Michael Stumvoll

Publications of Michael Stumvoll

• A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

  Authors: Alisa K Manning, Marie-France Hivert, Robert A Scott, Jonna L Grimsby, Nabila Bouatia-Naji, Han Chen, Denis Rybin, Ching-Ti Liu, Lawrence F Bielak, Inga Prokopenko [......] Tatijana Zemunik, Lina Zgaga, Nicholas J Wareham, Mark I McCarthy, Ines Barroso, Richard M Watanabe, Jose C Florez, Josée Dupuis, James B Meigs, Claudia Langenberg

  Nature genetics. 05/2012;

  Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of theRecent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

• CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?

  Authors: Jonas Rosendahl, Olfert Landt, Jana Bernadova, Peter Kovacs, Niels Teich, Hans Bödeker, Volker Keim, Claudia Ruffert, Joachim Mössner, Andreas Kage, Michael Stumvoll, David Groneberg, Renate Krüger, Werner Luck, Matthias Treiber, Michael Becker, Heiko Witt

  Gut. 03/2012;

  ObjectiveIn chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes.Design660 patientsObjectiveIn chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes.Design660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis.ResultsFrequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001).ConclusionsAccumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.

• Genetics of adiponectin.

  Authors: Jana Breitfeld, Michael Stumvoll, Peter Kovacs

  Biochimie. 03/2012;

  Anti-inflammatory, anti-atherogenic and anti-diabetic properties of adiponectin make this adipokine an attractive target in the metabolism research. Given its biological role, genetic variation inAnti-inflammatory, anti-atherogenic and anti-diabetic properties of adiponectin make this adipokine an attractive target in the metabolism research. Given its biological role, genetic variation in adiponectin affecting its function might consequently play a role in the pathophysiology of various metabolic disorders. In this light, genetic aspects of adiponectin including its gene structure, heritability of serum concentrations and the role of genetic variation have been addressed in multiple genetic studies. Here, we provide a brief summary of adiponectin genetics with focus on gene structure and genetic variation controlling circulating adiponectin levels. We summarize the main findings from genome-wide linkage and association studies that have revealed the major genetic determinants of serum adiponectin. Beside genetic variants in the adiponectin gene, several other genes/loci (ARL15, CDH13, KNG1, FER, ETV5) contributing to the variability in circulating adiponectin have been identified. The majority of these variants are significantly associated with metabolic phenotypes relevant to metabolic diseases (e.g. obesity or type 2 diabetes (T2D)). Considering the protective properties of adiponectin in diseases such as T2D, comprehensive analyses of genetic variants including rare as well as frequent polymorphisms might provide insights on the specific role of adiponectin in the pathophysiology of metabolic diseases.

• No Interactions Between Previously Associated 2-h Glucose Gene Variants and Physical Activity or BMI on 2-h Glucose Levels.

  Authors: Robert A Scott, Audrey Y Chu, Niels Grarup, Alisa K Manning, Marie-France Hivert, Dmitry Shungin, Anke Tönjes, Ajay Yesupriya, Daniel Barnes, Nabila Bouatia-Naji [......] Richard M Watanabe, Oluf Pedersen, James B Meigs, Erik Ingelsson, Inês Barroso, Jose C Florez, Paul W Franks, Josée Dupuis, Nicholas J Wareham, Claudia Langenberg

  Diabetes. 03/2012;

  Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-gram glucose challenge are used to diagnose diabetes andGene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-gram glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × Physical Activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

• Substantial Increase in Incidence of Severe Hypoglycemia Between 1997-2000 and 2007-2010: A German longitudinal population-based study.

