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Search Results: 1 - 10 of 44841 matches for " Michael Stumvoll "
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TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes
Andreas Holstein, Michael Hahn, Antje K?rner, Michael Stumvoll, Peter Kovacs
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-30
Abstract: We recruited 189 patients with T2D being treated with SUs and determined the rs7903146 diabetes risk genotype. We used a logistic regression with secondary SU failure defined as an A1C ≥7.0% after 6 months of SU treatment.In univariate regression analyses, TCF7L2 genotype was the only predictor of SU treatment failure. The rs7903146 T allele was significantly more frequent in the group of patients who failed to respond to SU (36%) than in the control group (26%) [P = 0.046; odds ratio (OR): 1.57 (1.01-2.45) in an additive mode of inheritance].Our data suggest that patients with diabetes risk alleles in TCF7L2 have an altered hypoglycaemic response to SUs resulting in earlier secondary failure.The TCF7L2-gene (TCF7L2; Transcription factor 7-like 2) encodes a transcription factor (Tcf-4) that is involved in the regulation of cellular proliferation and differentiation [1]. Variants in the TCF7L2 have initially been shown to be associated with an increased risk for type 2 diabetes (T2D) in a genome-wide analysis of the isolate population of Iceland [2]. The strongest associations with T2D with a clear gene dose effect were reported for the rs7903146 variant [3]. The initial findings have been replicated in independent studies in multiple ethnic populations and were summarized in a large global meta-analysis [4]. The risk alleles actually predicted the progression from impaired glucose tolerance to diabetes prospectively [5] and an increased severity of the disease [6] in adults. Also, TCF7L2 variants conferred a higher risk for early impairment of glucose metabolism emerging as soon as in childhood and adolescence [7]. Some clinical data suggested that the polymorphisms affected the capacity of pancreatic β-cells to secrete insulin rather than aggravating insulin resistance [5,8-13], possibly by impaired β-cell proinsulin-processing [14]. This was further supported by expression data suggesting a putative role of TCF7L2 in β-cell differentiation [12]. Considering the ro
Adipokine Pattern in Subjects with Impaired Fasting Glucose and Impaired Glucose Tolerance in Comparison to Normal Glucose Tolerance and Diabetes
Anke T?njes,Mathias Fasshauer,Jürgen Kratzsch,Michael Stumvoll,Matthias Blüher
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013911
Abstract: Altered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.
Serum Levels of Acylcarnitines Are Altered in Prediabetic Conditions
Manuel Mai, Anke T?njes, Peter Kovacs, Michael Stumvoll, Georg Martin Fiedler, Alexander Benedikt Leichtle
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082459
Abstract: Objective The role of mitochondrial function in the complex pathogenesis of type 2 diabetes is not yet completely understood. Therefore, the aim of this study was to investigate serum concentrations of short-, medium- and long-chain acylcarnitines as markers of mitochondrial function in volunteers with normal, impaired or diabetic glucose control. Methods Based on a 75 g oral glucose tolerance test, 1019 studied subjects were divided into a group with normal glucose tolerance (NGT; n = 636), isolated impaired fasting glycaemia (IFG; n = 184), impaired glucose tolerance (IGT; n = 87) or type 2 diabetes (T2D; n = 112). Serum concentrations of free carnitine and 24 acylcarnitines were measured by mass spectrometry. Results Serum levels of acetylcarnitine (C2), propionylcarnitine (C3), octanoylcarnitine (C8), malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH), hexanoylcarnitine (C6), octenoylcarnitine (C8:1), decanoylcarnitine (C10), decenoylcarnitine (C10:1), dodecanoylcarnitine (C12), tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), hydroxytetradecanoylcarnitine (C14OH), hydroxyhexadecanoylcarnitine (C16OH) and octadecenoylcarnitine (C18:1) were significantly different among the groups (all p<0.05 adjusted for age, gender and BMI). Between the prediabetic states C14:1, C14:2 and C18:1 showed significantly higher serum concentrations in persons with IGT (p<0.05). Compared to T2D the IFG and the IGT subjects showed lower serum concentrations of malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) (p<0.05). Conclusion Alterations in serum concentrations of several acylcarnitines, in particular tetradecenoylcarnitine (C14:1), tetradecadienylcarnitine (C14:2), octadecenoylcarnitine (C18:1) and malonylcarnitine/hydroxybutyrylcarnitine (C3DC+C4OH) are associated not only with T2D but also with prediabetic states.
