Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects

<p>Abstract</p> <p>Background</p> <p>Neuron-derived orphan receptor (Nor) 1, nuclear receptor (Nur) 77, and nuclear receptor-related protein (Nurr) 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the <it>NR4A3 </it>locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or β-cell dysfunction.</p> <p>Methods</p> <p>We genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms (SNPs) rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 (minor allele frequencies ≥ 0.05) covering 100% of genetic variation within the <it>NR4A3 </it>locus (with D' = 1.0, r²≥ 0.9) and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test (OGTT), and a hyperinsulinemic-euglycemic clamp (subgroup, N = 506). SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort (METSIM Study; Finland; N = 5265) for replication.</p> <p>Results</p> <p>All five SNPs were in Hardy-Weinberg equilibrium (p ≥ 0.7, all). The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 min(OGTT), AUC_C-peptide-to-AUC_Glucratio and the AUC_Ins30-to-AUC_Gluc30ratio with rs12686676 reaching the level of significance (p ≤ 0.03, all; additive model). The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p ≤ 0.03, additive model). There was no consistent association with glucose tolerance or insulin resistance in both study cohorts.</p> <p>Conclusion</p> <p>We conclude that common genetic variation within the <it>NR4A3 </it>locus determines insulin secretion. Thus, <it>NR4A3 </it>represents a novel candidate gene for β-cell function which was not covered by the SNP arrays of recent genome-wide association studies for type 2 diabetes mellitus.</p

Transglutaminase 6: a protein associated with central nervous system development and motor function.

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second β-barrel domain in man and a variant with truncated β-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca(2+) and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca(2+) and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons

Cloning and characterization of a tryptophanase gene from Enterobacter aerogenes SM-18

A tryptophanase gene from Enterobacter aerogenes SM-18 was cloned and sequenced. The structural gene for tryptophanase, tnaA, consisted of 1389 bp encoding 462 amino acid residues, and its nucleotide sequence and deduced amino acid sequence showed significant homology to those of tnaA from Escherichia coli K12. A short open reading frame consisting of 31 amino acid residues was found upstream of tnaA, and it showed some similarity to the E. coli tnaC gene known to be a cis-acting regulatory element for transcription. A partial open reading frame homologous to the 5' end of E. coli tnaB was observed at the 3'-flanking region of tnaA. These genes may thus constitute an operon as in E. coli

Proc. of The Fifth int. Sym. on Artificial Life and Robotics (AROB 5th&apos;00)

The formation of groups is of essential importance in biology. Aggregation is based on a simple dynamical model for the motion of each individual. It is shown that a swarm is formed within a short time span and is stable under perturbations. Keywords: Grouping behavior, stochastic control.

Visfatin induces oxidative stress in differentiated C2C12 myotubes in an Akt- and MAPK-independent, NFAB-dependent manner

Adipose tissue is an important endocrine and metabolic tissue that is actively involved in cross-talk with peripheral organs such as skeletal muscle. It is likely that adipose-derived factors may underlie the development of insulin resistance in muscle. Thus, the cross-talk between adipose and muscle may be important for the propagation of obesity-related diseases. Visfatin (Pre-B-cell colonyenhancing factor 1 homolog/Nampt) is a recently discovered adipokine with pleiotropic functions. The aim of this study was to examine the effect of visfatin on cellular stress responses and signalling pathways in skeletal muscle. Visfatin treatment of differentiated C2C12 myotubes generated reactive oxygen species (ROS) comprising both superoxide and hydrogen peroxide that was dependent on de novo transcription and translation. In differentiated C2C12 myoblasts, visfatin had no effects on insulinstimulated Akt phosphorylation nor on activation of the Akt signalling pathway. Additionally, visfatin-induced oxidative stress occurred independent of activation of the stress-activated protein kinases (MAPKs) ERK and p38. In contrast, phosphorylation of NFΚB was associated with visfatin-mediated generation of ROS and blockade of this pathway via selective IKK inhibition led to a partial reduction in oxidative stress. Furthermore, the generation of ROS following visfatin treatment was highly dependent on both de novo transcription and translation. Taken together, these findings provide novel insights for the unique pathophysiological role of visfatin in skeletal muscle