  Authors: Andreas Holstein, Olaf M Patzer, Kathrin Machalke, Judith D Holstein, Michael Stumvoll, Peter Kovacs

  Diabetes care. 03/2012;

  OBJECTIVETo compare the incidences of severe hypoglycemia and corresponding clinical circumstances in a German population between 2007-2010 and 1997-2000.RESEARCH DESIGN AND METHODSA screening forOBJECTIVETo compare the incidences of severe hypoglycemia and corresponding clinical circumstances in a German population between 2007-2010 and 1997-2000.RESEARCH DESIGN AND METHODSA screening for severe hypoglycemia was performed in the Lippe-Detmold area in Germany to sensitively detect severe hypoglycemia. This was defined as a symptomatic event requiring treatment with intravenous glucose and being confirmed by a blood glucose measurement of <50 mg/dL.RESULTSSevere hypoglycemia increased considerably from 264 events in 1997-2000 to 495 events in 2007-2010, which translated into an increase in frequency of severe hypoglycemia among all emergency admissions from 0.68 to 0.83% (P = 0.015). This was mostly related to intensification of antihyperglycemic therapy, particularly in the increasingly morbid group of hypoglycemic patients with type 2 diabetes indicated by lower HbA(1c), more comedication (3.3 vs. 7.7 drugs), and more concomitant diseases (3.6 vs. 4.4) (all P values <0.001).CONCLUSIONSWithin a 10-year period, there was an intensification of antihyperglycemic therapy in increasingly comorbid subjects, leading to a considerably higher incidence of severe hypoglycemia.

• Genome-wide association and functional follow-up reveals new Loci for kidney function.

  Authors: Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun [......] Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, Caroline S Fox

  PLoS genetics. 03/2012; 8(3):e1002584.

  Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, andChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

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• A genome-wide association search for type 2 diabetes genes in African Americans.

  Authors: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock [......] Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek

  PloS one. 01/2012; 7(1):e29202.

  African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was toAfrican Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

• A common variant of PNPLA3 (p.I148M) is not associated with alcoholic chronic pancreatitis.

  Authors: Jonas Rosendahl, Anke Tönjes, Dorit Schleinitz, Peter Kovacs, Johannes Wiegand, Claudia Ruffert, Moritz Jesinghaus, Robert Schober, Max Herms, Robert Grützmann [......] Michael Stumvoll, Stephan Böhm, Thomas Berg, Henning Wittenburg, Joachim Mössner, Rene te Morsche, Monique Derikx, Volker Keim, Heiko Witt, Joost P H Drenth

  PloS one. 01/2012; 7(1):e29433.

  Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse.Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6-3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls. The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis.

• The Ser1369Ala variant of ABCC8 and the risk for severe sulfonylurea-induced hypoglycemia in German patients with Type 2 diabetes.

  Authors: Judith Dina Holstein, Peter Kovacs, Olaf Patzer, Michael Stumvoll, Andreas Holstein

  Pharmacogenomics. 01/2012; 13(1):5-7; author reply 9-10.

  A letter in response to: Sato R, Watanabe H, Genma R et al. ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas. Pharmacogenomics 11(12), 1743-1750 (2010).

• COMP-Angiopoietin-1 Recovers Molecular Biomarkers of Neuropathy and Improves Vascularisation in Sciatic Nerve of ob/ob Mice.

  Authors: Joanna Kosacka, Marcin Nowicki, Nora Klöting, Matthias Kern, Michael Stumvoll, Ingo Bechmann, Heike Serke, Matthias Blüher

  PloS one. 01/2012; 7(3):e32881.