MicroRNA Expression in Human Omental and Subcutaneous Adipose Tissue
Nora Kl?ting, Susan Berthold, Peter Kovacs, Michael R. Sch?n, Mathias Fasshauer, Karen Ruschke, Michael Stumvoll, Matthias Blüher
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004699
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs, that play important regulatory roles in a variety of biological processes, including development, differentiation, apoptosis, and metabolism. In mammals, miRNAs have been shown to modulate adipocyte differentiation. Therefore, we performed a global miRNA gene expression assay in different fat depots of overweight and obese individuals to investigate whether miRNA expression in human adipose tissue is fat-depot specific and associated with parameters of obesity and glucose metabolism. Paired samples of abdominal subcutaneous (SC) and intraabdominal omental adipose tissue were obtained from fifteen individuals with either normal glucose tolerance (NGT, n = 9) or newly diagnosed type 2 diabetes (T2D, n = 6). Expression of 155 miRNAs was carried out using the TaqMan?MicroRNA Assays Human Panel Early Access Kit (Applied Biosystems, Darmstadt, Germany). We identified expression of 106 (68%) miRNAs in human omental and SC adipose tissue. There was no miRNA exclusively expressed in either fat depot, suggesting common developmental origin of both fat depots. Sixteen miRNAs (4 in NGT, 12 in T2D group) showed a significant fat depot specific expression pattern. We identified significant correlations between the expression of miRNA-17-5p, -132, -99a, -134, 181a, -145, -197 and both adipose tissue morphology and key metabolic parameters, including visceral fat area, HbA1c, fasting plasma glucose, and circulating leptin, adiponectin, interleukin-6. In conclusion, microRNA expression differences may contribute to intrinsic differences between omental and subcutaneous adipose tissue. In addition, human adipose tissue miRNA expression correlates with adipocyte phenotype, parameters of obesity and glucose metabolism.
Effects of Genetic Variants in ADCY5, GIPR, GCKR and VPS13C on Early Impairment of Glucose and Insulin Metabolism in Children
Jan Windholz, Peter Kovacs, Anke T?njes, Kathrin Dittrich, Susann Blüher, Wieland Kiess, Michael Stumvoll, Antje K?rner
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022101
Abstract: Objective Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of glucose and insulin metabolism in children. Research Design and Methods We genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305) in 638 Caucasian children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose and insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices) by linear regression analyses adjusted for age, sex, BMI-SDS and pubertal stage. Results The major allele (C) of rs2877716 (ADCY5) was nominally associated with decreased fasting plasma insulin (P = 0.008), peak insulin (P = 0.009) and increased QUICKI (P = 0.016) and Matsuda insulin sensitivity index (P = 0.013). rs17271305 (VPS13C) was nominally associated with 2 h blood glucose (P = 0.009), but not with any of the insulin or insulin sensitivity parameters. We found no association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated with anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity. Conclusions Our data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin metabolism and VPS13C in early impairment of blood glucose homeostasis.
COMP-Angiopoietin-1 Recovers Molecular Biomarkers of Neuropathy and Improves Vascularisation in Sciatic Nerve of ob/ob Mice
Joanna Kosacka, Marcin Nowicki, Nora Kl?ting, Matthias Kern, Michael Stumvoll, Ingo Bechmann, Heike Serke, Matthias Blüher
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032881
Abstract: Background 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 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. Methods and Findings 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. Conclusions 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.
Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts
Anke T?njes, Henning Wittenburg, Jan Halbritter, Olga Renner, Simone Harsch, Eduard F Stange, Frank Lammert, Michael Stumvoll, Peter Kovacs
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-149
Abstract: 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.The pathogenesis of gallstone disease is complex and a variety of environmental predisposing factors such as obesity and rapid weight loss, nutrition, certain medications and number of pregnancies have been identified [1-6]. However, human and murine data suggest a strong genetic component for the risk of gallstone formation [7-18]. Very recently, Renner et al. have identified SLC10A2 (apical sodium-dependent bile acid transporter; protein name ASBT) as a novel susceptibility gene for cholelithiasis in humans [19]. SLC10A2 encodes the cholangiocyte bile salt transporter protein whose expression is reduced by a lithogenic diet in mice [20] and mediates intestinal bile acid absorption [21,22]. ASBT is regulated by changes in gene expression in response to biliary bile salt concentration and inflammatory cytokines and is thought to enable cholangiocytes to sense biliary bile salts in order to activate intracellular signaling pathways [23] and to promote cholehepatic shunting of bile salts.
