Pharmacogenetics of oral antidiabetic drugs

Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K+ channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future

Magnetic ordering in Co2+-containing layered double hydroxides via the low-temperature heat capacity and magnetisation study

The low-temperature heat capacity and the magnetisation of Co2+ n Al3+ layered double hydroxides (LDH) with the cobalt-to-aluminium ratio n = 2 and 3 and intercalated with different anions have been studied in a wide range of magnetic fields up to 50 kOe. The heat capacity, C(T), was found to demonstrate a Schottky-like anomaly observed as a broad local maximum in the temperature dependence below 10 K. The effect is caused by a splitting of the ground-state Kramers doublet of Co2+ in the internal exchange field and correlates with magnetic ordering in these LDH. In low applied fields, the temperature-dependent dc magnetic susceptibility demonstrates a pronounced rise, which is associated with an onset of magnetic ordering. Both the heat capacity anomaly and the magnetic susceptibility peak are more pronounced for the LDH with n = 2 than for those with n = 3. This feature is associated with an excess of the honeycomb-like Co–Al coordination (which corresponds to a 2:1 Co–Al ordering) over the statistical cation distribution in Co2Al LDH, while a rather random cobalt-aluminium distribution is typical for Co3Al LDH. The temperature of the Schottky-like anomaly measured in a zero field is independent of the interlayer distance. Application of the magnetic field results in a widening of the anomaly range and a shift to higher temperatures. The observed experimental data are typical for a cluster spin glass ground state.publishe

Identification of molecular fluorophore as a component of carbon dots able to induce gelation in a fluorescent multivalent-metal-ion-free alginate hydrogel

We introduce a simple approach to fabricate fluorescent multivalent metal ion-free alginate hydrogels, which can be produced using carbon dots accessible from natural sources (citric acid and L-cysteine). Molecular fluorophore 5-oxo-2,3-dihydro-5H-[1,3]-thiazolo[3,2-a] pyridine-3,7-dicarboxylic acid (TPDCA), which is formed during the synthesis of carbon dots, is identified as a key segment for the crosslinking of hydrogels. The crosslinking happens through dynamic complexation of carboxylic acid groups of TPDCA and alginate cages along with sodium ions. The TPDCA derived hydrogels are investigated regarding to their thermal, rheological and optical properties, and found to exhibit characteristic fluorescence of this aggregated molecular fluorophore. Moreover, gradient hydrogels with tunable mechanical and optical properties and controlled release are obtained upon immersion of the hydrogel reactors in solutions of divalent metal ions (Ca2+, Cu2+, and Ni2+) with a higher affinity to alginate. © 2019, The Author(s).Qatar National Research Fund (Qatar foundation) [8-878-1-172]; Qatar University grant [QUCG-CAM-19/20-2]; Germany/Hong Kong Joint Research Scheme - Research Grants Council of Hong Kong; Germany Academic Exchange Service of Germany [G-CityU103/16]; VEGA Scientific Grant AgencyVedecka grantova agentura MSVVaS SR a SAV (VEGA) [2/0158/17

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Brain glutamate in anorexia nervosa: a magnetic resonance spectroscopy case control study at 7 Tesla

RATIONALE: Anorexia nervosa (AN) is a serious psychiatric disorder with high morbidity and mortality. There are no established pharmacological treatments and the neurobiology of the condition is poorly understood. Previous studies using magnetic resonance spectroscopy (MRS) have shown that AN may be associated with reductions in indices of brain glutamate; however, at conventional field strengths (≤3 T), it is difficult to separate glutamate from its precursor and metabolite, glutamine. OBJECTIVES: The objective of the present study was to use high field (7 T) MRS to measure concentrations of glutamate, in three separate brain voxels, in women with AN. METHODS: We studied 13 female participants with AN and 12 healthy female controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen. Neurometabolites were calculated using the unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid concentration in the voxel. RESULTS: We found that participants with AN had significantly lower concentrations of glutamate in all three voxels (mean reduction 8%, p = 0.002) but glutamine levels were not altered. Concentrations of N-acetylaspartate, creatine, GABA and glutathione were also unchanged. However, inositol was lower in AN participants in anterior cingulate (p = 0.022) and occipital cortex (p = 0.002). CONCLUSIONS: Women with AN apparently have widespread reductions in brain glutamate. Further work will be needed to assess if this change has pathophysiological relevance or whether it is a consequence of the many physical changes produced in AN by food restriction

Magnetic-Field Induced Slow Relaxation in the Ising-Like Quasi-One-Dimensional Ferromagnet KEr(MoO₄)₂

We present the study of spin dynamics of KEr(MoO₄)₂ in the magnetic field applied along the hard axis c. The temperature dependence of AC susceptibility in zero magnetic field studied at frequencies f=10, 100, and 1000 Hz indicated the absence of relaxation in the temperature range from 2 to 20 K. Application of magnetic field induced a slow magnetic relaxation, which was investigated in detail in the field 0.5 T. The highest intensity of the relaxation process, reflected by the values of imaginary susceptibility was observed at 2 K. With increasing temperature, the relaxation process is weaker and vanishes completely above 3.5 K. Corresponding Cole-Cole diagrams were constructed and analyzed within a single relaxation process which can be associated with a direct relaxation process with a bottleneck effect, τ ≈1/T^b, and b=1.4. The slow relaxation at 2 K intensifies with increasing magnetic field at least up to 1 T

Interlayer Dzyaloshinskii-Moriya interactions in a quasi-two-dimensional spin 1/2 antiferromagnet Cu(en)(H2O)(2)SO4

We present a theoretical study of magnetic interlayer exchange couplings in a quasi-two-dimensional quantum antiferromagnet Cu(en)(H2O)(2)SO4 (en = C2H8N2). We use symmetry arguments to construct the most general form of interlayer spin exchange interactions, and discuss the significance of individual terms. Particular attention is paid to the antisymmetric Dzyaloshinskii-Moriya spin anisotropy, allowed for the interlayer interactions in the ab-planes. We argue that it should not lead to weak ferromagnetism of neither conventional nor hidden type. Instead, the distribution of Dzyaloshinskii-Moriya vectors is typical for helimagnets. However, the occurrence of helimagnetism appears unlikely due to the assumed hierarchy of the magnitudes of spin interactions and the opposite chirality in adjacent ab-planes.Web of Science137594794