  Leptin-deficient ob/ob mice are a model of type 2 diabetes induced peripheral neuropathy. Ob/ob mice exhibit obesity, insulin resistance, hyperglycaemia, and alterations of peripheral nerve fibresLeptin-deficient ob/ob mice are a model of type 2 diabetes induced peripheral neuropathy. Ob/ob mice exhibit obesity, insulin resistance, hyperglycaemia, and alterations of peripheral nerve fibres and endoneural microvessels. Here we test the hypothesis that cartilage oligomeric matrix protein (COMP)-Ang-1, a soluble and stabile form of Ang-1 which promotes angiogenesis and nerve growth, improves regeneration of nerve fibres and endoneural microvessels in ob/ob mice. COMP-Ang-1 (100 ng/ml) or NaCl were intraperitoneally (i.p.) injected into male (N = 184), 3-month old, ob/ob or ob/+ mice for 7 and 21 days. We measured expression of Nf68, GAP43, Cx32, Cx26, Cx43, and TNFα in sciatic nerves using Western blot analysis. To investigate the inflammation in sciatic nerves, numbers of macrophages and T-cells were counted after immunofluorescence staining. In ultrathin section, number of myelinated/non-mylinated nerve fibers, g-ratio, the thickness of Schwann cell basal lamina and microvessel endothelium were investigated. Endoneural microvessels were reconstructed with intracardial FITC injection. Treatment with COMP-Ang-1 over 21 days significantly reduced fasting blood glucose and plasma cholesterol concentrations compared to saline treated ob/ob mice. In addition, COMP-Ang-1 treatment: 1) up-regulated expression of Nf68 and GAP43; 2) improved expression of gap junction proteins including connexin 32 and 26; 3) suppressed the expression of TNFα and Cx43 and 4) led to decreased macrophage and T-cell infiltration in sciatic nerve of ob/ob mice. The significant changes of sciatic nerve ultrastructure were not observed after 21-day long COMP-Ang-1 treatment. COMP-Ang-1 treated ob/ob mice displayed regeneration of small-diameter endoneural microvessels. Effects of COMP-Ang-1 corresponded to increased phosphorylation of Akt and p38 MAPK upon Tie-2 receptor. COMP-Ang-1 recovers molecular biomarkers of neuropathy, promotes angiogenesis and suppresses inflammation in sciatic nerves of ob/ob mice suggesting COMP-Ang-1 as novel treatment option to improve morphologic and protein expression changes associated with diabetic neuropathy.

• Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention.

  Authors: Matthias Blüher, Assaf Rudich, Nora Klöting, Rachel Golan, Yaakov Henkin, Eitan Rubin, Dan Schwarzfuchs, Yftach Gepner, Meir J Stampfer, Martin Fiedler, Joachim Thiery, Michael Stumvoll, Iris Shai

  Diabetes care. 12/2011; 35(2):342-9.

  Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continuedLong-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain. We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss. We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0-6) going in the opposite direction to that in the weight maintenance/regain phase (months 7-24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B. hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.

• C57BL/6JRj mice are protected against diet induced obesity (DIO).

  Authors: Matthias Kern, Anja Knigge, John T Heiker, Joanna Kosacka, Michael Stumvoll, Peter Kovacs, Matthias Blüher, Nora Klöting

  Biochemical and biophysical research communications. 12/2011; 417(2):717-20.

  The C57BL/6 (B6) is one of the oldest inbred mouse strains. It has been widely used as control strain in metabolism research for many decades. Preliminary data from our lab indicated that C57BL/6JRjThe C57BL/6 (B6) is one of the oldest inbred mouse strains. It has been widely used as control strain in metabolism research for many decades. Preliminary data from our lab indicated that C57BL/6JRj mice are not responding to diet induced obesity. Therefore, the aim of this study was to compare the two different B6 substrains, C57BL/6NTac and C57BL/6JRj, in regard to their response to diet induced obesity (DIO) and to investigate genetic differences which may explain such phenotypic differences. Sixteen male mice of C57BL/6NTac and C57BL/6JRj were fed a high fat diet (HFD) or standard chow diet (SD) for 10 weeks. Phenotypic characterization included measurements of bodyweight, physical activity, food intake and relative epigonadal fat mass. Genetic differences between both substrains were analyzed using a panel of 1449 single nucleotide polymorphism (SNP) markers. Our study revealed that C57BL/6JRj mice are protected against DIO independently from food intake and physical activity. Genetic SNP analysis among C57BL/6 mice identified genetic differences in at least 11 SNPs. Our data strongly support the importance of attention on the genetic background in obesity research.

• Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity.

  Authors: Rima Chakaroun, Matthias Raschpichler, Nora Klöting, Andreas Oberbach, Gesine Flehmig, Matthias Kern, Michael R Schön, Edward Shang, Tobias Lohmann, Miriam Dreßler, Mathias Fasshauer, Michael Stumvoll, Matthias Blüher

  Metabolism: clinical and experimental. 12/2011;

  Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory statesChemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery-induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.

• Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts.

