Ulrike Graefe‐Mody

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

Andrew Anand Brown, Juan J. Fernandez-Tajes, Mun‐Gwan Hong, Caroline Brorsson et autres

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 …

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Author Correction: Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Rosa Lundbye Allesøe, Agnete Troen Lundgaard, Ricardo Hernández Medina, Alejandro Aguayo‐Orozco et autres

In the version of this article initially published, Cristina Leal Rodríguez (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark) was omitted from the author list. The error has been corrected in the …

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

Rosa Lundbye Allesøe, Agnete Troen Lundgaard, Ricardo Hernández Medina, Alejandro Aguayo‐Orozco et autres

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 …

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Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Adem Y. Dawed, Andrea Mari, Andrew Anand Brown, Timothy James McDonald et autres

Background In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide …

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Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: An IMI DIRECT Study

Andrea Tura, Eleonora Grespan, Christian S. Göbl, Robert Wilhelm Koivula et autres

Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants …

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Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study

Roberto Bizzotto, Christopher Jennison, Angus G. Jones, Azra Kurbasic et autres

OBJECTIVE We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped …

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A reference map of potential determinants for the human serum metabolome

Noam Bar, Tal Korem, Omer Weissbrod, David Zeevi et autres

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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

H. Wilman, Constantinos A. Parisinos, Naeimeh Atabaki‐Pasdar, Matt Kelly et autres

BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. …

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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

Adem Y. Dawed, Kaixin Zhou, Nienke van Leeuwen, Anubha Mahajan et autres

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 …

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Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 ( HSD1 ) inhibitor in humans: liver and adipose tissue 11β‐ HSD1 inhibition after acute and multiple administrations over 2 weeks

Susanna Freude, Tim Heise, Hans Juergen Woerle, Arvid Jungnik et autres

AIMS: To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, after single- and repeated-dose administration. METHODS: The single-dose study included open-label administration of 200 mg BI 135585 in healthy volunteers, while in the …

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Comparable pharmacodynamics, efficacy, and safety of linagliptin 5 mg among Japanese, Asian and white patients with type 2 diabetes

Akiko Sarashina, Christian Friedrich, Susanne Crowe, Sanjay Dhanji Patel et autres

AIMS/INTRODUCTION: The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of …

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Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus

Silke Retlich, Vincent Duval, Ulrike Graefe‐Mody, Christian Friedrich et autres

BACKGROUND AND OBJECTIVES: Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in …

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