Showing papers by "Andreas Pfeiffer published in 2007"

CMS physics technical design report, volume II: Physics performance

Abstract: CMS is a general purpose experiment, designed to study the physics of pp collisions at 14 TeV at the Large Hadron Collider (LHC). It currently involves more than 2000 physicists from more than 150 institutes and 37 countries. The LHC will provide extraordinary opportunities for particle physics based on its unprecedented collision energy and luminosity when it begins operation in 2007. The principal aim of this report is to present the strategy of CMS to explore the rich physics programme offered by the LHC. This volume demonstrates the physics capability of the CMS experiment. The prime goals of CMS are to explore physics at the TeV scale and to study the mechanism of electroweak symmetry breaking--through the discovery of the Higgs particle or otherwise. To carry out this task, CMS must be prepared to search for new particles, such as the Higgs boson or supersymmetric partners of the Standard Model particles, from the start-up of the LHC since new physics at the TeV scale may manifest itself with modest data samples of the order of a few fb−1 or less. The analysis tools that have been developed are applied to study in great detail and with all the methodology of performing an analysis on CMS data specific benchmark processes upon which to gauge the performance of CMS. These processes cover several Higgs boson decay channels, the production and decay of new particles such as Z' and supersymmetric particles, Bs production and processes in heavy ion collisions. The simulation of these benchmark processes includes subtle effects such as possible detector miscalibration and misalignment. Besides these benchmark processes, the physics reach of CMS is studied for a large number of signatures arising in the Standard Model and also in theories beyond the Standard Model for integrated luminosities ranging from 1 fb−1 to 30 fb−1. The Standard Model processes include QCD, B-physics, diffraction, detailed studies of the top quark properties, and electroweak physics topics such as the W and Z0 boson properties. The production and decay of the Higgs particle is studied for many observable decays, and the precision with which the Higgs boson properties can be derived is determined. About ten different supersymmetry benchmark points are analysed using full simulation. The CMS discovery reach is evaluated in the SUSY parameter space covering a large variety of decay signatures. Furthermore, the discovery reach for a plethora of alternative models for new physics is explored, notably extra dimensions, new vector boson high mass states, little Higgs models, technicolour and others. Methods to discriminate between models have been investigated. This report is organized as follows. Chapter 1, the Introduction, describes the context of this document. Chapters 2-6 describe examples of full analyses, with photons, electrons, muons, jets, missing ET, B-mesons and τ's, and for quarkonia in heavy ion collisions. Chapters 7-15 describe the physics reach for Standard Model processes, Higgs discovery and searches for new physics beyond the Standard Model

CMS physics technical design report: Addendum on high density QCD with heavy ions

Abstract: This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies , will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction ? Quantum Chromodynamics (QCD) ? in extreme conditions of temperature, density and parton momentum fraction (low-x).This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include bulk observables, (charged hadron multiplicity, low pT inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high pT hadrons which yield tomographic information of the hottest and densest phases of the reaction.

An accurate risk score based on anthropometric, dietary, and lifestyle factors to predict the development of type 2 diabetes.

Abstract: OBJECTIVE —We aimed to develop a precise risk score for the screening of large populations for individuals at high risk of developing type 2 diabetes based on noninvasive measurements of major risk factors in German study populations. RESEARCH DESIGN AND METHODS —A prospective cohort study (European Prospective Investigation into Cancer and Nutrition [EPIC]-Potsdam study) of 9,729 men and 15,438 women aged 35–65 years was used to derive a risk score predicting incident type 2 diabetes. Multivariate Cox regression model coefficients were used to weigh each variable in the calculation of the score. Data from the EPIC-Heidelberg, the Tubingen Family Study for Type 2 Diabetes (TUF), and the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study were used to validate this score. RESULTS —Information on age, waist circumference, height, history of hypertension, physical activity, smoking, and consumption of red meat, whole-grain bread, coffee, and alcohol formed the German Diabetes Risk Score (mean 446 points [range 118–983]). The probability of developing diabetes within 5 years in the EPIC-Potsdam study increased from 0.3% for 300 to 23.2% for 750 score points. The area under the receiver-operator characteristic (ROC) curve was 0.84 in the EPIC-Potsdam and 0.82 in the EPIC-Heidelberg studies. Correlation coefficients between the German Diabetes Risk Score and insulin sensitivity in nondiabetic individuals were −0.56 in the TUF and −0.45 in the MeSyBePo studies. ROC values for undiagnosed diabetes were 0.83 in the TUF and 0.75 in the MeSyBePo studies. CONCLUSIONS —The German Diabetes Risk Score (available at www.dife.de) is an accurate tool to identify individuals at high risk for or with undiagnosed type 2 diabetes.

Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36.

Abstract: Background: Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY1–36 and the pharmacologically active PYY3–36 is indicated to determine the potential role in energy balance regulation. Aim: Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. Design: Total plasma PYY levels (PYY1–36 + PYY3–36) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY3–36 levels were measured in 17 lean and 15 obese individuals. Results: Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 ± 12.9 pg/ml, P < 0.05) compared...

Adiponectin oligomers in human serum during acute and chronic exercise: relation to lipid metabolism and insulin sensitivity.

Abstract: Beneficial effects of physical exercise include improved insulin sensitivity, which may be affected by a modulated release of adiponectin, which is exclusively synthesized in white adipose tissue and mediates insulin sensitivity. Adiponectin circulates in three different oligomers, which also have a distinct biological function. We therefore aimed to investigate the distribution of adiponectin oligomers in human serum in relation to physical activity. Thirty-eight lean and healthy individuals were investigated. Seven healthy women and 8 healthy men volunteered to investigate the effect of chronic exercise, at 3 different time points with different training intensities. These individuals were all highly trained and were compared to a control group with low physical activity (n = 15). For studying acute exercise effects, 8 healthy men participated in a bicycle test. Adiponectin was determined by ELISA, oligomers were detected by non-denaturating western blot. Total adiponectin and oligomers were unchanged by acute exercise. LDL cholesterol was significantly lower in the chronic exercise group (p = 0.03). Total adiponectin levels and oligomers were not different between these two groups and were unaltered by different training intensities. However, total adiponectin and specifically HMW oligomers correlated with HDL cholesterol (r = 0.459; p = 0.009). We conclude that acute and chronic exercise does not directly affect circulating adiponectin or oligomer distribution in lean and healthy individuals. Whether such regulation is relevant in individuals with a metabolic disorder remains to be determined. However, our data suggest that adiponectin oligomers have distinct physiological functions IN VIVO, and specifically HMW adiponectin is closely correlated with HDL cholesterol.

A Thr94Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects.

Abstract: Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in l...

Adipocyte fatty acid-binding protein is associated with markers of obesity, but is an unlikely link between obesity, insulin resistance, and hyperandrogenism in polycystic ovary syndrome women

Abstract: OBJECTIVE Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS. DESIGN Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women. RESULTS A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = -0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP. CONCLUSIONS Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.

Alterations of pancreatic beta-cell mass and islet number due to Ins2-controlled expression of Cre recombinase: RIP-Cre revisited; part 2.

Abstract: Tissue-specific disruption of genes by targeted expression of Cre recombinase in insulin-producing cells has been widely used to explore pathways involved in regulation of pancreatic beta-cell mass. One particular line of transgenic mice [B6.Cg-Tg(Ins2-cre)25Mgn/J], commonly called RIP-Cre, in which the expression of Cre recombinase is controlled by a short fragment of the rat insulin II gene promoter has been used on at least 20 genes in at least 27 studies. In the majority of these studies (15 out of 27) inactivation of the gene of interest was associated with alterations in islet architecture, islet mass, or pancreatic insulin content. We have tested the hypothesis that genomic integration or expression of Cre recombinase alone causes alterations of beta-cell mass by quantifying islet number and mass in RIP-Cre mice. We have observed a significant hypoplasia of beta-cells in young RIP-Cre mice, and a significant hyperplasia of islets in older RIP-Cre animals. These findings suggest that glucose intolerance and impaired insulin secretion previously described for younger RIP-Cre mice might be caused by transgene-associated islet hypoplasia, and that hyperplasia in older mice might reflect a compensatory response to transgene-related glucose intolerance.

Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue.

