Background: The MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm. Results: 13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women. Conclusion: In a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

• MeSH
• C-peptid MeSH
• diabetes mellitus 2. typu * epidemiologie   genetika   MeSH
• glukagon MeSH
• glukosa MeSH
• inzulin MeSH
• inzulinová rezistence * genetika   MeSH
• kinetika MeSH
• krevní glukóza MeSH
• lidé MeSH
• porucha glukózové tolerance * epidemiologie   genetika   MeSH
• prediabetes * MeSH
• receptor melatoninový MT2 * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The pathogenesis of adolescent idiopathic scoliosis (AIS), including the associated local changes in deep paravertebral muscles, is poorly understood. The asymmetric expression of several molecules involved in the melatonin signaling pathway, including melatonin receptors 1A/1B (MTNR1A/MTNR1B), estrogen receptor 2 (ESR2) and calmodulin (CALM1), has previously been suggested to be associated with AIS. However, this hypothesis is based on single studies in which the data were obtained by different methodological approaches. Therefore, to evaluate the symmetry of the mRNA expression levels of these molecules, 18 patients with AIS and 10 non‑scoliotic controls were enrolled in the present study. Muscle biopsy samples from deep paraspinal muscles (from the convexity and concavity of the scoliotic curve in patients with AIS, or from the left and right sides in controls) were obtained during spinal surgery. For each sample, the relative mRNA expression levels of MTNR1A, MTNR1B, CALM1 and ESR2 were analyzed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and were quantified according to the quantification cycle method. The results indicated that the mRNA expression levels of none of the investigated molecules were significantly different between samples obtained from the convex and concave side of the scoliotic curve in patients with AIS. In addition, no difference in expression was detected between the patients with AIS and the controls. With regards to MTNR1A and MTNR1B, their expression was very weak in paravertebral muscles, and in the majority of cases their expression could not be detected by repeated RT‑qPCR analysis. Therefore, these data do not support the previously suggested role of the asymmetric expression of molecules involved in the melatonin signaling pathway in deep paravertebral muscles in the pathogenesis of AIS.

• MeSH
• beta receptor estrogenů genetika   MeSH
• dítě MeSH
• dospělí MeSH
• exprese genu MeSH
• genetická predispozice k nemoci MeSH
• hluboké zádové svaly metabolismus   MeSH
• kalmodulin genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA MeSH
• mladiství MeSH
• mladý dospělý MeSH
• receptor melatoninový MT1 genetika   MeSH
• receptor melatoninový MT2 genetika   MeSH
• skolióza etiologie   metabolismus   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Melatonin functions as an essential regulator of various physiological processes in all vertebrate species. In mammals, two G protein-coupled melatonin receptors (GPCR) mediate some melatonin's actions: MT1 and MT2. Transmembrane domains (TM) of most GPCRs contain a set of highly conserved proline residues that presumably play important structural and functional roles. As TM segments of MT2 receptor display several interesting differences in expression of specific proline residues compared to other rhodopsin-like receptors (rGPCRs), we investigated the role of proline residues in the structure and function of this receptor. All prolines in TM segments of MT2 receptor were individually replaced with alanine and/or glycine. In addition, the unusual NAxxY motif located in TM7 was mutated to generate highly conserved NPxxY motif found in the majority of rGPCR proteins. Following transient expression in CHO-K1 cells, binding properties of the mutant receptors and their ability to transduce signals were analyzed using (125)I-mel- and [(35)S]GTPgammaS-binding assays, respectively. The impact of the performed mutations on the receptor structure was assessed by molecular dynamic simulations of MT2 receptors embedded in the fully hydrated phospholipid bilayer. Our results indicate that residues P174, P212 and P266 are important for the ligand binding and/or signaling of the human MT2 receptor. We also show that changes within the unusual NAxxY sequence in the TM7 (mutations A305P and A305V) produce defective MT2 receptors indicating an important role of this motif in the function of melatonin receptors.

• MeSH
• aminokyselinové motivy MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• financování organizované MeSH
• imunohistochemie MeSH
• klonování DNA MeSH
• konfokální mikroskopie MeSH
• křečci praví MeSH
• lidé MeSH
• melatonin metabolismus   MeSH
• membránové proteiny MeSH
• molekulární modely MeSH
• mutace MeSH
• počítačová simulace MeSH
• prolin fyziologie   MeSH
• radioizotopy jodu MeSH
• radioizotopy síry MeSH
• receptor melatoninový MT2 genetika   chemie   metabolismus   MeSH
• substituce aminokyselin MeSH
• terciární struktura proteinů MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH

• MeSH
• buněčné linie MeSH
• finanční podpora výzkumu jako téma MeSH
• kinetika MeSH
• lidé MeSH
• ligandy MeSH
• melatonin analogy a deriváty   metabolismus   MeSH
• molekulární modely MeSH
• mutageneze cílená MeSH
• receptor melatoninový MT2 genetika   chemie   metabolismus   MeSH
• rekombinantní proteiny genetika   chemie   metabolismus   MeSH
• substituce aminokyselin MeSH
• techniky in vitro MeSH
• terciární struktura proteinů MeSH
• vazebná místa imunologie   MeSH
• Check Tag
• lidé MeSH