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151. Machine Learning Approaches Reveal Metabolic Signatures of Incident Chronic Kidney Disease in Individuals With Prediabetes and Type 2 Diabetes

Author

Professur Public Health und Prävantion, Huang, Jialing;Huth, Cornelia;Covic, Marcela;Troll, Martina;Adam, Jonathan;Zukunft, Sven;Prehn, Cornelia;Wang, Li;Nano, Jana;Scheerer, Markus F.;Neschen, Susanne;Kastenmüller, Gabi;Suhre, Karsten;Laxy, Michael;Schliess, Freimut;Gieger, Christian;Adamski, Jerzy;Hrabe de Angelis, Martin;Peters, Annette;Wang-Sattler, Rui, Professur Public Health und Prävantion, and Huang, Jialing;Huth, Cornelia;Covic, Marcela;Troll, Martina;Adam, Jonathan;Zukunft, Sven;Prehn, Cornelia;Wang, Li;Nano, Jana;Scheerer, Markus F.;Neschen, Susanne;Kastenmüller, Gabi;Suhre, Karsten;Laxy, Michael;Schliess, Freimut;Gieger, Christian;Adamski, Jerzy;Hrabe de Angelis, Martin;Peters, Annette;Wang-Sattler, Rui

Published
2019

152. Pharmacokinetics of metformin in patients with gastrointestinal intolerance

Author

McCreight, Laura J., Stage, Tore B., Connelly, Paul, Lonergan, Mike, Nielsen, Flemming, Prehn, Cornelia, Adamski, Jerzy, Brøsen, Kim, and Pearson, Ewan R.

Subjects
Diarrhea, Male, Serotonin, Serotonin/blood, Gastrointestinal Diseases, Metabolic Clearance Rate, Antidiabetic drug, Severity of Illness Index, Overweight/complications, Hypoglycemic Agents/adverse effects, Body Mass Index, Bile Acids and Salts, Cohort Studies, Humans, Hypoglycemic Agents, Pharmacokinetics, Lactic Acid, Metformin/adverse effects, Antidiabetic Drug, Metformin, Type 2 Diabetes, Aged, antidiabetic drug, Diabetes Mellitus, Type 2/complications, Type 2 diabetes, Lactic Acid/blood, Original Articles, Middle Aged, Overweight, Gastrointestinal Diseases/blood, Abdominal Pain, Abdominal Pain/etiology, Bile Acids and Salts/blood, Diabetes Mellitus, Type 2, Diarrhea/etiology, Female, Original Article, type 2 diabetes, pharmacokinetics, Half-Life
Abstract

Aims: \ud To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool.\ud \ud Methods: \ud For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500‐mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes.\ud \ud Results: \ud The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7‐2.3) mg/L and 2.0 (1.8‐2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)0–24 16.9 (13.9‐18.6) and 13.9 (12.9‐16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0‐2.8 and 1.8‐3.0 mmol/L, respectively), and similar incremental AUC0–24 in each cohort: tolerant cohort 6.98 (95% CI 3.03‐10.93) and intolerant cohort 4.47 (95% CI –3.12‐12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different.\ud \ud Conclusions: \ud Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.

Published
2018

153. Ageing Investigation Using Two-Time-Point Metabolomics Data from KORA and CARLA Studies

Author

Chak, Choiwai, primary, Lacruz, Maria, additional, Adam, Jonathan, additional, Brandmaier, Stefan, additional, Covic, Marcela, additional, Huang, Jialing, additional, Meisinger, Christa, additional, Tiller, Daniel, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Berger, Ursula, additional, Gieger, Christian, additional, Peters, Annette, additional, Kluttig, Alexander, additional, and Wang-Sattler, Rui, additional

Published
2019
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155. Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring

Author

Renner, Simone, primary, Martins, Ana Sofia, additional, Streckel, Elisabeth, additional, Braun-Reichhart, Christina, additional, Backman, Mattias, additional, Prehn, Cornelia, additional, Klymiuk, Nikolai, additional, Bähr, Andrea, additional, Blutke, Andreas, additional, Landbrecht-Schessl, Christina, additional, Wünsch, Annegret, additional, Kessler, Barbara, additional, Kurome, Mayuko, additional, Hinrichs, Arne, additional, Koopmans, Sietse-Jan, additional, Krebs, Stefan, additional, Kemter, Elisabeth, additional, Rathkolb, Birgit, additional, Nagashima, Hiroshi, additional, Blum, Helmut, additional, Ritzmann, Mathias, additional, Wanke, Rüdiger, additional, Aigner, Bernhard, additional, Adamski, Jerzy, additional, Hrabe de Angelis, Martin, additional, and Wolf, Eckhard, additional

Published
2019
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156. β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9R239Xmice

Author

Hidalgo‐Gutiérrez, Agustín, primary, Barriocanal‐Casado, Eliana, additional, Bakkali, Mohammed, additional, Díaz‐Casado, M Elena, additional, Sánchez‐Maldonado, Laura, additional, Romero, Miguel, additional, Sayed, Ramy K, additional, Prehn, Cornelia, additional, Escames, Germaine, additional, Duarte, Juan, additional, Acuña‐Castroviejo, Darío, additional, and López, Luis C, additional

Published
2018
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158. The Munich MIDY Pig Biobank – A unique resource for studying organ crosstalk in diabetes

