TY - JOUR AB - OBJECTIVE: Upper reference values for thyroid volume are 25 ml for men and 18 ml for women. Thyroid volume alters with age, body weight, body height and iodine status, which is not considered in the current limits. The aim was to develop reference equations, considering age, body weight and height to calculate individual reference values for thyroid volume. DESIGN: This cross-sectional study, used data from three independent cohorts (SHIP-START, SHIP-TREND, KORA-F4) in Germany. SHIP-START-0, a population-based health survey carried out in Northern Germany, from 1997-2001. SHIP-TREND-0, a second independent sample of the same study region, carried out between 2008-2012. KORA F4, a population-based health survey, conducted between 2006-2008 in Southern Germany. METHODS: A total of 11,549 individuals (51% women) were included in data analysis. 8,606 individuals (45% women) were used as the thyroid-healthy reference population, when developing equations. Sex-stratified quantile regression models for the 95th percentile using age, body weight and height as explanatory variables, were performed. RESULTS: Overall reference value for men was 38.7 ml, for women 28.6 ml. According to the established cut-offs, 34% of the overall population would have had goitre compared to 7% when using our equations. CONCLUSION: Upper reference values for thyroid volume are too low for an adult, previously iodine deficient population and do not consider age, body weight and height. Using individualised equations reduces the prevalence of thyroid enlargement substantially and can lead to a decrease in overdiagnoses and use of medical resources. AU - Ittermann, T.* AU - Angelow, A.* AU - Chenot, J.F.* AU - Völzke, H.* AU - Heier, M. AU - Linkohr, B. AU - Peters, A. AU - Meisinger, C.* AU - Kiel, S.* C1 - 74804 C2 - 57598 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 728-736 TI - Thyroid volume - new reference values for defining thyroid enlargement. JO - Eur. J. Endocrinol. VL - 192 IS - 6 PB - Oxford Univ Press PY - 2025 SN - 0804-4643 ER - TY - JOUR AB - Familial Glucocorticoid Deficiency Type 1 (FGD1) is a rare autosomal recessive disease caused by pathogenic variants in the MC2R gene. This case report presents the first documented instance of FGD1 caused by a homozygous 1.421 kb deletion affecting the non-coding promoter region of MC2R. The patient, a 9-year-old girl, presented with severe cortisol insufficiency and hyperpigmentation starting at birth. Genetic testing initially missed the deletion, as standard whole-exome sequencing in 2016 did not include a copy number variation analysis. However, a whole-genome sequencing analysis in 2024 identified the deletion. The variant was inherited through paternal uniparental disomy (UPD), a rare genetic mechanism that caused the homozygous state. This case underscores the value of utilizing current genetic testing approaches, especially in cases where clinical features strongly suggest a genetic etiology despite inconclusive initial genetic testing results. Additionally, it highlights the need to consider non-coding regions and UPD in genetic diagnostics. AU - Müller-Nedebock, A.C.* AU - Wenzel, E. AU - Pfäffle, R.* C1 - 75254 C2 - 57891 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - K5-K10 TI - Uniparental disomy leads to a novel cause of MC2R-related familial glucocorticoid deficiency type 1. JO - Eur. J. Endocrinol. VL - 193 IS - 2 PB - Oxford Univ Press PY - 2025 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Concentrations of soluble alpha klotho (sαKL) are higher in active acromegaly compared to healthy controls. However, reference intervals based on large population-based samples are lacking, and the impact of many biological variables is unclear. DESIGN: Cross-sectional study. METHODS: We measured sαKL concentrations in samples from an adult population (20-89 years, 435 males, 455 females). Associations with sex, age, body mass index, waist-hip-ratio, estimated glomerular filtration rate (eGFR), IGF-I and IGFBP 3, glucose-, lipid-, calcium- and liver-metabolism, fasting, and estrogen status were analyzed. Reference intervals were calculated using LMS quantile regression with a Box-Cox transformation to normality. We also analyzed sαKL in patients with non-functioning pituitary adenoma (NFPA, n=18) and prolactinoma (n=65). RESULTS: Across all ages, sαKL concentrations (pg/mL, median (IQR)) were slightly, but significantly higher in females compared to males (678 (537-859) vs. 651 (537-812), p=0.01), suggesting an impact of estrogens. SαKL exhibited a weak negative correlation with age, and positive correlations with eGFR and IGF-I (p<0.001 for both). Correlations to other biological factors including glucose, liver and calcium metabolism and duration of fasting were negligible (p>0.05 for all). Compared to sαKL, IGF-I more often was correlated significantly to other biological variables. SαKL was not different in patients with NFPA, but slightly higher in patients with prolactinoma (p<0.05). CONCLUSION: Our findings suggest sαKL is a stable GH-sensitive biomarker, that may be less impacted by biological variables compared to IGF-I and IGFBP 3. Our reference intervals will facilitate the potential use of sαKL in GH-related diseases. AU - Schweizer, J.R.O.L.* AU - Schilbach, K.* AU - Haenelt, M.* AU - Gagliardo, A.* AU - Peters, A. AU - Thorand, B. AU - Störmann, S.* AU - Schopohl, J.* AU - Reincke, M.* AU - Lauseker, M.* AU - Bidlingmaier, M.* C1 - 74331 C2 - 57464 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 631-640 TI - Soluble alpha klotho - impact of biological variables and reference intervals for adults. JO - Eur. J. Endocrinol. VL - 192 IS - 5 PB - Oxford Univ Press PY - 2025 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36). RESULTS: In PPGLs, estradiol and progesterone (1 µm) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα-positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µm) displayed no effects, but higher doses of testosterone (10 µm) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences-tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects. CONCLUSION: We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity. AU - Wang, K.