  Authors: Anke Tönjes, Henning Wittenburg, Jan Halbritter, Olga Renner, Simone Harsch, Eduard F Stange, Frank Lammert, Michael Stumvoll, Peter Kovacs

  BMC medical genetics. 11/2011; 12:149.

  Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis inRecently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.

• Successful simultaneous pancreas kidney transplantation in maturity-onset diabetes of the young type 5.

  Authors: Jan Halbritter, Christof Mayer, Anette Bachmann, Franz M Rasche, Dirk Uhlmann, Michael Stumvoll, Tom H Lindner

  Transplantation. 10/2011; 92(8):e45-7.

• A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol.

  Authors: Ida Surakka, Aaron Isaacs, Lennart C Karssen, Pirkka-Pekka P Laurila, Rita P S Middelberg, Emmi Tikkanen, Janina S Ried, Claudia Lamina, Massimo Mangino, Wilmar Igl [......] H-Erich Wichmann, Christian Gieger, Marjo-Riitta Järvelin, Nicholas G Martin, Albert Hofman, Mark I McCarthy, Leena Peltonen, Cornelia M van Duijn, Yurii S Aulchenko, Samuli Ripatti

  PLoS genetics. 10/2011; 7(10):e1002333.

  Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screenRecent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

• Effects of a 2-y dietary weight-loss intervention on cholesterol metabolism in moderately obese men.

  Authors: Alexander B Leichtle, Christin Helmschrodt, Uta Ceglarek, Iris Shai, Yaakov Henkin, Dan Schwarzfuchs, Rachel Golan, Yftach Gepner, Meir J Stampfer, Matthias Blüher, Michael Stumvoll, Joachim Thiery, Georg M Fiedler

  The American journal of clinical nutrition. 09/2011; 94(5):1189-95.

  Long-term dietary weight loss results in complex metabolic changes. However, its effect on cholesterol metabolism in obese subjects is still unclear. We assessed the effects of 2 y of weight lossLong-term dietary weight loss results in complex metabolic changes. However, its effect on cholesterol metabolism in obese subjects is still unclear. We assessed the effects of 2 y of weight loss achieved with various diet regimens on phytosterols (markers of intestinal cholesterol absorption), lanosterol (marker of de novo cholesterol synthesis), and changes in apolipoprotein concentrations. We conducted the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT-a study of low-fat, Mediterranean, and low-carbohydrate diets). We assessed circulating phytosterol and lanosterol concentrations and their ratios to cholesterol and apolipoproteins A-I and B-100 in 90 DIRECT participants at 0, 6, and 24 mo. We observed a significant upregulation of the markers of cholesterol absorption (campesterol: +16.8%, P < 0.001) and a downregulation of the markers of cholesterol synthesis (lanosterol: -16.5%, P = 0.008) during the active weight-loss phase (first 6 mo, weight loss of 5%, 6%, and 10% in the 3 diet groups, respectively), followed by a rebound (campesterol: -6.2%, P = 0.045; lanosterol: +43.7%, P < 0.001) during the next 18 mo (weight gain of 1%, 1%, and 2% in the 3 diet groups, respectively). HDL cholesterol continuously increased during the study (17.0%, P < 0.001), whereas LDL cholesterol remained constant. At the end of the 24-mo follow-up period, campesterol (P < 0.001) and lanosterol (P = 0.016) amounts were significantly higher than baseline values. The concentration of apolipoprotein B-100 correlated with cholesterol metabolism (ρ = 0.299 and P = 0.020 for lanosterol; ρ = -0.105 and NS for campesterol), and the homeostasis model assessment of insulin resistance correlated with lanosterol (ρ = 0.09, P = 0.001). Long-term weight loss is related to a characteristic response suggestive of altered cholesterol and apolipoprotein metabolism. Various diets have a similar effect on these effects. DIRECT is registered at clinicaltrials.gov as NCT00160108.

• Surprising thoracic tumour mass.

  Authors: Anke Tönjes, Steffen Peterson, Matthias Seiwerts, Michael Stumvoll, Dagmar Führer

  Emergency medicine journal : EMJ. 08/2011;

• Dietary intervention induces flow of changes within biomarkers of lipids, inflammation, liver enzymes, and glycemic control.