Abstract: Summary Objective The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone increases insulin sensitivity, which, in animal models, is comparable to the effect of a reduction in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. We therefore investigated whether rosiglitazone-induced insulin sensitivity is associated with changes in 11β-HSD1 activity in different tissues. Methods An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp were performed in seven male volunteers [age 59·3 ± 3·0 years, body mass index (BMI) 29·3 ± 4·1 kg/m2] with impaired glucose tolerance before and after 8 weeks of rosiglitazone treatment. To assess hepatic 11β-HSD1 activity, serum cortisol levels were measured after oral administration of cortisone acetate. 11β-HSD1 activity and mRNA expression were assessed in abdominal subcutaneous fat biopsies. Total-body 11β-HSD activities were estimated by calculating the urinary ratios of glucocorticoid metabolites. Results As expected, rosiglitazone improved insulin resistance and postprandial hyperglycaemia. In parallel, 11β-HSD1 mRNA expression [100 ± 0% (reference) vs. 68·5 ± 9·3%, P < 0·01] and activity [0·18 ± 0·02 vs. 0·13 ± 0·02 pmol/min/mg, P < 0·05] decreased in abdominal subcutaneous fat, while an increase in hepatic 11β-HSD1 activity was detected [the area under the curve (AUC) for the cortisol/cortisone ratio was 1319 ± 76 vs. 955 ± 59; P < 0·05]. No changes in BMI, waist-to-hip ratio (WHR) and whole-body 11β-HSD1 activity were found. Conclusions Part of the beneficial effects of rosiglitazone may be mediated by a reduction in the 11β-HSD1 mRNA expression and activity in subcutaneous abdominal fat.

Variable Expression of Cre Recombinase Transgenes Precludes Reliable Prediction of Tissue-Specific Gene Disruption by Tail-Biopsy Genotyping

Abstract: The Cre/loxP-system has become the system of choice for the generation of conditional so-called knockout mouse strains, i.e. the tissue-specific disruption of expression of a certain target gene. We here report the loss of expression of Cre recombinase in a transgenic mouse strain with increasing number of generations. This eventually led to the complete abrogation of gene expression of the inserted Cre cDNA while still being detectable at the genomic level. Conversely, loss of Cre expression caused an incomplete or even complete lack of disruption for the protein under investigation. As Cre expression in the tissue of interest in most cases cannot be addressed in vivo during the course of a study, our findings implicate the possibility that individual tail-biopsy genotypes may not necessarily indicate the presence or absence of gene disruption. This indicates that sustained post hoc analyses in regards to efficacy of disruption for every single study group member may be required.

Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia.

Abstract: Lipid-lowering therapy is associated with reduced cardiovascular risk. The aim of the present study was to investigate whether lipid-lowering therapy might be associated with changes in the concentrations of metabolically important hormone concentrations. We performed a randomised cross-over open-label trial with atorvastatin (10 mg/day) and fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men, 8 women, age 60.0±6.8 years, body mass index 30.0±3.0 kg/m2) with type 2 diabetes mellitus and mixed hyperlipoproteinaemia. Plasma ghrelin (RIA, Phoenix Pharmaceuticals, Mountain View, CA, USA), adiponectin (ELISA, Biovendor, Heidelberg, Germany) as well as resistin (ELISA, Linco Research, St. Charles, MO, USA) concentrations were measured before and after atorvastatin as well as before and after fenofibrate. Ghrelin (462±84 pg/ml before vs. 464±102 pg/ml after atorvastatin, n.s.; 454±85 pg/ml before vs. 529±266 pg/ml after fenofibrate, n.s.), resistin (24.4±7.4 pg/ml before vs. 23.7±9.1 pg/ml after atorvastatin, n.s.; 23.4±8.2 pg/ml before vs. 19.9±5.5 pg/ml after fenofibrate, n.s.), adiponectin (10.89±5.33 pg/ml before vs. 12.41±5.75 pg/ml after atorvastatin, n.s.; 12.58±9.87 pg/ml before vs. 10.27±5.23 pg/ml after fenofibrate, n.s.) and insulin levels did not change significantly during lipid-lowering therapy. In patients with type 2 diabetes and mixed hyperlipoproteinaemia, short-term atorvastatin as well as fenofibrate therapy had no significant effects on adiponectin, ghrelin or resistin levels.

Verification of precipitation from regional climate simulations and remote-sensing observations with respect to ground-based observations in the upper Danube catchment

Abstract: An evaluation of precipitation fields for four selected months simulated by the regional climate model At-moMM5 and provided by the satellite retrieval method AtmoSat is presented As reference, observations at 5 km resolution on a daily and monthly basis are used We applied conventional verification tools (root mean square error, grid-point based categorical error scores, etc) as well as the new error score SAL, which separately considers aspects of the structure, amplitude and location of the precipitation field in a predefined area We also discussed the advantages and disadvantages of each of the scores The aim of our evaluation was to unfold the strengths and weaknesses of AtmoMM5 and AtmoSat to calculate daily and monthly high resolution precipitation As a result we found that the catchment averaged monthly mean precipitation is simulated with an acceptable accuracy by both methods The spatial pattern of the monthly precipitation (typically with a precipitation maximum in the alpine foreland) can only be reproduced by AtmoMM5 Regarding the daily precipitation, our evaluation revealed that both methods still need improvement The deviations to the observations increase with decreasing precipitation amount resulting in large uncertainties in case of very dry conditions Overall, we can conclude that AtmoMM5 is better suited to simulate precipitation at 5 km resolution on a daily basis than AtmoSat

Reduced expression of mitochondrial frataxin in mice exacerbates diet-induced obesity.