* AU - Fischer, A.* AU - Maccio, U.* AU - Zitzmann, K.* AU - Robledo, M.* AU - Lauseker, M.* AU - Bauer, J.* AU - Bechmann, N.* AU - Gahr, S.* AU - Maurer, J.* AU - Peischer, L.* AU - Reul, A.* AU - Nieß, H.* AU - Zimmermann, P.* AU - Ilmer, M.* AU - Schilbach, K.* AU - Knösel, T.* AU - Kroiss, M.* AU - Fassnacht, M.* AU - Müller, S.A.* AU - Morand, G.B.* AU - Huber, A.* AU - Vetter, D.* AU - Lehmann, K.* AU - Kulcsar, Z.* AU - Mohr, H. AU - Pellegata, N.S. AU - Hantel, C.* AU - Reincke, M.* AU - Beuschlein, F.* AU - Pacak, K.* AU - Grossman, A.B.* AU - Auernhammer, C.J.* AU - Nölting, S.* C1 - 73016 C2 - 56898 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 46-60 TI - Impact of sex hormones on pheochromocytomas, paragangliomas, and gastroenteropancreatic neuroendocrine tumors. JO - Eur. J. Endocrinol. VL - 192 IS - 1 PB - Oxford Univ Press PY - 2025 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Hypothyroidism has been proposed as a potential contributor to steatotic liver disease (SLD), but existing data shows conflicting results in euthyroid subjects. Therefore, we investigated the association between thyroid function and intrahepatic lipids (IHLs) during a 36-months randomized controlled trial evaluating a diet known to reduce liver fat. DESIGN: 502 eligible subjects (aged 50 to 80 y, ≥ 1 risk factor for unhealthy aging) were randomly assigned to either follow a diet rich in unsaturated fatty acids, plant protein and fiber (intervention group, IG), or dietary recommendations of the German Nutrition Society (control group (CG)). METHODS: Serum levels of thyroid hormones (THs) as well as IHLs, defined via magnetic resonance spectroscopy, were measured within an euthyroid subgroup without significant alcohol consumption at baseline (n = 332) and after 12 months (n = 243). Ratio of T3/T4 was used to assess whole body deiodinase activity. Estimates of glucose and lipid metabolism were analyzed. RESULTS: Only fT3 and T3/T4 ratio showed a significant positive correlation with IHL at baseline. We observed a significant decline in fT3, T3, fT3/fT4 ratio and T3/T4 ratio in CG and IG after 12 months without significant differences between groups. TSH, fT4 and T4 remained stable. A larger improvement of IHL during dietary intervention was seen in those subjects with a lower decline in T3 concentrations. CONCLUSIONS: Altered TH balance indicates a possible compensatory upregulation of whole body TH activity in subjects with increased liver fat. This might be also relevant during improvement of hepatic steatosis. AU - Sommer-Ballarini, M.* AU - Nguyen, T.H.* AU - Pletsch-Borba, L.* AU - Wernicke, C.* AU - Tacke, F.* AU - Schwerdtle, T.* AU - Pellowski, D.* AU - Machann, J. AU - Spranger, J.* AU - Wirth, E.K.* AU - Mai, K.* C1 - 71300 C2 - 56033 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 183-191 TI - Impact of peripheral thyroid hormone balance on liver fat: Insights from the NutriAct trial. JO - Eur. J. Endocrinol. VL - 191 IS - 2 PB - Oxford Univ Press PY - 2024 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: The therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) include chemotherapy with cyclophosphamide/vincristine/dacarbazine (CVD), temozolomide monotherapy, radionuclide therapies, and tyrosine kinase inhibitors such as sunitinib. The objective of this multicenter retrospective study was to evaluate and compare the responses of mPPGLs including those with pathogenic variants in succinate dehydrogenase subunit B (SDHB), to different systemic treatments. DESIGN: This is a retrospective analysis of treatment responses of mPPGL patients (n = 74) to systemic therapies. METHODS: Patients with mPPGLs treated at 6 specialized national centers were selected based on participation in the ENSAT registry. Survival until detected progression (SDP) and disease-control rates (DCRs) at 3 months were evaluated based on imaging reports. RESULTS: For the group of patients with progressive disease at baseline (83.8% of 74 patients), the DCR with first-line CVD chemotherapy was 75.0% (n = 4, SDP 11 months; SDHB [n = 1]: DCR 100%, SDP 30 months), with somatostatin peptide receptor-based radionuclide therapy (PPRT) 85.7% (n = 21, SDP 17 months; SDHB [n = 10]: DCR 100%, SDP 14 months), with 131I-meta-iodobenzylguanidine (131I-MIBG) 82.6% (n = 23, SDP 43 months; SDHB [n = 4]: DCR 100%, SDP 24 months), with sunitinib 100% (n = 7, SDP 18 months; SDHB [n = 3]: DCR 100%, SDP 18 months), and with somatostatin analogs 100% (n = 4, SDP not reached). The DCR with temozolomide as second-line therapy was 60.0% (n = 5, SDP 10 months; SDHB [n = 4]: DCR 75%, SDP 10 months). CONCLUSIONS: We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations. AU - Fischer, A.* AU - Kloos, S.* AU - Remde, H.* AU - Dischinger, U.* AU - Pamporaki, C.* AU - Timmers, H.J.L.M.* AU - Robledo, M.* AU - Fliedner, S.M.J.* AU - Wang, K.* AU - Maurer, J.* AU - Reul, A.* AU - Bechmann, N.* AU - Hantel, C.* AU - Mohr, H. AU - Pellegata, N.S. AU - Bornstein, S.* AU - Kroiss, M.* AU - Auernhammer, C.J.* AU - Reincke, M.* AU - Pacak, K.* AU - Grossman, A.B.* AU - Beuschlein, F.* AU - Nölting, S.* C1 - 68761 C2 - 54971 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 546-565 TI - Responses to systemic therapy in metastatic pheochromocytoma/paraganglioma: A retrospective multicenter cohort study. JO - Eur. J. Endocrinol. VL - 189 IS - 5 PB - Oxford Univ Press PY - 2023 SN - 0804-4643 ER - TY - JOUR AB - Glucocorticoids are essential hormones produced by the adrenal cortex with prominent circadian rhythmicity and in times of stress. Glucocorticoids maintain liver homeostasis through coordinated activities that control the major pathways of energy metabolism. Glucocorticoids activate the glucocorticoid receptor (GR), a nuclear hormone receptor that regulates the transcription of hundreds of genes in response to ligand. This review aims to provide a comprehensive overview of glucocorticoid receptor signaling impact on glucose, amino acid, and lipid metabolism in the liver. We integrate fundamental and current findings elucidating key GR-regulated pathways from a physiologic, biochemical, and molecular point-of-view. Here, we