Common Genetic Variation near MC4R Has a Sex-Specific Impact on Human Brain Structure and Eating Behavior
Annette Horstmann, Peter Kovacs, Stefan Kabisch, Yvonne Boettcher, Haiko Schloegl, Anke T?njes, Michael Stumvoll, Burkhard Pleger, Arno Villringer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074362
Abstract: Obesity is associated with genetic and environmental factors but the underlying mechanisms remain poorly understood. Recent genome-wide association studies (GWAS) identified obesity- and type 2 diabetes-associated genetic variants located within or near genes that modulate brain activity and development. Among the top hits is rs17782313 near MC4R, encoding for the melanocortin-4-receptor, which is expressed in brain regions that regulate eating. Here, we hypothesized rs17782313-associated changes in human brain regions that regulate eating behavior. Therefore, we examined effects of common variants at rs17782313 near MC4R on brain structure and eating behavior. Only in female homozygous carriers of the risk allele we found significant increases of gray matter volume (GMV) in the right amygdala, a region known to influence eating behavior, and the right hippocampus, a structure crucial for memory formation and learning. Further, we found bilateral increases in medial orbitofrontal cortex, a multimodal brain structure encoding the subjective value of reinforcers, and bilateral prefrontal cortex, a higher order regulation area. There was no association between rs17782313 and brain structure in men. Moreover, among female subjects only, we observed a significant increase of ‘disinhibition’, and, more specifically, on ‘emotional eating’ scores of the Three Factor Eating Questionnaire in carriers of the variant rs17782313’s risk allele. These findings suggest that rs17782313’s effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific.
Sex-Dependent Influences of Obesity on Cerebral White Matter Investigated by Diffusion-Tensor Imaging
Karsten Mueller,Alfred Anwander,Harald E. M?ller,Annette Horstmann,J?ran Lepsien,Franziska Busse,Siawoosh Mohammadi,Matthias L. Schroeter,Michael Stumvoll,Arno Villringer,Burkhard Pleger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018544
Abstract: Several studies have shown that obesity is associated with changes in human brain function and structure. Since women are more susceptible to obesity than men, it seems plausible that neural correlates may also be different. However, this has not been demonstrated so far. To address this issue, we systematically investigated the brain's white matter (WM) structure in 23 lean to obese women (mean age 25.5 y, std 5.1 y; mean body mass index (BMI) 29.5 kg/m2, std 7.3 kg/m2) and 26 lean to obese men (mean age 27.1 y, std 5.0 y; mean BMI 28.8 kg/m2, std 6.8 kg/m2) with diffusion-weighted magnetic resonance imaging (MRI). There was no significant age (p>0.2) or BMI (p>0.7) difference between female and male participants. Using tract-based spatial statistics, we correlated several diffusion parameters including the apparent diffusion coefficient, fractional anisotropy (FA), as well as axial (λ∥) and radial diffusivity (λ⊥) with BMI and serum leptin levels. In female and male subjects, the putative axon marker λ∥ was consistently reduced throughout the corpus callosum, particularly in the splenium (r = ?0.62, p<0.005). This suggests that obesity may be associated with axonal degeneration. Only in women, the putative myelin marker λ⊥ significantly increased with increasing BMI (r = 0.57, p<0.005) and serum leptin levels (r = 0.62, p<0.005) predominantly in the genu of the corpus callosum, suggesting additional myelin degeneration. Comparable structural changes were reported for the aging brain, which may point to accelerated aging of WM structure in obese subjects. In conclusion, we demonstrate structural WM changes related to an elevated body weight, but with differences between men and women. Future studies on obesity-related functional and structural brain changes should therefore account for sex-related differences.
Eigenvector Centrality Mapping for Analyzing Connectivity Patterns in fMRI Data of the Human Brain
Gabriele Lohmann,Daniel S. Margulies,Annette Horstmann,Burkhard Pleger,Joeran Lepsien,Dirk Goldhahn,Haiko Schloegl,Michael Stumvoll,Arno Villringer,Robert Turner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010232
Abstract: Functional magnetic resonance data acquired in a task-absent condition (“resting state”) require new data analysis techniques that do not depend on an activation model. In this work, we introduce an alternative assumption- and parameter-free method based on a particular form of node centrality called eigenvector centrality. Eigenvector centrality attributes a value to each voxel in the brain such that a voxel receives a large value if it is strongly correlated with many other nodes that are themselves central within the network. Google's PageRank algorithm is a variant of eigenvector centrality. Thus far, other centrality measures - in particular “betweenness centrality” - have been applied to fMRI data using a pre-selected set of nodes consisting of several hundred elements. Eigenvector centrality is computationally much more efficient than betweenness centrality and does not require thresholding of similarity values so that it can be applied to thousands of voxels in a region of interest covering the entire cerebrum which would have been infeasible using betweenness centrality. Eigenvector centrality can be used on a variety of different similarity metrics. Here, we present applications based on linear correlations and on spectral coherences between fMRI times series. This latter approach allows us to draw conclusions of connectivity patterns in different spectral bands. We apply this method to fMRI data in task-absent conditions where subjects were in states of hunger or satiety. We show that eigenvector centrality is modulated by the state that the subjects were in. Our analyses demonstrate that eigenvector centrality is a computationally efficient tool for capturing intrinsic neural architecture on a voxel-wise level.
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