Abstract: Published evidence suggests that adiposity in humans may be linked to impaired energy expenditure for reasons widely unresolved We have generated mice with a systemic impairment of oxidative phosphorylation (OXPHOS) due to aP2 cre-mediated targeted disruption, and unexpectedly ubiquitous reduction of mitochondrial frataxin protein expression Only when maintained on a high-calorie diet resembling Westernized eating habits, these animals accumulate additional body fat, leading to increased body mass, and develop diabetes mellitus, despite the fact that both calorie uptake and physical activity were identical to that in control animals This phenotype is caused by a mild but significant reduction in total energy expenditure paralleled by increased expression of ATP citrate lyase, a rate-limiting step in de novo synthesis of fatty acids and triglycerides Taken together, these findings indicate that a limited impairment in oxidative metabolism within the mitochondria directly predisposes mammals to excessive body weight gain

Comparison of relative and attributable risk of myocardial infarction and stroke according to C-reactive protein and low-density lipoprotein cholesterol levels.

Abstract: C-reactive protein (CRP) was proposed as a stronger predictor of cardiovascular events than low-density lipoprotein cholesterol (LDL-C); however, these associations may differ between myocardial infarction (MI) and stroke. We compared statistically the associations of CRP and LDL-C levels with risk of MI versus stroke and examined to what extent consideration of CRP or LDL-C increases the population attributable fractions (PAFs) of MI and stroke beyond traditional risk factors among 27,548 subjects from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study in a case-cohort design. Among subjects without prior MI or stroke, 156 developed MI and 132 stroke during 6.0 years of follow-up. In adjusted competing risk analyses CRP was positively related to MI and stroke (P difference between endpoints = 0.55), whereas LDL-C was related to MI but not stroke (P difference between endpoints = 0.003). The PAF for smoking, diabetes, and hypertension combined was 0.76 for MI, and 0.58 for stroke. With additional consideration of CRP the PAFs were 0.80 and 0.68, while with addition of LDL-C the PAFs were 0.88 and 0.55. We conclude that CRP is equally strongly related to risk of MI and stroke, whereas LDL-C is related to risk of MI but not stroke. Consideration of LDL-C beyond smoking, diabetes and hypertension may increase the PAF of MI slightly more than CRP. In contrast, consideration of CRP but not of LDL-C may increase the PAF of stroke beyond these factors.

Means and method for diagnosing diabetes

Abstract: The present invention relates to a method for diagnosing diabetes or a predisposition thereof comprising determining at least one metabolite in a test sample of a subject suspected to suffer from diabetes or to have a predisposition therefor and comparing said at least one metabolite to a reference, whereby diabetes or a predisposition therefor is to be diagnosed. Moreover, the present invention encompasses a collection of metabolites, a data collection comprising characteristic values of metabolites and a storage medium comprising said data collection. Furthermore, the present invention also relates to a system comprising means for comparing characteristic values of metabolites of a sample operatively linked to a data storage medium. Further encompassed by the present invention are diagnostic means comprising at least one metabolite and the use of said at least one metabolite for the manufacture of diagnostic means for diagnosing diabetes. Finally, the present invention pertains to a method for identifying diabetes-related metabolites.

Means and method for predicting diabetes

Abstract: The present invention relates to a method for diagnosing a predisposition for diabetes comprising determining at least one metabolite in a test sample of a subject suspected to have a predisposition for diabetes and comparing said at least one metabolite to a reference, whereby a predisposition for diabetes is to be diagnosed. Moreover, the present invention encompasses a collection of metabolites, a data collection comprising characteristic values of metabolites and a storage medium comprising said data collection. Furthermore, the present invention also relates to a system comprising means for comparing characteristic values of metabolites of a sample operatively linked to a data storage medium. Further encompassed by the present invention are diagnostic means comprising at least one metabolite and the use of said at least one metabolite for the manufacture of diagnostic means for diagnosing a predisposition for diabetes. Finally, the present invention pertains to a method for identifying diabetes- related metabolites.

The simultaneous measurement of plasma-aldosterone- and -renin-concentration allows rapid classification of all disorders of the renin-aldosterone system.