focus on the transcriptional regulation of well-characterized hepatic GR target genes, and on those GR co-factors that coordinate nutritional and hormonal signals. AU - Quagliarini, F. AU - Makris, K. AU - Friano, M.E. AU - Uhlenhaut, N.H. C1 - 67784 C2 - 54262 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - R111-R130 TI - EJE Prize 2023: Genes on steroids-genomic control of hepatic metabolism by the glucocorticoid receptor. JO - Eur. J. Endocrinol. VL - 188 IS - 5 PB - Oxford Univ Press PY - 2023 SN - 0804-4643 ER - TY - JOUR AB - Objectives: Some individuals develop type 2 diabetes mellitus (T2DM) despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that insulin growth factor 1 (IGF1) and its binding proteins 1 and 2 predict the onset of T2DM in prediabetes patients and determine the capacity for metabolic regeneration. Design: We measured fasting serum IGF1, insulin growth factor-binding protein 1 (IGFBP1) and IGFBP2 in three randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up. Methods: Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. Three hundred and forty-five subjects finished the first year of intervention. Results: The interventions significantly improved body weight (BMI: -3.24%, P < 0.001), liver fat (-36.8%, P < 0.001), insulin sensitivity (IS) (homeostatic model assessment-insulin resistance: -6.3%, P < 0.001) and insulin secretion (disposition index: +35%, P < 0.001) in the cohort. Fourteen percent developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and nonalcoholic fatty liver disease had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs 146.6 µg/L) and IGFBP1 was higher (3.32 vs 2.09 µg/L) in subjects who developed T2DM (n = 57), resulting in a significant prediction of diabetes incidence (hazard ratio (HR) IGF1: 0.991 µg/L, P = 0.003; HR IGFBP1: 1.061 µg/L, P = 0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral fat and hepatic fat in response to 1 year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1. Conclusions: Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention. AU - Meyer, N.M.T.* AU - Kabisch, S.* AU - Dambeck, U.* AU - Honsek, C.* AU - Kemper, M.* AU - Gerbracht, C.* AU - Arafat, A.M.* AU - Birkenfeld, A.L. AU - Schwarz, P.E. AU - Machann, J. AU - Osterhoff, M.A.* AU - Weickert, M.O.* AU - Pfeiffer, A.F.H.* C1 - 66281 C2 - 53125 SP - 555-565 TI - Low IGF1 and high IGFBP1 predict diabetes onset in prediabetic patients. JO - Eur. J. Endocrinol. VL - 187 IS - 4 PY - 2022 SN - 0804-4643 ER - TY - JOUR AB - Background: Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study. Methods: From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors. Results: In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = −12.43, P < 0.001), end-systolic volume (β = −7.12, P < 0.001), stroke volume (β = −5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = −0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes. Conclusions: Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment. AU - Krüchten, R.V.* AU - Lorbeer, R.* AU - Rospleszcz, S. AU - Storz, C.* AU - Askani, E.* AU - Kulka, C.* AU - Rathmann, W.* AU - Peters, A. AU - Karrasch, S. AU - Bamberg, F.* AU - Schlett, C.* AU - Mujaj, B.* C1 - 61129 C2 - 50053 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 289-298 TI - Serum insulin is associated with right ventricle function parameters and lung volumes in subjects free of cardiovascular disease. JO - Eur. J. Endocrinol. VL - 184 IS - 2 PB - Bioscientifica Ltd PY - 2021 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translate these alterations into functional autonomy and potentially malignant behavior have not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. DESIGN AND METHODS: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. RESULTS: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 5.06E-11) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knock-down of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. CONCLUSIONS: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings. AU - Murakami, M.* AU - Sun, N. AU - Greunke, C. AU - Feuchtinger, A. AU - Kircher, S.* AU - Deutschbein, T.* AU - Papathomas, T.* AU - Bechmann, N.* AU - Wallace, P.W.* AU - Peitzsch, M.* AU - Korpershoek, E.* AU - Friemel, J.* AU - Gimenez Roqueplo, A.P.* AU - Robledo, M.* AU - Timmers, H.J.* AU - Canu, L.* AU - Weber, A.* AU - de Krijger, R.R.* AU - Fassnacht, M.* AU - Knösel, T.* AU - Kirchner, T.* AU - Reincke, M.* AU - Walch, A.K. AU - Kroiss, M.* AU - Beuschlein, F.* C1 - 62032 C2 - 50626 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 179-191 TI - Mass spectrometry imaging identifies metabolic patterns associated with malignant potential in pheochromocytoma and paraganglioma. JO - Eur. J. Endocrinol. VL - 185 IS - 1 PB - Bioscientifica Ltd PY - 2021 SN - 0804-4643 ER - TY - JOUR AB - Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far.Methods: In a central lab, circulating Pro-NT was quantified in three in dependent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice.Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P = 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals.Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD. AU - Tönjes, A.* AU - Hoffmann, A.* AU - Kralisch, S.* AU - Qureshi, A.R.* AU - Klöting, N.* AU - Scholz, M.* AU - Schleinitz, D.* AU - Bachmann, A.* AU - Kratzsch, J.* AU - Nowicki, M.* AU - Paeschke, S.* AU - Wirkner, K.* AU - Enzenbach, C.* AU - Baber, R.* AU - Beige, J.* AU - Anders, M.* AU - Bast, I.* AU - Blüher, M. AU - Kovacs, P.* AU - Löffler, M.* AU - Zhang, M.Z.* AU - Harris, R.C.* AU - Stenvinkel, P.* AU - Stumvoll, M.* AU - Fasshauer, M.* AU - Ebert, T.