Author

Blutke, Andreas, Renner, Simone, Flenkenthaler, Florian, Backman, Mattias, Haesner, Serena, Kemter, Elisabeth, Ländström, Erik, Braun-Reichhart, Christina, Albl, Barbara, Streckel, Elisabeth, Rathkolb, Birgit, Prehn, Cornelia, Palladini, Alessandra, Grzybek, Michal, Krebs, Stefan, Bauersachs, Stefan, Bähr, Andrea, Brühschwein, Andreas, Deeg, Cornelia A., De Monte, Erica, Dmochewitz, Michaela, Eberle, Caroline, Emrich, Daniela, Fux, Robert, Groth, Frauke, Gumbert, Sophie, Heitmann, Antonia, Hinrichs, Arne, Keßler, Barbara, Kurome, Mayuko, Leipig-Rudolph, Miriam, Matiasek, Kaspar, Öztürk, Hazal, Otzdorff, Christiane, Reichenbach, Myriam, Reichenbach, Horst Dieter, Rieger, Alexandra, Rieseberg, Birte, Rosati, Marco, Saucedo, Manuel Nicolas, Schleicher, Anna, Schneider, Marlon R., Simmet, Kilian, Steinmetz, Judith, Übel, Nicole, Zehetmaier, Patrizia, Jung, Andreas, Adamski, Jerzy, Coskun, Ünal, Hrabě de Angelis, Martin, Simmet, Christian, Ritzmann, Mathias, Meyer-Lindenberg, Andrea, Blum, Helmut, Arnold, Georg J., Fröhlich, Thomas, Wanke, Rüdiger, and Wolf, Eckhard

Published
2017
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159. Targeted Metabolomics as a Tool in Discriminating Endocrine From Primary Hypertension.

Author

Erlic, Zoran, Reel, Parminder, Reel, Smarti, Amar, Laurence, Pecori, Alessio, Larsen, Casper K., Tetti, Martina, Pamporaki, Christina, Prehn, Cornelia, Adamski, Jerzy, Prejbisz, Aleksander, Ceccato, Filippo, Scaroni, Carla, Kroiss, Matthias, Dennedy, Michael C., Deinum, Jaap, Langton, Katharina, Mulatero, Paolo, Reincke, Martin, and Lenzini, Livia

Subjects
ESSENTIAL hypertension, METABOLOMICS, CUSHING'S syndrome, HYPERTENSION
Abstract

Context: Identification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL], and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.Objective: Use TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.Methods: Retrospective analyses of PHT and EHT patients from a European multicenter study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a "classical approach" (CA) (performing a series of univariate and multivariate analyses) and a "machine learning approach" (MLA) (using random forest) were used.The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n = 59) and EHT (n = 223 with 40 CS, 107 PA, and 76 PPGL), respectively.Results: From 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 16 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The receiver operating characteristic curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).Conclusion: TM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance. [ABSTRACT FROM AUTHOR]

Published
2021
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160. Circulating glutamate concentration as a biomarker of visceral obesity and associated metabolic alterations

Author

Maltais-Payette, Ina, Boulet, Marie-Michèle, Prehn, Cornelia, Adamski, Jerzy, Tchernof, André, Maltais-Payette, Ina, Boulet, Marie-Michèle, Prehn, Cornelia, Adamski, Jerzy, and Tchernof, André

Abstract

Background Visceral adipose tissue (VAT) area is a strong predictor of obesity-related cardiometabolic alterations, but its measurement is costly, time consuming and, in some cases, involves radiation exposure. Glutamate, a by-product of branched-chain-amino-acid (BCAA) catabolism, has been shown to be increased in visceral obese individuals. In this follow-up data analysis, we aimed to investigate the ability of plasma glutamate to identify individuals with visceral obesity and concomitant metabolic alterations. Methods Measurements of adiposity, targeted blood metabolomics and cardiometabolic risk factors were performed in 59 healthy middle-aged women. Visceral and subcutaneous adipose tissue areas were measured by computed tomography (CT) whereas body fat and lean mass were assessed by dual-energy x-ray absorptiometry (DEXA). Results The univariate Pearson correlation coefficient between glutamate and VAT area was r = 0.46 (p < 0.001) and it was r = 0.36 (p = 0.006) when adjusted for total body fat mass. Glutamate allowed to identify individuals with VAT areas ≥100 cm2 (ROC_AUC: 0.78, 95% CI: 0.66–0.91) and VAT ≥130 cm2 (ROC_AUC: 0.71, 95% CI: 0.56–0.87). The optimal glutamate concentration threshold determined from the ROC curve (glutamate ≥34.6 μmol/L) had a greater sensitivity than the metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTW) phenotype to identify individuals with VAT ≥100 cm2 (83% for glutamate vs 52% for the MetS and 35% for the HTW). Variance analysis showed that women with a high circulating glutamate level (≥34.6 μmol/L) had an altered metabolic profile, particularly regarding total triglyceride levels and the amount of triglycerides and cholesterol in very-low-density lipoproteins (all p < 0.01). Conclusion Circulating glutamate is strongly associated with VAT area and may represent a potential screening tool for visceral obesity and alterations of the metabolic profile.

