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440 results on '"Machicao, Fausto"'

1. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Human Genome, Nutrition, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Published
2018

2. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A, Gustafsson, Stefan, Rybin, Denis, Stančáková, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A, Rice, Ken, Morris, Andrew P, Mägi, Reedik, Tönjes, Anke, Prokopenko, Inga, Kleber, Marcus E, Delgado, Graciela, Silbernagel, Günther, Jackson, Anne U, Appel, Emil V, Grarup, Niels, Lewis, Joshua P, Montasser, May E, Landenvall, Claes, Staiger, Harald, Luan, Jian’an, Frayling, Timothy M, Weedon, Michael N, Xie, Weijia, Morcillo, Sonsoles, Martínez-Larrad, María Teresa, Biggs, Mary L, Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Færch, Kristine, Gómez-Zumaquero, Juan Miguel, Goodarzi, Mark O, Kizer, Jorge R, Koistinen, Heikki A, Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K, Martín-Núñez, Gracia María, Rojo-Martínez, Gemma, Rotter, Jerome I, Siscovick, David S, Zmuda, Joseph M, Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jørgensen, Torben J, Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A, Wareham, Nicholas J, Fritsche, Andreas, Häring, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O’Connell, Jeff R, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, März, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M, Kuusisto, Johanna, Laakso, Markku, Meigs, James B, Dupuis, Josée, Ingelsson, Erik, and Florez, Jose C

Subjects
Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Chemokines, CC, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-bcl-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Published
2016

3. Genome-wide analysis of PDX1 target genes in human pancreatic progenitors

Author

Wang, Xianming, Sterr, Michael, Burtscher, Ingo, Chen, Shen, Hieronimus, Anja, Machicao, Fausto, Staiger, Harald, Häring, Hans-Ulrich, Lederer, Gabriele, Meitinger, Thomas, Cernilogar, Filippo M., Schotta, Gunnar, Irmler, Martin, Beckers, Johannes, Hrabě de Angelis, Martin, Ray, Michael, Wright, Christopher V.E., Bakhti, Mostafa, and Lickert, Heiko

Published
2018
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6. Identification of proliferative and mature β-cells in the islets of Langerhans

Author

Bader, Erik, Migliorini, Adriana, Gegg, Moritz, Moruzzi, Noah, Gerdes, Jantje, Roscioni, Sara S., Bakhti, Mostafa, Brandl, Elisabeth, Irmler, Martin, Beckers, Johannes, Aichler, Michaela, Feuchtinger, Annette, Leitzinger, Christin, Zischka, Hans, Wang-Sattler, Rui, Jastroch, Martin, Tschop, Matthias, Machicao, Fausto, Staiger, Harald, Haring, Hans-Ulrich, Chmelova, Helena, Chouinard, Julie A., Oskolkov, Nikolay, Korsgren, Olle, Speier, Stephan, and Lickert, Heiko

Subjects
Islands of Langerhans -- Physiological aspects, Cells -- Identification and classification, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential (1-5); understanding the [...]

Published
2016

15. Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans

Author

Lutz, Stefan Z., Falcenberg, Mathias, Machicao, Fausto, Peter, Andreas, Kächele, Martin, Randrianarisoa, Elko, Lehn-Stefan, Angela, Wagner, Robert, Machann, Jürgen, Schick, Fritz, Heni, Martin, Ullrich, Axel, Fritsche, Andreas, Stefan, Norbert, Häring, Hans-Ulrich, Staiger, Harald, and Kantartzis, Konstantinos

Subjects
Adult, G-Protein-Coupled Receptor Kinase 5, Male, Genotype, Cardiovascular Abnormalities, lcsh:R, lcsh:Medicine, Cholesterol, LDL, Middle Aged, Carotid Intima-Media Thickness, Lipids, Polymorphism, Single Nucleotide, Article, Diabetes Mellitus, Type 2, Humans, Insulin, Female, Genetic Predisposition to Disease, lcsh:Q, Insulin Resistance, lcsh:Science
Abstract

Genetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.

Published
2018
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16. The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway

Author

‘t Hart, Leen M., Fritsche, Andreas, Nijpels, Giel, van Leeuwen, Nienke, Donnelly, Louise A., Dekker, Jacqueline M., Alssema, Marjan, Fadista, Joao, Carlotti, Françoise, Gjesing, Anette P., Palmer, Colin N.A., van Haeften, Timon W., Herzberg-Schäfer, Silke A., Simonis-Bik, Annemarie M.C., Houwing-Duistermaat, Jeanine J., Helmer, Quinta, Deelen, Joris, Guigas, Bruno, Hansen, Torben, Machicao, Fausto, Willemsen, Gonneke, Heine, Robert J., Kramer, Mark H.H., Holst, Jens J., de Koning, Eelco J.P., Häring, Hans-Ulrich, Pedersen, Oluf, Groop, Leif, de Geus, Eco J.C., Slagboom, P. Eline, Boomsma, Dorret I., Eekhoff, Elisabeth M.W., Pearson, Ewan R., and Diamant, Michaela

Published
2013
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19. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