* C1 - 59851 C2 - 49071 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 233-244 TI - Pro-neurotensin depends on renal function and is related to all-cause mortality in chronic kidney disease. JO - Eur. J. Endocrinol. VL - 183 IS - 3 PB - Bioscientifica Ltd PY - 2020 SN - 0804-4643 ER - TY - JOUR AB - Objective: Excess catecholamine release by pheochromocytomas and paragang liomas (PPGL) leads to characteristic clinical features and increased morbidity and mortality. The in fluence of PPGLs on metabolism is ill described but may impact diagnosis and management. The objective of this study wa s to systematically and quantitatively study PPGL-induced metabolic changes at a systems level. Design: Targeted metabolomics by liquid chromatography-tandem mass spe ctrometry of plasma specimens in a clinically well-characterized prospective cohort study. Methods: Analyses of metabolic profiles of plasma specimens from 56 pros pectively enrolled and clinically well-characterized patients (23 males, 33 females) with catecholamin e-producing PPGL before and after surgery, as well as measurement of 24-h urinary catecholamine using LC-MS/MS. Results: From 127 analyzed metabolites, 15 were identified with significa nt changes before and after surgery: Five amino acids/biogenic amines (creatinine, histidine, ornithine, sarcosine, tyrosine) and one glycerophospholipid (PCaeC34:2) with increased concentrations and six glycerophospholipids (PCaaC38:1, PCaaC42:0, PCaeC40:2, PCaeC42:5, PCaeC44:5, PCaeC44:6), two sphingomyelins (SMC24:1, SMC26:1) and hexose with decreased levels after surgery. Patients with a noradrenergic tumor phenotype had more pronounced alterations compared to those with an adrenergic tumor phenotype. Weak, but significant correlation s for 8 of these 15 metabolites with total urine catecholamine levels were identified. Conclusions: This first large prospective metabolomics analysis of PPGL pati ents demonstrates broad metabolic consequences of catecholamine excess. Robust impact on lipid an d amino acid metabolism may contribute to increased morbidity of PPGL patients. AU - Erlic, Z.* AU - Kurlbaum, M.* AU - Deutschbein, T.* AU - Noelting, S.* AU - Prejbisz, A.* AU - Timmers, H.J.* AU - Richter, S.* AU - Prehn, C. AU - Weismann, D.* AU - Adamski, J. AU - Januszewicz, A.* AU - Reincke, M.* AU - Fassnacht, M.* AU - Robledo, M.* AU - Eisenhofer, G.* AU - Beuschlein, F.* AU - Kroiss, M.* C1 - 57667 C2 - 47865 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 647-657 TI - Metabolic impact of pheochromocytoma/ paraganglioma: Targeted metabolomics in patients before and after tumor removal. JO - Eur. J. Endocrinol. VL - 181 IS - 6 PB - Bioscientifica Ltd PY - 2019 SN - 0804-4643 ER - TY - JOUR AB - Objective: We investigated the association of circulating fetuin-A with incident T2D particularly examining potential sex differences. Additionally, we determined whether putative associations were independent of subclinical inflammation, adiponectin and liver fat content. Design: Case-cohort study plus systematic meta-analysis. Methods: We investigated the association between baseline fetuin-A levels and incident T2D in the MONICA/KORA Augsburg study using Cox proportional hazards analyses. Furthermore, we conducted a systematic review within PubMed and EMBASE and pooled association estimates of eligible studies with the MONICA/KORA Augsburg data using a DerSimonian-Laird random effects model. Results: Within MONICA/KORA Augsburg, 930 participants developed incident T2D (median follow-up: 14 years). We observed a significant association between fetuin-A and T2D risk after multivariable adjustment including C-reactive protein and adiponectin. The strength of the association was similar in males and females (P value for sex interaction >0.55). Seven eligible published studies were identified in addition to the MONICA/KORA Augsburg study for the meta-analysis. The pooled hazard ratio (95% CI) for incident T2D per 1 standard deviation (s.d.) increment of fetuin-A was 1.24 (1.14-1.34) for the multivariable adjusted model. Our sex-stratified meta-analysis yielded relative risk estimates per 1 s.d. of 1.19 (1.04-1.38) in males and 1.29 (1.15-1.46) in females. Further individual adjustment for subclinical inflammation, adiponectin and liver fat content had almost no impact on the strength of the association. Conclusions: Higher fetuin-A levels are associated with incident T2D in both males and females independently of subclinical inflammation, adiponectin and liver fat content. AU - Sujana, C. AU - Huth, C. AU - Zierer, A. AU - Meesters, S. AU - Sudduth-Klinger, J.* AU - Koenig, W.* AU - Herder, C.* AU - Peters, A. AU - Thorand, B. C1 - 52963 C2 - 44494 CY - Bristol SP - 389-398 TI - Association of fetuin-A with incident type 2 diabetes: Results from the MONICA/KORA Augsburg study and a systematic meta-analysis. JO - Eur. J. Endocrinol. VL - 178 IS - 4 PB - Bioscientifica Ltd PY - 2018 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data. DESIGN: Cross-sectional study. METHODS: Subjects (n=149) were classified according to clinical and hormonal characteristics: Cushing's syndrome (n=46), adrenocortical adenomas with autonomous cortisol secretion (n=31) or without hypercortisolism (n=27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls (n=42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed. RESULTS: Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories, and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases. CONCLUSIONS: Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism, and incomplete β-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism. AU - di Dalmazi, G.* AU - Quinkler, M.* AU - Deutschbein, T.* AU - Prehn, C. AU - Rayes, N.* AU - Kroiss, M.* AU - Berr, C.M.* AU - Stalla, G.K.* AU - Fassnacht, M.* AU - Adamski, J. AU - Reincke, M.* AU - Beuschlein, F.