  Authors: Rachel Golan, Amir Tirosh, Dan Schwarzfuchs, Ilana Harman-Boehm, Joachim Thiery, Georg Martin Fiedler, Matthias Blüher, Michael Stumvoll, Iris Shai

  Nutrition (Burbank, Los Angeles County, Calif.). 08/2011; 28(2):131-7.

  To determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetesTo determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetes (T2D). We examined the dynamics and intercorrelations among changes in biomarkers during the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT) in 322 participants (including 46 with T2D; 52 y of age, body mass index 31 kg/m(2)) throughout rapid weight loss (0-6 mo) and weight-maintenance/regain (7-24 mo) phases. The 2-y increase of high-density lipoprotein cholesterol was greater in participants with T2D (+9.41 versus+6.57 mg/dL, P < 0.05), although they tended to have smaller waist circumferences (-2.1 versus -4.0 cm, P = 0.08). In models adjusted for age, sex, and weight loss, the 2-year decrease of triacylglycerols was associated with increases of low-density and high-density lipoprotein cholesterol. An increase of apolipoprotein A1 was associated with a decrease in high-sensitive C-reactive protein (P < 0.05 for all comparisons). Exclusively in participants with T2D, the 2-year decrease in triacylglycerols was further correlated with decreases in apolipoprotein B100 and liver enzymes, and a decrease in fasting glucose correlated with decreases in low-density lipoprotein cholesterol, apolipoprotein B100, and alanine aminotransferase (P < 0.05 for all comparisons). In the entire group, multivariate models adjusted for age, sex, intervention group, and 6-mo weight loss identified decreased high-sensitive C-reactive protein at 6 mo as an exclusive predictor of a greater decrease in triacylglycerols (β = 0.154, P = 0.008) and a greater increase in high-density lipoprotein cholesterol (β = -0.452, P = 0.005) during the subsequent 18 mo. Long-term dietary intervention induces a flow of changes within biomarkers and the cross-talk is likely to be stronger in T2D. A decrease in systemic inflammation during the weight-loss phase may predict greater long-term improvement in lipids (www.ClinicalTrials.gov, identifier NCT00160108).

• Role of genetic variation in the human sodium-glucose cotransporter 2 gene (SGLT2) in glucose homeostasis.

  Authors: Uta Enigk, Jana Breitfeld, Dorit Schleinitz, Kerstin Dietrich, Jan Halbritter, Antje Fischer-Rosinsky, Beate Enigk, Ines Müller, Joachim Spranger, Andreas Pfeiffer, Michael Stumvoll, Peter Kovacs, Anke Tönjes

  Pharmacogenomics. 08/2011; 12(8):1119-26.

  Mutations in the sodium-glucose cotransporter 2 (SGLT2), as well as treatment with SGLT2 inhibitors result in reduced fasting glucose levels, HbA(1c) and BMI. We therefore investigated the effects ofMutations in the sodium-glucose cotransporter 2 (SGLT2), as well as treatment with SGLT2 inhibitors result in reduced fasting glucose levels, HbA(1c) and BMI. We therefore investigated the effects of common genetic variation in SGLT2 on human Type 2 diabetes and related traits. Four HapMap tagging SNPs covering the common genetic variation in SGLT2 (r² > 0.8 and minor allele frequency > 0.01) were genotyped for subsequent association studies on BMI, Type 2 diabetes and related metabolic traits in 1013 Sorbs (Germany). An independent cohort from Berlin (n = 2042) was taken for replication. The rs9934336 G-allele was nominally associated with increased 30-min plasma glucose, 120-min insulin concentrations and AUC120min(glucose) during oral glucose tolerance test in 907 nondiabetic Sorbs (p < 0.05). In the combined analysis including the Sorbs and the Berlin cohort, rs9934336 was nominally associated with 120-min insulin concentrations (adjusted p < 0.05) in nondiabetic subjects (n = 2590). Our data suggest a role of SGLT2 genetic variation in the regulation of glucose homeostasis and promote pharmacogenomic studies to clarify the efficacy of antidiabetic treatment by SGLT2 inhibitors.