Author

't Hart, Leen M., Fritsche, Andreas, Nijpels, Giel, van Leeuwen, Nienke, Donnelly, Louise A., Dekker, Jacqueline M., Alssema, Marjan, Fadista, Joao, Carlotti, Francoise, Gjesing, Anette P., Palmer, Colin N.A., van Haeften, Timon W., Herzberg-Schafer, Silke A., Simonis-Bik, Annemarie M.C., Houwing-Duistermaat, Jeanine J., Helmer, Quinta, Deelen, Joris, Guigas, Bruno, Hansen, Torben, Machicao, Fausto, Willemsen, Gonneke, Heine, Robert J., Kramer, Mark H.H., Hoist, Jens J., de Koning, Eelco J.P., Haring, Hans-Ulrich, Pedersen, Oluf, Groop, Leif, de Geus, Eco J.C., Slagboom, P. Eline, Boomsma, Dorret I., Eekhoff, Elisabeth M.W., Pearson, wan R., and Diamant, Michaela

Subjects
Genetic susceptibility -- Research, Glucose metabolism -- Physiological aspects -- Genetic aspects -- Research, Type 2 diabetes -- Risk factors -- Genetic aspects -- Research, Glucagon -- Physiological aspects -- Genetic aspects -- Research, Health
Abstract

The incretin hormone glucagon-like peptide 1 (GLP-I) promotes glucose homeostasis and enhances B-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 x [10.sup.-7]). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmo/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment., The incretin hormone glucagon-like peptide 1 (GLP-1) is released after a meal by L cells in the distal parts of the gastrointestinal tract, and it potentiates glucose-dependent insulin secretion by [...]

Published
2013
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24. Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

Author

‘t Hart, Leen M., Simonis-Bik, Annemarie M., Nijpels, Giel, van Haeften, Timon W., Schäfer, Silke A., Houwing-Duistermaat, Jeanine J., Boomsma, Dorret I., Groenewoud, Marlous J., Reiling, Erwin, van Hove, Els C., Diamant, Michaela, Kramer, Mark H.H., Heine, Robert J., Maassen, J. Antonie, Kirchhoff, Kerstin, Machicao, Fausto, Häring, Hans-Ulrich, Slagboom, P. Eline, Willemsen, Gonneke, Eekhoff, Elisabeth M., de Geus, Eco J., Dekker, Jacqueline M., and Fritsche, Andreas

Published
2010

31. Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps

Author

t' Hart, Leen M., Simonis-Bik, Annemarie M., Nijpels, Giel, van Haeften, Timon W., Schafer, Silke A., Houwing-Duistermaat, Jeanine J., Boomsma, Dorret I., Groenewoud, Marlous J., Reiling, Erwin, van Hove, Els C., Diamant, Michaela, Kramer, Mark H.H., Heine, Robert J., Maassen, J. Antonie, Kirchhoff, Kerstin, Machicao, Fausto, Haring, Hans-Ulrich, Slagboom, P. Eline, Willemsen, Gonneke, Eekhoff, Elisabeth M., de Geus, Eco J., Dekker, Jacqueline M., and Fritsche, Andreas

Subjects
Pancreatic beta cells -- Research, Type 2 diabetes -- Genetic aspects -- Risk factors, Allelomorphism -- Research, Health
Abstract

OBJECTIVE--At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS--A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS--The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x [10.sup.-6]). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x [10.sup.-3]). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different. CONCLUSIONS--A combined risk allele score for eight known β-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci., Type 2 diabetes is a polygenic disease in which the contribution of a number of detrimental gene variants in combination with environmental factors is thought to be necessary for the [...]

Published
2010
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40. Heremans-Schmid glycoprotein/ fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans

Author

Stefan, Norbert, Hennige, Anita M., Staiger, Harald, Machann, Jurgen, Schick, Fritz, Krober, Stefan M., Machicao, Fausto, Fritsche, Andreas, and Haring, Hans-Ulrich

Subjects
Diabetes -- Research, Insulin resistance -- Risk factors -- Research, Alpha fetoproteins -- Research, Type 2 diabetes -- Causes of -- Research -- Risk factors, Health, Research, Risk factors, Causes of
Abstract

OBJECTIVE--The [α.sub.2]-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal [...]

Published
2006

44. Genetic and insulin secretion: gene variants in the IGF genes

Author

Hart, Leen M., Fritsche, Andreas, Rietveld, Ingrid, Dekker, Jacqueline M., Nijpels, Giel, Machicao, Fausto, Stumvoll, Michael, van Duijn, Cornelia M., Haring, Hans U., Heine, Robert J., Maassen, J. Antonie, and van Haeften, Timon W.

Subjects
Pancreatic beta cells -- Health aspects -- Case studies, Type 2 diabetes -- Case studies -- Genetic aspects -- Health aspects, Immunoglobulin genes -- Case studies -- Health aspects, Health, Case studies, Genetic aspects, Health aspects
Abstract

IGFs are important regulators of pancreatic β-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI., IGFs are regulators of processes like growth and metabolism (1-3). IGF-I and IGF-II also contribute to pancreatic β-cell growth and development by regulating β-cell replication, renewal, and apoptosis (4,5). Deregulation [...]

Published
2004

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