* C1 - 51232 C2 - 42791 CY - Bristol SP - 227-237 TI - Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome. JO - Eur. J. Endocrinol. VL - 177 IS - 2 PB - Bioscientifica Ltd PY - 2017 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Cross-sectional studies found that higher levels of the novel adipokine omentin-1 were associated with higher adiponectin and lower levels of risk factors for type 2 diabetes, but its relevance for incident type 2 diabetes is currently not understood. Therefore, this study investigated whether serum omentin-1 was associated with changes in glycaemia and incident type 2 diabetes independently of adiponectin. DESIGN AND METHODS: The study was based on participants aged 62-81 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort. Associations of baseline serum levels of omentin-1 and adiponectin with changes in glycaemia were assessed in 471 non-diabetic participants, associations between both adipokines and incident type 2 diabetes in 76 cases and 430 non-cases (follow-up time 6.5 years). Multivariable linear and logistic regression models were adjusted for multiple potential confounders. RESULTS: Higher serum levels of omentin-1 were associated with increases in fasting glucose, 2-hour glucose and HbA1c (all P<0.001) and with incident type 2 diabetes (adjusted OR (95% CI) 1.40 (1.03; 1.90) per SD of log2-transformed omentin-1; P=0.032). These associations were independent from adiponectin levels, which showed associations with changes in glycaemia and risk of type 2 diabetes in the opposite direction. We found no statistically significant interactions of omentin-1 with adiponectin or sex in the association with incident type 2 diabetes (all P>0.1). CONCLUSIONS: Systemic levels of omentin-1 were positively associated with increases in glycaemia and incident type 2 diabetes in this older population. These associations were independent of potential confounders including adiponectin. AU - Herder, C.* AU - Kannenberg, J.M.* AU - Niersmann, C.* AU - Huth, C. AU - Carstensen-Kirberg, M.* AU - Wittenbecher, C.* AU - Schulze, M.B.* AU - Blüher, M.* AU - Rathmann, W.G.* AU - Peters, A. AU - Roden, M.* AU - Meisinger, C. AU - Thorand, B. C1 - 51487 C2 - 43242 CY - Bristol SP - 277-286 TI - Independent and opposite associations of serum levels of omentin-1 and adiponectin with increases of glycaemia and incident type 2 diabetes in an older population: KORA F4/FF4 Study. JO - Eur. J. Endocrinol. VL - 177 IS - 4 PB - Bioscientifica Ltd PY - 2017 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: To compare the effects of acyl ghrelin (AG) and desacyl ghrelin (DAG) on blood pressure (BP), heart rate (HR) and other autonomic parameters in healthy humans and to elucidate the hormonal mechanisms through which AG could exert its cardiovascular effects. DESIGN: Seventeen healthy participants underwent frequent monitoring of systolic (sBP) and diastolic blood pressure (dBP), HR, respiratory rate (RR) and body surface temperature (Temp) during continuous infusion of AG, DAG, combined AG + DAG or saline control before and during an IV glucose tolerance test on 4 separate days. Plasma catecholamines, renin and aldosterone levels were also measured. Differences in outcome measures between treatment groups were assessed using mixed-model analysis. RESULTS: Compared to the saline control, AG and combined AG + DAG infusions decreased sBP, dBP, mean arterial blood pressure (MAP), HR and Temp. In contrast, DAG infusion did not alter BP, RR or Temp, but did decrease HR. The AG and AG + DAG infusions also raised plasma aldosterone levels compared to saline (P < 0.001) without affecting renin or catecholamine levels. CONCLUSIONS: The decrease in BP, HR, RR and Temp with AG infusion suggests mediation through the autonomic nervous system. The lack of response to DAG suggests that these autonomic effects require activation of the ghrelin receptor. AU - Zhang, C.J.* AU - Bidlingmaier, M.* AU - Altaye, M.* AU - Page, L.C.* AU - D'Alessio, D.* AU - Tschöp, M.H. AU - Tong, J.* C1 - 55469 C2 - 46175 SP - 123-132 TI - Acute administration of acyl, but not desacyl ghrelin, decreases blood pressure in healthy humans. JO - Eur. J. Endocrinol. VL - 176 IS - 2 PY - 2017 SN - 0804-4643 ER - TY - JOUR AB - CONTEXT: Alterations in the cAMP signalling pathway are common in hormonally-active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas, respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. AIM: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. DESIGN: Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome-sequencing (n=36). RESULTS: By targeted sequencing known activating mutations in GNAS were detected in 5 cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole exome sequencing identified 134 protein-altering somatic mutations in 31/36 tumors with a median of 3 mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, 7 genes involved in cAMP signalling pathway were affected in 14 of 36 samples and 8 samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No correlation between genetic alterations and the clinical data was observed. CONCLUSIONS: This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway calcium signalling might be involved in the pathogenesis of these tumors. AU - Ronchi, C.L.* AU - Peverelli, E.* AU - Herterich, S.* AU - Weigand, I.* AU - Mantovani, G.* AU - Schwarzmayr, T. AU - Sbiera, S.* AU - Allolio, B.* AU - Honegger, J.* AU - Appenzeller, S.* AU - Lania, A.* AU - Reincke, M.* AU - Calebiro, D.* AU - Spada, A.* AU - Buchfelder, M.* AU - Flitsch, J.* AU - Strom, T.M.* AU - Fassnacht, M.* C1 - 47590 C2 - 40672 CY - Bristol SP - 363-372 TI - Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. JO - Eur. J. Endocrinol. VL - 174 IS - 3 PB - Bioscientifica Ltd PY - 2016 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Reduced circulating omentin levels have been reported in obesity and type 2 diabetes, but data were mostly derived from univariate analyses in small study samples. This study aimed to investigate the relationship between omentin, abnormal glucose tolerance and related metabolic factors in a large population-based cross-sectional study. DESIGN AND METHODS: Serum omentin was measured by ELISA in 1092 participants of the German KORA F4 survey (2006-2008). Associations between omentin serum levels, glucose tolerance (assessed with an oral glucose tolerance test) and diabetes-related factors were estimated using logistic and linear regression models respectively. RESULTS: Serum levels of omentin were not related to categories of glucose tolerance. However, serum omentin was positively associated with whole-body insulin sensitivity index (ISI (composite)) and HDL cholesterol and showed inverse associations with 2-h post-load glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance, BMI and triglycerides (all P≤0.03 after adjustment for age, sex and lifestyle factors). Further adjustment for BMI and/or serum lipids attenuated the associations with parameters of glucose metabolism, whereas adjustment for serum adiponectin virtually abolished all aforementioned associations. In contrast, adjustment for omentin had no effect on the positive association between adiponectin levels and ISI (composite). CONCLUSIONS: The data from this large population-based cohort show that circulating omentin levels are associated with insulin sensitivity. Our observations further suggest that omentin acts via upregulation of adiponectin, which in turn affects lipid metabolism and thereby also indirectly enhances insulin sensitivity, but mechanistic studies are required to corroborate this hypothesis. AU - Herder, C.