Published
2018

161. Circulating steroid levels as correlates of adipose tissue phenotype in premenopausal women

Author

Marchand, Geneviève B., Carreau, Anne-Marie, Laforest, Sofia, Côté, Julie Anne, Daris, Marleen, Cianflone, Katherine M., Prehn, Cornelia, Adamski, Jerzy, Tchernof, André, Marchand, Geneviève B., Carreau, Anne-Marie, Laforest, Sofia, Côté, Julie Anne, Daris, Marleen, Cianflone, Katherine M., Prehn, Cornelia, Adamski, Jerzy, and Tchernof, André

Abstract

Background: Obesity-related alterations in the circulating steroid hormone profile remain equivocal in women. Our objective was to identify circulating steroid levels that relate to increased adiposity and altered adipose phenotype in premenopausal women. Materials and methods: In a sample of 42 premenopausal women (age 46±3 years; BMI 27.1±4.2 kg/m2 ), 19 plasma steroids were quantified by ESI-LC-MS/MS. Body composition and fat distribution were assessed by dual-energy X-ray absorptiometry and computed tomography, respectively. Markers of adipose tissue function including adipocyte size distributions, radiological attenuation, and macrophage infiltration were also analyzed in surgically obtained visceral and subcutaneous fat samples. Results: Many negative correlations were observed between adiposity measurements such as BMI, body fat percentage or total abdominal adipose tissue area and plasma levels of androstenedione (r=-0.33 to -0.39, p≤0.04), androsterone (r=-0.30 to -0.38, p≤0.05) and plasma levels of steroid precursor pregnenolone (r=-0.36 to -0.46, p≤0.02). Visceral adipocyte hypertrophy was observed in patients with low pregnenolone concentrations (p<0.05). Visceral adipose tissue radiologic attenuation, a potential marker of adipocyte size, was also positively correlated with pregnenolone levels (r=0.33, p<0.05). Low levels of pregnenolone were related to increased number of macrophages infiltrating visceral and subcutaneous adipose tissue (p<0.05). Conclusion: Plasma levels of androgens and their precursors are lower in women with increased adiposity and visceral adipocyte hypertrophy. Low circulating pregnenolone concentration may represent a marker of adipose tissue dysfunction.

Published
2018

162. Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease

Author

Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890), Jia, Jie; Conlon, Thomas M.; Sarker, Rim S. J.; Tasdemir, Demet; Smirnova, Natalia F.; Srivastava, Barkha; Verleden, Stijn E.; Guneş, Gizem; Wu, Xiao; Prehn, Cornelia; Gao, Jiaqi; Heinzelmann, Katharina; Lintelmann, Jutta; Irmler, Martin; Pfeiffer, Stefan; Schloter, Michael; Zimmermann, Ralf; de Angelis, Martin Hrabe; Beckers, Johannes; Adamski, Jerzy; Eickelberg, Oliver; Yıldırım, Ali Önder, School of Medicine, Department of Pulmonology, Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890), Jia, Jie; Conlon, Thomas M.; Sarker, Rim S. J.; Tasdemir, Demet; Smirnova, Natalia F.; Srivastava, Barkha; Verleden, Stijn E.; Guneş, Gizem; Wu, Xiao; Prehn, Cornelia; Gao, Jiaqi; Heinzelmann, Katharina; Lintelmann, Jutta; Irmler, Martin; Pfeiffer, Stefan; Schloter, Michael; Zimmermann, Ralf; de Angelis, Martin Hrabe; Beckers, Johannes; Adamski, Jerzy; Eickelberg, Oliver; Yıldırım, Ali Önder, School of Medicine, and Department of Pulmonology

Abstract

The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus-associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD. In both COPD patients and cigarette smoke (CS)-exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS-induced B-cell migration and iBALT formation. Mice deficient in CH25H or the oxysterol receptor EBI2 exhibited decreased iBALT and subsequent CS-induced emphysema. Further, inhibition of the oxysterol pathway using clotrimazole resolved iBALT formation and attenuated CS-induced emphysema invivo therapeutically. Collectively, our studies are the first to mechanistically interrogate oxysterol-dependent iBALT formation in the pathogenesis of COPD, and identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs., NA

Published
2018

163. Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study

Author

Molnos, Sophie, Wahl, Simone, Haid, Mark, Eekhoff, E. Marelise W., Pool, René, Floegel, Anna, Deelen, Joris, Much, Daniela, Prehn, Cornelia, Breier, Michaela, Draisma, Harmen H., van Leeuwen, Nienke, Simonis-Bik, Annemarie M.C., Jonsson, Anna Elisabet, Willemsen, Gonneke, Bernigau, Wolfgang, Wang-Sattler, Rui, Suhre, Karsten, Peters, Annette, Thorand, Barbara, Herder, Christian, Rathmann, Wolfgang, Roden, Michael, Gieger, Christian, Kramer, Mark H.H., van Heemst, Diana, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Schulze, Matthias B., Pischon, Tobias, de Geus, Eco J.C., Boeing, Heiner, Boomsma, Dorret I., Ziegler, Anette G., Slagboom, P. Eline, Hummel, Sandra, Beekman, Marian, Grallert, Harald, Brunak, Søren, McCarthy, Mark I., Gupta, Ramneek, Pearson, Ewan R., Adamski, Jerzy, 'T Hart, Leen M., Molnos, Sophie, Wahl, Simone, Haid, Mark, Eekhoff, E. Marelise W., Pool, René, Floegel, Anna, Deelen, Joris, Much, Daniela, Prehn, Cornelia, Breier, Michaela, Draisma, Harmen H., van Leeuwen, Nienke, Simonis-Bik, Annemarie M.C., Jonsson, Anna Elisabet, Willemsen, Gonneke, Bernigau, Wolfgang, Wang-Sattler, Rui, Suhre, Karsten, Peters, Annette, Thorand, Barbara, Herder, Christian, Rathmann, Wolfgang, Roden, Michael, Gieger, Christian, Kramer, Mark H.H., van Heemst, Diana, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Schulze, Matthias B., Pischon, Tobias, de Geus, Eco J.C., Boeing, Heiner, Boomsma, Dorret I., Ziegler, Anette G., Slagboom, P. Eline, Hummel, Sandra, Beekman, Marian, Grallert, Harald, Brunak, Søren, McCarthy, Mark I., Gupta, Ramneek, Pearson, Ewan R., Adamski, Jerzy, and 'T Hart, Leen M.