Abstract: OBJECTIVE: The determination of the plasma aldosterone (PAC) to the plasma renin concentration (PRC) ratio is an accepted screening tool for primary hyperaldosteronism (PHyperA). DESIGN: To assess the diagnostic significance of this ratio for other disorders of the renin-aldosterone-system (RAS), we examined 60 patients with different adrenal diseases, 32 patients with essential hypertension and 76 normotensive healthy volunteers. The aldosterone (pmol/L) and renin (mU/L) concentrations were measured in one plasma sample by an automated chemiluminescence assay (Nichols Advantage ® ). RESULTS: Patients with PHyperA (n=31) had a PAC/PRC ratio between 105 and 2328 and could be distinguished without overlap from the essential hypertension group (ratio: range 2.7-49) and normal healthy volunteers (ratio: range 0.9-71). Fourteen patients with primary hypoaldosteronism showed low PAC/PRC ratios (range 0.21-0.98) and low PAC values (range: 42-100). Seven patients with secondary hypoaldosteronism had normal PAC/PRC ratios (range 2.8-23.2) and low PAC values (range: 42-116). Eight patients with secondary hyperaldosteronism had normal PAC/PRC ratios (range 7.8-67.9) and elevated PAC values (range: 803-2917). The graphic presentation of these data allowed the differentiation of all major disorders of the RAS. CONCLUSIONS: The measurement of PAC/PRC ratios using this automated system provides a sensitive and rapid screening method for PHyperA. Moreover, the measurement of both the PAC and the PAC/PRC ratio allows differentiation of other disorders of the RAS.

CMS physics technical design report: Addendum on high density QCD with heavy ions RID B-1239-2012

Abstract: This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies , will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction ? Quantum Chromodynamics (QCD) ? in extreme conditions of temperature, density and parton momentum fraction (low-x).This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include bulk observables, (charged hadron multiplicity, low pT inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high pT hadrons which yield tomographic information of the hottest and densest phases of the reaction.

Improved glucose metabolism in mice lacking α-tocopherol transfer protein

Abstract: Conflicting evidence suggests a possible role for vitamin E in mammalian glucose metabolism and the protection from type 2 diabetes. The alpha-tocopherol transfer protein (α-TTP) mediates the transfer of α-tocopherol (α-TOH) from hepatocytes to very-low-density lipoproteins, thereby controlling plasma levels of α-TOH. The aim of this study was to investigate the putative impact of α-TTP knock-out on glucose metabolism in mice. Mice deficient for α-TTP and wild-type control littermates were fed a diet containing 200 mg α-tocopheryl acetate per kg to ameliorate α-TOH deficiency in knock-out mice. We investigated fasting and postprandial plasma glucose, insulin and triglyceride levels of both groups of mice at different ages. All genotypes and age groups were further subjected to glucose and insulin tolerance tests, and number of insulin-producing islets of Langerhans were determined. Plasma α-TOH levels of knock-out mice were 34% the levels of wild-type controls: Any signs of α-TOH deficiency were absent at any age. Unexpectedly, serum glucose levels both in the fasted and in the fed state were lower in α-TTP-deficient mice at any age. Removal rates for intraperitoneally injected glucose were found to be significantly increased in young α-TTP-deficient mice. This improved glucose tolerance was caused by increased insulin secretion in response to an intraperitoneal glucose challenge due to an increased number of pancreatic islets, as well as by increased sensitivity to intraperitoneally injected insulin, both significantly promoting glucose metabolism in α-TTP-deficient mice. Our findings suggest that α-TTP-deficiency in states of α-TOH supplementation unexpectedly promotes glucose tolerance in mice due to both increased insulin secretion and insulin action, suggesting differential roles of α-TTP and α-TOH in the pathogenesis of type 2 diabetes mellitus.

Adipose tissue and diabetes therapy: do we hit the target?

Abstract: Factors derived from adipose tissue are believed to play a central role in the development and progression of diabetes and its vascular complications. Insulin resistance and vascular function are directly affected these factors, i.e., by free fatty acids, inflammatory adipocytokines, thrombotic and antifibrinolytic factors and by adiponectin, and adipokine with insulin sensitizing and anti-inflammatory actions. Targeting these factors by antidiabetic agents should result in improved metabolism and in a reduction of vascular risk. We therefore analyzed antidiabetic treatment strategies with regard to improvements of adipose tissue derived risk factors. This shows that weight loss remains an extremely powerful tool to reduce all of these risk factors. Thiazolidinediones and rimonabant are most potent in improving numerous adipose derived risk factors but studies demonstrating reduced mortality are not yet available. Metformin has little effect on any of the adipose tissue derived factors but appears to reduce diabetes related mortality according to limited evidence. Sulfonylureas and insulin have rather limited effects on adipose tissue derived factors and are likely to exert beneficial effects mainly by improved glucose metabolism and its consequences.

