) and hydrolysis (alkaline, acidic and neutral). It was found that content of ether linkages influences the thermal stability and hydrolytic degradation behavior of the analyzed polyurethanes. Hydrolytic degradation proceeds faster in alkaline media, in agreement with the expected susceptibility of ester COO¿ bonds to degradation in the polyester urethanes.Peer Reviewe

Degradation under composting conditions of lysine-modified polyurethane based on PCL obtained by lipase biocatalysis

Enzymatic polymerization has a large potential as an environmentally friendly synthetic process. Lipase is a renewable catalyst with high catalytic activity from which it is possible to develop a versatile method for the production of sustainable polyurethanes. In this work oligomeric PCL-diol was synthesized using biocatalysis with immobilized Yarrowia lipolytica lipase (YLL) and diethyleneglycol as initiator. Then, two different linear polyurethanes were prepared. One was obtained directly from the previous synthesized PCL-diol and hexamethylene diisocyanate, named PU, and the other one has been obtained by incorporating L-lysine amino acid as end group (lys-PU). PU and lys-PU disintegration under composting conditions was evaluated. The influence of the presence of L-lysine on the disintegration performance of PU was studied by evaluating the disintegration degree, monitoring the weight loss. Structural and morphological changes were followed by Fourier transformed infrared spectroscopy (FTIR) and by scanning electron microscopy (SEM).Authors thank Spanish Ministry of Economy, Industry and Competitiveness, MINEICO, ( and MAT2013-48059-C2-1-R MAT2017-88123-P) cofinanced with FEDER funds, Regional Government of Madrid (S2013/MIT-2862) and Consejo Nacional de Ciencia y Tecnología (CONACYT, Grant 153922) for the financial support. M.P. Arrieta and L. Peponi acknowledge the Juan de la Cierva (FJCI-2014-20630) and Ramon y Cajal (RYC-2014-15595) contracts from the MINECO, respectively. Authors also acknowledge Prof. Juan López Martínez (Universitat Politécnica de Valencia, Spain) for his assistance with colorimetric measurements.Peer Reviewe

Bio-Catalysis for the Functionalization of Cellulose Nanocrystals

In this work, the chemical modification of cellulose nanocrystals (NCs) using an enzyme as a catalyst has been performed by a “grafting from” reaction, in order to covalently functionalize the external surface of NCs with both poly(L-lactic acid) (PLLA) and poly(ε-caprolactone) (PCL) by ring-opening polymerization. Firstly, cellulose nanocrystals were prepared from commercial cellulose microcrystals by acid hydrolysis and then functionalized by using Yarrowia lipolytica lipase immobilized on Lewatit resin as a catalyst. To confirm the success of the grafting reactions, H-NMR has been performed as well as FT-IR and Raman spectroscopy. Moreover, thermogravimetric analysis has been used to determine the amount of polymeric chains grafted onto the surface of cellulose nanocrystals. Furthermore, the crystalline nature of the polymeric chains grafted onto the cellulose surface has been studied by DSC, X-ray scattering, as well as SAXS analysis. To our knowledge, it is the first time that a biocatalyst approach has been used to obtain biopolymeric functionalized cellulose nanocrystals.This research was funded by the Ministerio de Ciencia e Innovación (PID2021-123753NB-C31; PID2020-119047RB-I00)