Abstract

Aims/hypothesis: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. Methods: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case–control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. Results: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p <9.2 × 10−7). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10−3) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [β 0.97 ± 0.09], p = 1.0 × 10−27). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10−15), leading to modest improvements in the receiver operating characteristics when added to a model containing a set

Published
2018

164. Night Shift Work Affects Urine Metabolite Profiles of Nurses with Early Chronotype

Author

Rotter, Markus, primary, Brandmaier, Stefan, additional, Covic, Marcela, additional, Burek, Katarzyna, additional, Hertel, Johannes, additional, Troll, Martina, additional, Bader, Erik, additional, Adam, Jonathan, additional, Prehn, Cornelia, additional, Rathkolb, Birgit, additional, Hrabe de Angelis, Martin, additional, Grabe, Hans, additional, Daniel, Hannelore, additional, Kantermann, Thomas, additional, Harth, Volker, additional, Illig, Thomas, additional, Pallapies, Dirk, additional, Behrens, Thomas, additional, Brüning, Thomas, additional, Adamski, Jerzy, additional, Lickert, Heiko, additional, Rabstein, Sylvia, additional, and Wang-Sattler, Rui, additional

Published
2018
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165. Comparison of metabolite networks from four German population-based studies

Author

Iqbal, Khalid, primary, Dietrich, Stefan, additional, Wittenbecher, Clemens, additional, Krumsiek, Jan, additional, Kühn, Tilman, additional, Lacruz, Maria Elena, additional, Kluttig, Alexander, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, von Bergen, Martin, additional, Kaaks, Rudolf, additional, Schulze, Matthias B, additional, Boeing, Heiner, additional, and Floegel, Anna, additional

Published
2018
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166. Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo

Author

Mycielska, Maria E., primary, Dettmer, Katja, additional, Rümmele, Petra, additional, Schmidt, Katharina, additional, Prehn, Cornelia, additional, Milenkovic, Vladimir M., additional, Jagla, Wolfgang, additional, Madej, Gregor M., additional, Lantow, Margareta, additional, Schladt, Moritz, additional, Cecil, Alexander, additional, Koehl, Gudrun E., additional, Eggenhofer, Elke, additional, Wachsmuth, Christian J., additional, Ganapathy, Vadivel, additional, Schlitt, Hans J., additional, Kunzelmann, Karl, additional, Ziegler, Christine, additional, Wetzel, Christian H., additional, Gaumann, Andreas, additional, Lang, Sven A., additional, Adamski, Jerzy, additional, Oefner, Peter J., additional, and Geissler, Edward K., additional

Published
2018
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167. Cholesterol metabolism promotes B‐cell positioning during immune pathogenesis of chronic obstructive pulmonary disease

Author

Jia, Jie, primary, Conlon, Thomas M, additional, Sarker, Rim SJ, additional, Taşdemir, Demet, additional, Smirnova, Natalia F, additional, Srivastava, Barkha, additional, Verleden, Stijn E, additional, Güneş, Gizem, additional, Wu, Xiao, additional, Prehn, Cornelia, additional, Gao, Jiaqi, additional, Heinzelmann, Katharina, additional, Lintelmann, Jutta, additional, Irmler, Martin, additional, Pfeiffer, Stefan, additional, Schloter, Michael, additional, Zimmermann, Ralf, additional, Hrabé de Angelis, Martin, additional, Beckers, Johannes, additional, Adamski, Jerzy, additional, Bayram, Hasan, additional, Eickelberg, Oliver, additional, and Yildirim, Ali Önder, additional

Published
2018
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168. Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Author

Hirose, Misa, primary, Schilf, Paul, additional, Gupta, Yask, additional, Zarse, Kim, additional, Künstner, Axel, additional, Fähnrich, Anke, additional, Busch, Hauke, additional, Yin, Junping, additional, Wright, Marvin N., additional, Ziegler, Andreas, additional, Vallier, Marie, additional, Belheouane, Meriem, additional, Baines, John F, additional, Tautz, Diethard, additional, Johann, Kornelia, additional, Oelkrug, Rebecca, additional, Mittag, Jens, additional, Lehnert, Hendrik, additional, Othman, Alaa, additional, Jöhren, Olaf, additional, Schwaninger, Markus, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Shima, Kensuke, additional, Rupp, Jan, additional, Häsler, Robert, additional, Fuellen, Georg, additional, Köhling, Rüdiger, additional, Ristow, Michael, additional, and Ibrahim, Saleh M., additional

Published
2018
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171. Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques

Author

Tomas, Lukas, primary, Edsfeldt, Andreas, additional, Mollet, Inês G, additional, Perisic Matic, Ljubica, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Paulsson-Berne, Gabrielle, additional, Hedin, Ulf, additional, Nilsson, Jan, additional, Bengtsson, Eva, additional, Gonçalves, Isabel, additional, and Björkbacka, Harry, additional

Published
2018
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172. Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice

Author

Xie, Kan, primary, Ryan, Devon P., additional, Pearson, Brandon L., additional, Henzel, Kristin S., additional, Neff, Frauke, additional, Vidal, Ramon O., additional, Hennion, Magali, additional, Lehmann, Isabelle, additional, Schleif, Melvin, additional, Schröder, Susanne, additional, Adler, Thure, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Schütz, Anna-Lena, additional, Prehn, Cornelia, additional, Mickael, Michel E., additional, Weiergräber, Marco, additional, Adamski, Jerzy, additional, Busch, Dirk H., additional, Ehninger, Gerhard, additional, Matynia, Anna, additional, Jackson, Walker S., additional, Wolf, Eckhard, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Bonn, Stefan, additional, Hrabě de Angelis, Martin, additional, and Ehninger, Dan, additional