Effect of immunosuppressive and other drugs on the cortisol-cortisone shuttle in human kidney and liver.

Abstract: Background Impaired 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) has been suggested in patients with hypertension or renal disease, where it may contribute to sodium retention and hypertension. 11beta-HSD1, which is expressed predominantly in liver and adipose tissue, influences glucose homeostasis and fat distribution by altering intracellular cortisol (F) concentrations. We tested immunosuppressive drugs that cause hypertension, and substances that interfere with steroidogenesis or influence glucose homeostasis for their ability to influence the inhibition of 11beta-HSD isozymes. Methods For inhibition experiments, we used microsomes prepared from unaffected parts of human liver segments and resected human kidney cortex because of hepatocarcinoma or renal cell cancer. The inhibitory potency of several compounds was evaluated in concentrations from 10(-9)-10(-5) mol/l. Results Only sirolimus, but not cyclosporine A, tacrolimus, mycophenolate mofetil, or azathioprine showed a slight inhibition of 11beta-HSD2 activity. None of the drugs that inhibit steroidogenesis (suramine, mitotane, etomidate, and aminogluthethimide) or steroid metabolism (rifampicine) influenced 11beta-HSDs, nor did ginsenoides Re, Rc, and Rb1. Among sulfonylureas, only gliclazide decreased significantly 11beta-HSD1 activity. Conclusions Increased blood pressure due to immunosuppressive drugs is probably not caused by direct inhibition of 11beta-HSD2. An additional glucose lowering effect of sulfonylurea gliclazide may be due to its ability to inhibit 11beta-HSD1.

Cell-type specific regulation of the human 11beta-hydroxysteroid dehydrogenase type 1 promoter

Abstract: The intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone into the more active metabolite cortisol. Overexpression of 11beta-HSD1 was associated with features of the metabolic syndrome such as obesity or impaired glucose tolerance. Despite this considerable impact of 11beta-HSD1, the human 11beta-HSD1 promoter has not been described in detail yet. We therefore cloned eight different promoter fragments of the 5'-upstream region of the known transcription/translation-start up to -3034 bp into the luciferase-reporter vector pGL3. A low-cost in-house assay was developed and validated to detect firefly and renilla luciferase activity. Promoter fragments were analysed in human HepG2 and undifferentiated and differentiated murine 3T3-L1 cells. A differential regulation of the human 11beta-HSD1 promoter depending upon the cell type was observed. Specifically, a strong repressor of the basal promoter activity was found between -85 and -172 bp in HepG2 cells only, while an additional repressor appeared to be active between -342 and -823 bp in both, the hepatic and the adipose cell line. The presented data suggest a cell-type specific regulation of the 11beta-HSD1 promoter, which is in agreement with existing expression data from animal and human studies. The described promoter constructs will allow subsequent studies about the role of specific hormonal, metabolic and transcription factors to finally characterise the regulation of the human 11beta-HSD1-promoter in more detail.

Method for diagnosing diabetes type II

Abstract: The present invention relates to a method for diagnosing diabetes or a predisposition thereof comprising determining at least one metabolite in a test sample of a subject suspected to suffer from diabetes or to have a predisposition therefor and comparing said at least one metabolite to a reference, whereby diabetes or a predisposition therefor is to be diagnosed. Moreover, the present invention encompasses a collection of metabolites, a data collection comprising characteristic values of metabolites and a storage medium comprising said data collection. Furthermore, the present invention also relates to a system comprising means for comparing characteristic values of metabolites of a sample operatively linked to a data storage medium. Further encompassed by the present invention are diagnostic means comprising at least one metabolite and the use of said at least one metabolite for the manufacture of diagnostic means for diagnosing diabetes. Finally, the present invention pertains to a method for identifying diabetes-related metabolites.

Analysis of statistical algorithms for the comparison of data distributions in physic experiments

Abstract: The relative power of statistical algorithms for the comparison of data distributions was examined for selected physics use cases. Various Goodness-of-Fit tests, applicable to binned and unbinned data sets, were evaluated. The results provide guidance about the usage of a particular test in certain scenarios.