* AU - Ouwens, D.M.* AU - Carstensen, M.* AU - Kowall, B.* AU - Huth, C. AU - Meisinger, C. AU - Rathmann, W.* AU - Roden, M.* AU - Thorand, B. C1 - 43552 C2 - 36671 CY - Bristol SP - 423-432 TI - Adiponectin may mediate the association between omentin, circulating lipids and insulin sensitivity: Results from the KORA F4 study. JO - Eur. J. Endocrinol. VL - 172 IS - 4 PB - Bioscientifica Ltd PY - 2015 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Iron has been suggested to play a role in the etiology of type 2 diabetes mellitus. Except for ferritin, evidence is sparse for other markers of iron metabolism which are regulated differently and might act through independent pathways. We therefore investigated the associations of serum ferritin, transferrin, soluble transferrin receptor (sTfR), transferrin saturation (TSAT), sTfR-to-log10ferritin (sTfR-F) index, and iron with impaired glucose metabolism (IGM / 'prediabetes'), type 2 diabetes, and four continuous glycemic traits. DESIGN AND METHODS: Data from 2,893 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany) was investigated through regression analysis. The results were adjusted for socio-demographic, life-style and obesity measures as well as metabolic, inflammatory and other iron biomarkers following a step-wise approach. Non-linearity was tested by adding a non-linear spline component to the model. RESULTS: Ferritin and transferrin were positively associated with IGM (4th vs 1st sex-specific quartile: ferritin OR=2.08 [95%CI 1.43-3.04], transferrin OR=1.89 [1.32-2.70]), type 2 diabetes (ferritin OR=1.98 [1.22-3.22], transferrin OR=2.42 [1.54-3.81]) and fasting as well as 2-h glucose. TSAT (OR=0.55 [0.34-0.88]) and iron (OR=0.61 [0.38-0.97]) were inversely associated with type 2 diabetes, sTfR-F-index was inversely associated with IGM (OR=0.67 [0.48-0.95]). There was no strong evidence for non-linear relationships. CONCLUSIONS: The observed associations of several markers of iron metabolism with hyperglycemia and insulin resistance suggest that iron stores as well as iron-related metabolic pathways contribute to the pathogenesis of IGM and type 2 diabetes. Moreover, TSAT levels are decreased in type 2 diabetic patients. AU - Huth, C. AU - Beuerle, S. AU - Zierer, A. AU - Heier, M. AU - Herder, C.* AU - Kaiser, T.* AU - Koenig, W.* AU - Kronenberg, F.* AU - Oexle, K.* AU - Rathmann, W.* AU - Roden, M.* AU - Schwab, S. AU - Seissler, J.* AU - Stöckl, D. AU - Meisinger, C. AU - Peters, A. AU - Thorand, B. C1 - 46611 C2 - 37662 SP - 643-653 TI - Biomarkers of iron metabolism are independently associated with impaired glucose metabolism and type 2 diabetes: The KORA F4 Study. JO - Eur. J. Endocrinol. VL - 173 IS - 5 PY - 2015 SN - 0804-4643 ER - TY - JOUR AB - Objetive: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for Multiple endocrine neoplasia type 1 (MEN1) syndrome have been described, leaving the highly variable clinical presentation of the patients unaccounted for. Design: Because the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (Menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of one hundred patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% confidence intervals (CIs) using logistic regression. Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR= 2.55, p= 0.019, C.I.= 1.013-5.76). Among patients ≥30 y old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (3-4 glands affected vs. 1-2 glands affected; OR=18.33; p=0.002, C.I.=2.88-16.41). This finding remained significant after Bonferroni multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, enteropancreatic and adrenocortical tumors. Conclusions: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease. AU - Longuini, V.C.* AU - Lourenco-Jr, D.M.* AU - Sekiya, T.* AU - Meirelles, O.D.* AU - Goncalves, T.D.* AU - Coutinho, F.L.* AU - Francisco, G.* AU - Osaki, L.H.* AU - Chammas, R.* AU - Alves, V.A.* AU - Siqueira, S.A.* AU - Schlesinger, D.* AU - Naslavsky, M.S.* AU - Zatz, M.* AU - Duarte, Y.A.* AU - Lebrao, M.L.* AU - Gama, P.* AU - Lee, M.S. AU - Molatore, S. AU - Pereira, M.A.* AU - Jallad, R.S.* AU - Bronstein, M.D.* AU - Cunha Neto, M.B.* AU - Liberman, B.* AU - Fragoso, M.C.* AU - Toledo, S.P.* AU - Pellegata, N.S. AU - Toledo, R.A.* C1 - 31603 C2 - 34599 CY - Bristol SP - 335-342 TI - Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. JO - Eur. J. Endocrinol. VL - 171 IS - 3 PB - Bioscientifica Ltd PY - 2014 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Data on the association between type 2 diabetes mellitus (T2DM) and thyroid volume are sparse. An experimental study demonstrated an inhibitory effect of metformin on the growth of human thyroid cells. So far no study on humans has investigated potentially modulating effects of metformin on the association between T2DM and thyroid volume. Therefore, we investigated these effects in a population-based cohort study. DESIGN AND METHODS: We used data from the Study of Health in Pomerania and included 2570 individuals for cross-sectional and 1088 individuals for longitudinal analyses. T2DM was defined by physician-diagnosed self-report or intake of antidiabetic medication. RESULTS: In the cross-sectional data, females with T2DM treated with antidiabetic medication other than metformin had a larger thyroid volume (β=4.69; 95% CI 1.87 to 7.50) and a higher odds ratio (OR) for goiter (OR=1.71; 95% CI 1.05 to 2.79) than females without T2DM, whereas in males, no such association was detected. In females or males treated with metformin, T2DM was not associated with thyroid volume or goiter. In longitudinal analyses, incident T2DM not treated with metformin was significantly associated with a higher risk for incident goiter in the total population (incidence rate ratio (IRR)=1.70; 95% CI 1.10 to 2.91). Individuals with T2DM having changed from metformin to other antidiabetic agents during follow-up also had a higher risk for incident goiter than individuals without T2DM (IRR=2.71; 95% CI 1.74 to 4.20). CONCLUSIONS: We demonstrate an inhibitory effect of metformin on prevalent and incident goiter. Anti-goitrogenous effects of metformin add to the general benefits of metformin treatment of T2DM. AU - Ittermann, T.