Published
2018
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173. Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis

Author

Galsgaard, Katrine D., primary, Winther-Sørensen, Marie, additional, Ørskov, Cathrine, additional, Kissow, Hannelouise, additional, Poulsen, Steen S., additional, Vilstrup, Hendrik, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Jepsen, Sara L., additional, Hartmann, Bolette, additional, Hunt, Jenna, additional, Charron, Maureen J., additional, Pedersen, Jens, additional, Wewer Albrechtsen, Nicolai J., additional, and Holst, Jens J., additional

Published
2018
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174. Multi-Omics Insights into Functional Alterations of the Liver in Insulin-Deficient Diabetes Mellitus

Author

Backman, Mattias, primary, Flenkenthaler, Florian, additional, Blutke, Andreas, additional, Dahlhoff, Maik, additional, Ländström, Erik, additional, Renner, Simone, additional, Philippou-Massier, Julia, additional, Krebs, Stefan, additional, Rathkolb, Birgit, additional, Prehn, Cornelia, additional, Grzybek, Michal, additional, Coskun, Ünal, additional, Adamski, Jerzy, additional, Angelis, Martin Hrabĕ de, additional, Wanke, Rüdiger, additional, Fröhlich, Thomas, additional, Arnold, Georg J., additional, Blum, Helmut, additional, and Wolf, Eckhard, additional

Published
2018
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178. Serum metabolites and risk of myocardial infarction and ischemic stroke: a targeted metabolomic approach in two German prospective cohorts

Author

Floegel, Anna, primary, Kühn, Tilman, additional, Sookthai, Disorn, additional, Johnson, Theron, additional, Prehn, Cornelia, additional, Rolle-Kampczyk, Ulrike, additional, Otto, Wolfgang, additional, Weikert, Cornelia, additional, Illig, Thomas, additional, von Bergen, Martin, additional, Adamski, Jerzy, additional, Boeing, Heiner, additional, Kaaks, Rudolf, additional, and Pischon, Tobias, additional

Published
2017
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180. Improvement of myocardial infarction risk prediction via inflammation-associated metabolite biomarkers

Author

Ward-Caviness, Cavin K., Xu, Tao, Aspelund, Thor, Thorand, Barbara, Montrone, Corinna, Meisinger, Christa, Dunger-Kaltenbach, Irmtraud, Zierer, Astrid, Yu, Zhonghao, Helgadottir, Inga R., Harris, Tamara B., Launer, Lenore J., Ganna, Andrea, Lind, Lars, Eiriksdottir, Gudny, Waldenberger, Melanie, Prehn, Cornelia, Suhre, Karsten, Illig, Thomas, Adamski, Jerzy, Ruepp, Andreas, Koenig, Wolfgang, Gudnason, Vilmundur, Emilsson, Valur, Wang-Sattler, Rui, Peters, Annette, Ward-Caviness, Cavin K., Xu, Tao, Aspelund, Thor, Thorand, Barbara, Montrone, Corinna, Meisinger, Christa, Dunger-Kaltenbach, Irmtraud, Zierer, Astrid, Yu, Zhonghao, Helgadottir, Inga R., Harris, Tamara B., Launer, Lenore J., Ganna, Andrea, Lind, Lars, Eiriksdottir, Gudny, Waldenberger, Melanie, Prehn, Cornelia, Suhre, Karsten, Illig, Thomas, Adamski, Jerzy, Ruepp, Andreas, Koenig, Wolfgang, Gudnason, Vilmundur, Emilsson, Valur, Wang-Sattler, Rui, and Peters, Annette

Abstract

Objective The comprehensive assaying of low-molecular-weight compounds, for example, metabolomics, provides a unique tool to uncover novel biomarkers and understand pathways underlying myocardial infarction (MI). We used a targeted metabolomics approach to identify biomarkers for MI and evaluate their involvement in the pathogenesis of MI. Methods and results Using three independent, prospective cohorts (KORA S4, KORA S2 and AGES-REFINE), totalling 2257 participants without a history of MI at baseline, we identified metabolites associated with incident MI (266 cases). We also investigated the association between the metabolites and high-sensitivity C reactive protein (hsCRP) to understand the relation between these metabolites and systemic inflammation. Out of 140 metabolites, 16 were nominally associated (p<0.05) with incident MI in KORA S4. Three metabolites, arginine and two lysophosphatidylcholines (LPC 17: 0 and LPC 18:2), were selected as biomarkers via a backward stepwise selection procedure in the KORA S4 and were significant (p<0.0003) in a meta-analysis comprising all three studies including KORA S2 and AGES-REFINE. Furthermore, these three metabolites increased the predictive value of the Framingham risk score, increasing the area under the receiver operating characteristic score in KORA S4 (from 0.70 to 0.78, p=0.001) and AGES-REFINE study (from 0.70 to 0.76, p=0.02), but was not observed in KORA S2. The metabolite biomarkers attenuated the association between hsCRP and MI, indicating a potential link to systemic inflammatory processes. Conclusions We identified three metabolite biomarkers, which in combination increase the predictive value of the Framingham risk score. The attenuation of the hsCRP-MI association by these three metabolites indicates a potential link to systemic inflammation.

