Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes:An IMI direct study

OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin

Structural-Properties Of Amorphous Hydrogenated Carbon .1. A High-Resolution Neutron-Diffraction Study

The structure of samples of amorphous hydrogenated carbon, prepared from acetylene and propane precursors, containing 35 and 32 at.% hydrogen, respectively, was investigated by time-of-flight neutron diffraction in the range 0.2-50 angstrom-1 using the ISIS spallation source. The large dynamic range of the data ensures a real-space resolution sufficient to reveal directly the proportions of sp2 and sp3 hybridized carbon. The results show that, in these hard carbon materials, the carbon-atom sites are predominantly sp2 bonded, and the carbon-carbon single bond:carbon-carbon double bond ratio is about 2.5:1. The detailed information on atomic correlations thus provided is used to discuss current structural models, and in particular the data are used to show that these models require significant modification

Effects of ZnO addition on thermal properties, degradation and biocompatibility of P45Mg24Ca16Na(15−x)Znx glasses

Four phosphate-based glass formulations in the system P45Mg24Ca16Na(15-x)Znx, referred to as P45Znx (x = 0, 5, 10 and 15 mol%), were prepared using a melt quenching process. The effect of ZnO addition on density, molar volume, thermal properties and degradation rates were studied. An increase in the glass transition, crystallisation, melting and liquidus temperatures were seen when replacing Na2O with ZnO. The molar volume of the bulk glasses was seen to decrease with increasing ZnO content. The dissolution rate of the zinc-free glass was 2.48 × 10-8 kg m-2 s-1 and addition of 5 mol% ZnO resulted in a reduction of the dissolution rate to 1.68 × 10-8 kg m-2 s-1. However, further addition of ZnO from 5 mol% to 15 mol% increased the dissolution rate of the glass system. The glasses were deliberately crystallised and XRD studies identified the Z n2P2O7 phase for glass code P45Zn5, and Zn(PO3)2 phase for P45Zn10 and P45Zn15 glasses. Cyto-compatibility studies were conducted using MG63 cells for 14 days. An overall increase in the metabolic activity and DNA concentration of cells was seen from day 1 to day 14 for all glass formulations investigated. However, increasing ZnO content from 0 to 15 mol% seemed to have a negative effect on the cellular activity. Interestingly, a remarkably higher ALP activity was seen at day 14 for glass codes P45Zn5 and P45Zn10 in comparison with the TCP control and the P45Zn0 glass

The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1:An IMI DIRECT Study

ContextThe role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood.ObjectiveWe investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D.MethodsWe analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D.ResultsOur multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes.ConclusionThese studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes : an IMI-DIRECT study

Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.Peer reviewe

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities. [Abstract copyright: © 2023. The Author(s).

A Review of Current Methodologies for Regional Evapotranspiration Estimation from Remotely Sensed Data

An overview of the commonly applied evapotranspiration (ET) models using remotely sensed data is given to provide insight into the estimation of ET on a regional scale from satellite data. Generally, these models vary greatly in inputs, main assumptions and accuracy of results, etc. Besides the generally used remotely sensed multi-spectral data from visible to thermal infrared bands, most remotely sensed ET models, from simplified equations models to the more complex physically based two-source energy balance models, must rely to a certain degree on ground-based auxiliary measurements in order to derive the turbulent heat fluxes on a regional scale. We discuss the main inputs, assumptions, theories, advantages and drawbacks of each model. Moreover, approaches to the extrapolation of instantaneous ET to the daily values are also briefly presented. In the final part, both associated problems and future trends regarding these remotely sensed ET models were analyzed to objectively show the limitations and promising aspects of the estimation of regional ET based on remotely sensed data and ground-based measurements