* AU - Markus, M.R.* AU - Schipf, S.* AU - Derwahl, M.* AU - Meisinger, C. AU - Völzke, H.* C1 - 24953 C2 - 31732 SP - 9-15 TI - Metformin inhibits goitrogenous effects of type 2 diabetes. JO - Eur. J. Endocrinol. VL - 169 IS - 1 PB - Bioscientifica Ltd. PY - 2013 SN - 0804-4643 ER - TY - JOUR AB - Background: Ghrelin stimulates GH secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and des-acyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG. Objectives: To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women. Methods: In study 1, AG (1, 3, and 5 mu g/kg per h) was infused over 65 min in 12 healthy (8 F/4 M) subjects in randomized order. In study 2, AG (1 mg/kg per h), DAG (4 mu g/kg per h), or both were infused over 210 min in ten healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study 1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis. Results: After the 1, 3, and 5 mu g/kg per h doses of AG, there was a dose-dependent increase in the maximum concentration (C-max) and area under the curve (AUC((0-last))) of AG and total ghrelin. Among the different AG doses, there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG: AG ratio was similar to 2:1 during steady-state infusion of AG. Infusion of AG caused an increase in DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity. Conclusions: The pharmacokinetics of AG and total ghrelin appears to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation. AU - Tong, J.* AU - Dave, N.* AU - Mugundu, G.M.* AU - Davis, H.W.* AU - Gaylinn, B.D.* AU - Thorner, M.O.* AU - Tschöp, M.H. AU - D'Alessio, D.* AU - Desai, P.B.* C1 - 25150 C2 - 31833 SP - 821-828 TI - The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. JO - Eur. J. Endocrinol. VL - 168 IS - 6 PB - Bioscientifica Ltd. PY - 2013 SN - 0804-4643 ER - TY - JOUR AB - Objective: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects. Methods: Data were obtained from the first follow-ups of the population-based Study of Health in Pomerania (SHIP; n=1392) and the Cooperative Health Research in the Region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies. Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC. Results: The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects. Conclusions: A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients AU - Hannemann, A.* AU - Bidlingmaier, M.* AU - Friedrich, N.* AU - Manolopoulou, J.* AU - Spyroglou, A.* AU - Völzke, H.* AU - Beuschlein, F.* AU - Seissler, J.* AU - Rettig, R.* AU - Felix, S.B.* AU - Biffar, R.* AU - Döring, A. AU - Meisinger, C. AU - Peters, A. AU - Wichmann, H.-E. AU - Nauck, M.* AU - Wallaschofski, H.* AU - Reincke, M.* C1 - 7754 C2 - 29805 SP - 7-15 TI - Screening for primary aldosteronism in hypertensive subjects: Results from two German epidemiological studies. JO - Eur. J. Endocrinol. VL - 167 IS - 1 PB - Bioscientifica Ltd PY - 2012 SN - 0804-4643 ER - TY - JOUR AB - Objective: To investigate regional variations in the frequency of undiagnosed thyroid disorders among 25- to 88-year-old men and women in two communities in the northeast and the south of Germany. In addition, autoantibodies to thyroperoxidase (TPO-Abs) and urinary iodine excretion were determined. Methods: Two population-based surveys of men and women using a common standardized protocol, the Study of Health in Pomerania (SHIP) in the northeast of Germany (2505 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) in the south of Germany (2316 participants), were compared with regard to the frequency of undiagnosed thyroid disorders. Results: Compared with the northeast of Germany, urinary iodine excretion and serum thyroid-stimulating hormone (TSH) levels were significantly higher in the south. The median urinary iodine concentration was 110 mu g/l (64; 169 mu g/l) in SHIP and 151 mu g/l (97; 214 mu g/l) in KORA, and the median TSH value was 0.81 mIU/l (0.56; 1.15 mIU/l) in SHIP and 1.22 mIU/l (0.84; 1.80 mIU/l) in KORA. The frequency of elevated TSH (TSH >= 2.12 mIU/l) was 4.3% in SHIP and 14.1% in KORA (P<0.001); the corresponding values for suppressed TSH (<0.25 mIU/l) were 3.5 and 1.7% (P<0.001). The proportion of ultrasonographic findings was 55.5% in SHIP and 68.0% in KORA. The frequency of serum TPO-Abs did not differ significantly between northeast and south Germany. Conclusions: There were considerable regional disparities in the frequency of thyroid disorders within Germany. These differences can be explained not only by different regional histories of natural iodine deficiency but also by current differences in the iodine supply under an identical nationwide iodine fortification program. AU - Meisinger, C. AU - Ittermann, T.* AU - Wallaschofski, H.* AU - Heier, M. AU - Below, H.* AU - Krämer, A.* AU - Döring, A. AU - Nauck, M.* AU - Völzke, H.