Published
2017
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181. Plasma and Serum Metabolite Association Networks : Comparability within and between Studies Using NMR and MS Profiling

Author

Suarez-Diez, Maria, Adam, Jonathan, Adamski, Jerzy, Chasapi, Styliani A., Luchinat, Claudio, Peters, Annette, Prehn, Cornelia, Santucci, Claudio, Spyridonidis, Alexandros, Spyroulias, Georgios A., Tenori, Leonardo, Wang-Sattler, Rui, Saccenti, Edoardo, Suarez-Diez, Maria, Adam, Jonathan, Adamski, Jerzy, Chasapi, Styliani A., Luchinat, Claudio, Peters, Annette, Prehn, Cornelia, Santucci, Claudio, Spyridonidis, Alexandros, Spyroulias, Georgios A., Tenori, Leonardo, Wang-Sattler, Rui, and Saccenti, Edoardo

Abstract

Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA-MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some differences arise like in the case of amino acids.

Published
2017

182. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

Author

Fuchs, Helmut, Sabrautzki, Sibylle, Przemeck, Gerhard K. H., Leuchtenberger, Stefanie, Lorenz-Depiereux, Bettina, Becker, Lore, Rathkolb, Birgit, Horsch, Marion, Garrett, Lillian, Östereicher, Manuela A., Hans, Wolfgang, Abe, Koichiro, Sagawa, Nobuho, Rozman, Jan, Vargas-Panesso, Ingrid L., Sandholzer, Michael, Lisse, Thomas S., Adler, Thure, Aguilar-Pimentel, Juan Antonio, Calzada-Wack, Julia, Ehrhard, Nicole, Elvert, Ralf, Gau, Christine, Hölter, Sabine M., Micklich, Katja, Moreth, Kristin, Prehn, Cornelia, Puk, Oliver, Racz, Ildiko, Stoeger, Claudia, Vernaleken, Alexandra, Michel, Dian, Diener, Susanne, Wieland, Thomas, Adamski, Jerzy, Bekeredjian, Raffi, Busch, Dirk H., Favor, John, Graw, Jochen, Klingenspor, Martin, Lengger, Christoph, Maier, Holger, Neff, Frauke, Ollert, Markus, Stoeger, Tobias, Yildirim, Ali Önder, Strom, Tim M., Zimmer, Andreas, Wolf, Eckhard, Wurst, Wolfgang, Klopstock, Thomas, Beckers, Johannes, Gailus-Durner, Valerie, and Hrabé de Angelis, Martin

Subjects
Male, mouse model, genetics [Energy Metabolism], QH426-470, Investigations, pleitropy, Kidney, Kidney Function Tests, Bone and Bones, metabolism [Bone and Bones], Mice, systemic phenotype, ddc:570, pathology [Osteitis Deformans], Genetics, Animals, physiopathology [Kidney], Exome, Genetic Association Studies, Skeleton, Glycoproteins, Mice, Knockout, metabolism [Osteitis Deformans], SCUBE3, Gene Expression Profiling, Calcium-Binding Proteins, metabolism [Kidney], Chromosome Mapping, High-Throughput Nucleotide Sequencing, Osteitis Deformans, abnormalities [Skeleton], Disease Models, Animal, genetics [Osteitis Deformans], Phenotype, Mutation, Scube3 protein, mouse, Female, genetics [Glycoproteins], Paget disease of bone (PDB), Energy Metabolism
Abstract

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3(N294K/N294K)), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3(N294K/N294K) mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3(N294K/N294K) mice. The Scube3(N294K/N294K) mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Published
2016

183. Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study

Author

Molnos, Sophie, primary, Wahl, Simone, additional, Haid, Mark, additional, Eekhoff, E. Marelise W., additional, Pool, René, additional, Floegel, Anna, additional, Deelen, Joris, additional, Much, Daniela, additional, Prehn, Cornelia, additional, Breier, Michaela, additional, Draisma, Harmen H., additional, van Leeuwen, Nienke, additional, Simonis-Bik, Annemarie M. C., additional, Jonsson, Anna, additional, Willemsen, Gonneke, additional, Bernigau, Wolfgang, additional, Wang-Sattler, Rui, additional, Suhre, Karsten, additional, Peters, Annette, additional, Thorand, Barbara, additional, Herder, Christian, additional, Rathmann, Wolfgang, additional, Roden, Michael, additional, Gieger, Christian, additional, Kramer, Mark H. H., additional, van Heemst, Diana, additional, Pedersen, Helle K., additional, Gudmundsdottir, Valborg, additional, Schulze, Matthias B., additional, Pischon, Tobias, additional, de Geus, Eco J. C., additional, Boeing, Heiner, additional, Boomsma, Dorret I., additional, Ziegler, Anette G., additional, Slagboom, P. Eline, additional, Hummel, Sandra, additional, Beekman, Marian, additional, Grallert, Harald, additional, Brunak, Søren, additional, McCarthy, Mark I., additional, Gupta, Ramneek, additional, Pearson, Ewan R., additional, Adamski, Jerzy, additional, and ’t Hart, Leen M., additional

Published
2017
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185. Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Author

Hirose, Misa, primary, Schilf, Paul, additional, Gupta, Yask, additional, Zarse, Kim, additional, Künstner, Axel, additional, Busch, Hauke, additional, Yin, Junping, additional, Wright, Marvin N, additional, Ziegler, Andreas, additional, Vallier, Marie, additional, Belheouane, Meriem, additional, Baines, John F, additional, Tautz, Diethard, additional, Johann, Kornelia, additional, Oelkrug, Rebecca, additional, Mittag, Jens, additional, Lehnert, Hendrik, additional, Othman, Alaa, additional, Jöhren, Olaf, additional, Schwaninger, Markus, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Shima, Kensuke, additional, Rupp, Jan, additional, Haesler, Robert, additional, Fuellen, Georg, additional, Köhling, Rüdiger, additional, Ristow, Michael, additional, and Ibrahim, Saleh M, additional

Published
2017
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186. Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome

Author

Di Dalmazi, Guido, primary, Quinkler, Marcus, additional, Deutschbein, Timo, additional, Prehn, Cornelia, additional, Rayes, Nada, additional, Kroiss, Matthias, additional, Berr, Christina M, additional, Stalla, Günter, additional, Fassnacht, Martin, additional, Adamski, Jerzy, additional, Reincke, Martin, additional, and Beuschlein, Felix, additional

Published
2017
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187. Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes

Author

Jäger, Susanne, primary, Wahl, Simone, additional, Kröger, Janine, additional, Sharma, Sapna, additional, Hoffmann, Per, additional, Floegel, Anna, additional, Pischon, Tobias, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Müller-Nurasyid, Martina, additional, Waldenberger, Melanie, additional, Strauch, Konstantin, additional, Peters, Annette, additional, Gieger, Christian, additional, Suhre, Karsten, additional, Grallert, Harald, additional, Boeing, Heiner, additional, Schulze, Matthias B., additional, and Meidtner, Karina, additional

Published
2017
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188. Fgf9 Y162C Mutation Alters Information Processing and Social Memory in Mice

Author

Garrett, Lillian, primary, Becker, Lore, additional, Rozman, Jan, additional, Puk, Oliver, additional, Stoeger, Tobias, additional, Yildirim, Ali Önder, additional, Bohla, Alexander, additional, Eickelberg, Oliver, additional, Hans, Wolfgang, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Klopstock, Thomas, additional, Rácz, Ildikó, additional, Zimmer, Andreas, additional, Klingenspor, Martin, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Wurst, Wolfgang, additional, Hrabě de Angelis, Martin, additional, Graw, Jochen, additional, and Hölter, Sabine M., additional

Published
2017
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189. Plasma and Serum Metabolite Association Networks: Comparability within and between Studies Using NMR and MS Profiling

Author

Suarez-Diez, Maria, primary, Adam, Jonathan, additional, Adamski, Jerzy, additional, Chasapi, Styliani A., additional, Luchinat, Claudio, additional, Peters, Annette, additional, Prehn, Cornelia, additional, Santucci, Claudio, additional, Spyridonidis, Alexandros, additional, Spyroulias, Georgios A., additional, Tenori, Leonardo, additional, Wang-Sattler, Rui, additional, and Saccenti, Edoardo, additional

Published
2017
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190. Association of Atopic Dermatitis with Cardiovascular Risk Factors and Diseases

Author

Standl, Marie, primary, Tesch, Falko, additional, Baurecht, Hansjörg, additional, Rodríguez, Elke, additional, Müller-Nurasyid, Martina, additional, Gieger, Christian, additional, Peters, Annette, additional, Wang-Sattler, Rui, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Kronenberg, Florian, additional, Schulz, Holger, additional, Koletzko, Sibylle, additional, Schikowski, Tamara, additional, von Berg, Andrea, additional, Lehmann, Irina, additional, Berdel, Dietrich, additional, Heinrich, Joachim, additional, Schmitt, Jochen, additional, and Weidinger, Stephan, additional

Published
2017
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191. LysoPC-acyl C16:0 is associated with brown adipose tissue activity in men

Author

Boon, Mariëtte R., primary, Bakker, Leontine E. H., additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Vosselman, Maarten J., additional, Jazet, Ingrid M., additional, Arias-Bouda, Lenka M. Pereira, additional, van Lichtenbelt, Wouter D. Marken, additional, van Dijk, Ko Willems, additional, Rensen, Patrick C. N., additional, and Mook-Kanamori, Dennis O., additional

Published
2017
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192. Improvement of myocardial infarction risk prediction via inflammation-associated metabolite biomarkers

Author

Ward-Caviness, Cavin K, primary, Xu, Tao, additional, Aspelund, Thor, additional, Thorand, Barbara, additional, Montrone, Corinna, additional, Meisinger, Christa, additional, Dunger-Kaltenbach, Irmtraud, additional, Zierer, Astrid, additional, Yu, Zhonghao, additional, Helgadottir, Inga R, additional, Harris, Tamara B, additional, Launer, Lenore J, additional, Ganna, Andrea, additional, Lind, Lars, additional, Eiriksdottir, Gudny, additional, Waldenberger, Melanie, additional, Prehn, Cornelia, additional, Suhre, Karsten, additional, Illig, Thomas, additional, Adamski, Jerzy, additional, Ruepp, Andreas, additional, Koenig, Wolfgang, additional, Gudnason, Vilmundur, additional, Emilsson, Valur, additional, Wang-Sattler, Rui, additional, and Peters, Annette, additional

Published
2017
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194. Interlaboratory Reproducibility of a Targeted Metabolomics Platform for Analysis of Human Serum and Plasma

Author

Siskos, Alexandros P., primary, Jain, Pooja, additional, Römisch-Margl, Werner, additional, Bennett, Mark, additional, Achaintre, David, additional, Asad, Yasmin, additional, Marney, Luke, additional, Richardson, Larissa, additional, Koulman, Albert, additional, Griffin, Julian L., additional, Raynaud, Florence, additional, Scalbert, Augustin, additional, Adamski, Jerzy, additional, Prehn, Cornelia, additional, and Keun, Hector C., additional

Published
2016
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195. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms

Author

Zimprich, Annemarie, primary, Mroz, Gabi, additional, Meyer zu Reckendorf, Christopher, additional, Anastasiadou, Sofia, additional, Förstner, Philip, additional, Garrett, Lillian, additional, Hölter, Sabine M., additional, Becker, Lore, additional, Rozman, Jan, additional, Prehn, Cornelia, additional, Rathkolb, Birgit, additional, Moreth, Kristin, additional, Wurst, Wolfgang, additional, Klopstock, Thomas, additional, Klingenspor, Martin, additional, Adamski, Jerzy, additional, Wolf, Eckhard, additional, Bekeredjian, Raffi, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, de Angelis, Martin Hrabe, additional, and Knöll, Bernd, additional

Published
2016
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196. Cardiovascular Risk Factors Associated With Blood Metabolite Concentrations and Their Alterations During a 4-Year Period in a Population-Based Cohort

Author

Lacruz, Maria Elena, primary, Kluttig, Alexander, additional, Tiller, Daniel, additional, Medenwald, Daniel, additional, Giegling, Ina, additional, Rujescu, Dan, additional, Prehn, Cornelia, additional, Adamski, Jerzy, additional, Frantz, Stefan, additional, Greiser, Karin Halina, additional, Emeny, Rebecca Thwing, additional, Kastenmüller, Gabi, additional, and Haerting, Johannes, additional

Published
2016
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198. 12-months metabolic changes among gender dysphoric individuals under cross-sex hormone treatment: a targeted metabolomics study

Author

Auer, Matthias K., primary, Cecil, Alexander, additional, Roepke, Yasmin, additional, Bultynck, Charlotte, additional, Pas, Charlotte, additional, Fuss, Johannes, additional, Prehn, Cornelia, additional, Wang-Sattler, Rui, additional, Adamski, Jerzy, additional, Stalla, Günter K., additional, and T’Sjoen, Guy, additional

Published
2016
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199. Multi-omics insights into functional alterations of the liver in insulin-deficient diabetes mellitus.

Author

Backman, Mattias, Flenkenthaler, Florian, Blutke, Andreas, Dahlhoff, Maik, Ländström, Erik, Renner, Simone, Philippou-Massier, Julia, Krebs, Stefan, Rathkolb, Birgit, Prehn, Cornelia, Grzybek, Michal, Coskun, Ünal, Rothe, Michael, Adamski, Jerzy, de Angelis, Martin Hrabĕ, Wanke, Rüdiger, Fröhlich, Thomas, Arnold, Georg J., Blum, Helmut, and Wolf, Eckhard

Abstract

The liver regulates the availability of insulin to other tissues and is the first line insulin response organ physiologically exposed to higher insulin concentrations than the periphery. Basal insulin during fasting inhibits hepatic gluconeogenesis and glycogenolysis, whereas postprandial insulin peaks stimulate glycogen synthesis. The molecular consequences of chronic insulin deficiency for the liver have not been studied systematically. We analyzed liver samples of a genetically diabetic pig model (MIDY) and of wild-type (WT) littermate controls by RNA sequencing, proteomics, and targeted metabolomics/lipidomics. Cross-omics analyses revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis in the MIDY samples. In particular, the concentrations of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and of retinol dehydrogenase 16 (RDH16), which catalyzes the first step in retinoic acid biogenesis, were highly increased. Accordingly, elevated levels of retinoic acid, which stimulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK1), were measured in the MIDY samples. In contrast, pathways related to extracellular matrix and inflammation/pathogen defense response were less active than in the WT samples. The first multi-omics study of a clinically relevant diabetic large animal model revealed molecular signatures and key drivers of functional alterations of the liver in insulin-deficient diabetes mellitus. The multi-omics data set provides a valuable resource for comparative analyses with other experimental or clinical data sets. • MIDY pigs were used to study consequences of insulin-deficient diabetes for the liver. • RDH16 and HMGCS2 were drivers of stimulated gluconeogenesis and ketogenesis in MIDY pigs. • Hepatic immune functions and extracellular matrix were reduced in MIDY pigs. • This multi-omics data resource is valuable for analyses of other liver omics data sets. [ABSTRACT FROM AUTHOR]

Published
2019
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200. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice

Author

Franko, Andras, Huypens, Peter, Neschen, Susanne, Irmler, Martin, Rozman, Jan, Rathkolb, Birgit, Neff, Frauke, Prehn, Cornelia, Dubois, Guillaume, Baumann, Martina, Massinger, Rebecca, Gradinger, Daniel, Przemeck, Gerhard K. H., Repp, Birgit, Aichler, Michaela, Feuchtinger, Annette, Schommers, Philipp, Stoehr, Oliver, Sanchez-Lasheras, Carmen, Adamski, Jerzy, Peter, Andreas, Prokisch, Holger, Beckers, Johannes, Walch, Axel K., Fuchs, Helmut, Wolf, Eckhard, Schubert, Markus, Wiesner, Rudolf J., de Angelis, Martin Hrabe, Franko, Andras, Huypens, Peter, Neschen, Susanne, Irmler, Martin, Rozman, Jan, Rathkolb, Birgit, Neff, Frauke, Prehn, Cornelia, Dubois, Guillaume, Baumann, Martina, Massinger, Rebecca, Gradinger, Daniel, Przemeck, Gerhard K. H., Repp, Birgit, Aichler, Michaela, Feuchtinger, Annette, Schommers, Philipp, Stoehr, Oliver, Sanchez-Lasheras, Carmen, Adamski, Jerzy, Peter, Andreas, Prokisch, Holger, Beckers, Johannes, Walch, Axel K., Fuchs, Helmut, Wolf, Eckhard, Schubert, Markus, Wiesner, Rudolf J., and de Angelis, Martin Hrabe

Abstract

Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondria! mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondria) performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

Published
2016

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