* C1 - 10406 C2 - 30256 SP - 363-371 TI - Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany. JO - Eur. J. Endocrinol. VL - 167 IS - 3 PB - Bioscientifica Ltd. PY - 2012 SN - 0804-4643 ER - TY - JOUR AB - Background: Metabolic alterations and endothelial dysfunction are interrelated processes in type 2 diabetes (T2D) and metabolic syndrome (MetS) that often develop in parallel. We assessed the association of vasoactive precursor peptides (VPPs) with MetS and T2D. Design and methods: Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) were measured by novel sensitive assays in 1590 participants of the population-based KORA F4 study. The association of the VPPs with T2D, MetS defined by IDF criteria, the components of MetS, and insulin resistance (IR) was assessed in logistic regression models. Results: Elevated levels of CT-proET-1 and MR-proADM were associated with T2D, MetS, and IR in age- and sex-adjusted models. After adjustment for age, sex, former vascular complications, lifestyle factors, high-sensitive C-reactive protein, and serum creatinine, significant associations with MetS were found for MR-proADM (OR=5.94, 95% CI 3.78-9.33) and CT-proET-1 (OR=5.18, 95% CI 3.48-7.71) (top quartile vs bottom quartile). CT-proET-1 and MR-proADM were strongly associated with all components of MetS as defined by IDF criteria. After multivariable adjustment, association of CT-proET-1 and MR-proADM with pathological glucose tolerance and T2D disappeared and a borderline association with IR was found only for CT-proET-1 (OR=1.34, 95% CI 0.96-1.87). Conclusions: We here demonstrate for the first time that plasma levels of both MR-proADM and CT-proET-1 levels are related to MetS and its components, thus suggesting that they possibly have a role as a surrogate biomarker for the disease and its complications. AU - Seissler, J. AU - Feghelm, N.* AU - Then, C.* AU - Meisinger, C. AU - Herder, C.* AU - Koenig, W.* AU - Peters, A. AU - Roden, M.* AU - Lechner, A. AU - Kowall, B.* AU - Rathmann, W.* C1 - 11488 C2 - 30745 SP - 847-853 TI - Vasoregulatory peptides pro-endothelin-1 and pro-adrenomedullin are associated with metabolic syndrome in the population-based KORA F4 study. JO - Eur. J. Endocrinol. VL - 167 IS - 6 PB - Bioscientifica Ltd. PY - 2012 SN - 0804-4643 ER - TY - JOUR AB - The aim of this study was to analyze the potential association of the plasma aldosterone concentration (PAC) with the metabolic syndrome (MetS) and its components in two German population-based studies. We selected 2830 and 2901 participants (31-80 years) from the follow-ups of the Study of Health in Pomerania (SHIP)-1 and the Cooperative Health Research in the Region of Augsburg (KORA) F4 respectively. MetS was defined as the presence of at least three out of the following five criteria: waist circumference ≥94 cm (men (m)) and ≥80 cm (women (w)); high-density lipoprotein (HDL) cholesterol <1.0 mmol/l (m) and <1.3 mmol/l (w); blood pressure ≥130/85 mmHg or antihypertensive treatment; non-fasting glucose (SHIP-1) ≥8 mmol/l, fasting glucose (KORA F4) ≥5.55 mmol/l or antidiabetic treatment; non-fasting triglycerides (SHIP-1) ≥2.3 mmol/l, fasting triglycerides (KORA F4) ≥1.7 mmol/l, or lipid-lowering treatment. We calculated logistic regression models by comparing the highest study- and sex-specific PAC quintiles versus all lower quintiles. MetS was common with 48.1% (m) and 34.8% (w) in SHIP-1 and 42.7% (m) and 27.5% (w) in KORA F4. Our logistic regression models revealed associations of PAC with MetS, elevated triglycerides, and decreased HDL cholesterol in SHIP-1 and KORA F4. Our findings add to the increasing evidence supporting a relation between aldosterone and MetS and suggest that aldosterone may be involved in the pathophysiology of MetS and lipid metabolism disorders. AU - Hannemann, A.* AU - Meisinger, C. AU - Bidlingmaier, M.* AU - Döring, A. AU - Thorand, B. AU - Heier, M. AU - Belcredi, P. AU - Ladwig, K.-H. AU - Wallaschofski, H.* AU - Friedrich, N.* AU - Schipf, S.* AU - Lüdemann, J.* AU - Rettig, R.* AU - Peters, J.* AU - Völzke, H.* AU - Seissler, J.* AU - Beuschlein, F.* AU - Nauck, M.* AU - Reincke, M.* C1 - 6046 C2 - 28757 CY - Oslo, Norway SP - 751-768 TI - Association of plasma aldosterone with the metabolic syndrome in two German populations. JO - Eur. J. Endocrinol. VL - 164 IS - 5 PB - Scandinavian Univ. Press PY - 2011 SN - 0804-4643 ER - TY - JOUR AB - Genome-wide association studies have shown that the melatonin receptor 1B (MTNR1B) gene locus is strongly associated with fasting glucose and β-cell function. However, data are rather limited to the adult population and normal-weight children. So far, little is known whether similar associations are present in overweight and obese children and adolescents. The aim is to investigate an MTNR1B polymorphism in a sample of 310 overweight and obese children and adolescents (mean body mass index standard deviation score (BMI-SDS)): 2.74 (± 0.55), mean age: 14 (± 2) years), who participated in a short-term weight-loss program based on energy reduction, physical activity, and behavior therapy. We investigated an association between genotype and fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and of β-cell function (HOMA-B), and anthropometric parameters and their change during intervention.The minor G allele of polymorphism rs10830963 was significantly associated with increased fasting glucose (0.205  mmol/l, P<0.0001) and decreased HOMA-B (-0.353, P < 0.0001). Categorizing the sample into BMI-SDS groups, these significant associations were abolished in children with BMI-SDS below 2.5 but remained in those with higher BMI-SDS values with stronger β-estimates. The P value for the genotype × BMI-SDS category interaction was 0.012 for fasting glucose and 0.083 for HOMA-B. There was no significant association between genotype and anthropometric parameters and their change during intervention. This is the first single study, replicating the association between the MTNR1B locus and diabetes-related traits in overweight and obese children and adolescents. The effect sizes in children and adolescents seem to be stronger than in adults and differed among BMI-SDS categories. AU - Holzapfel, C. AU - Siegrist, M.* AU - Rank, M.* AU - Langhof, H.* AU - Grallert, H. AU - Baumert, J.J. AU - Irimie, C.* AU - Klopp, N. AU - Wolfarth, B.* AU - Illig, T. AU - Hauner, H.* AU - Halle, M. C1 - 6047 C2 - 28758 SP - 205-212 TI - Association of a MTNR1B gene variant with fasting glucose and HOMA-B in children and adolescents with high BMI-SDS. JO - Eur. J. Endocrinol. VL - 164 IS - 2 PB - Scandinavian Univ. Press PY - 2011 SN - 0804-4643 ER - TY - JOUR AB - Context Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T(3)) and low/normal thyroxine (T(4)). MCT8 contributes to hormone release from the thyroid gland. Objective To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice. Design Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8(-/y) model. Results We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (l-T(4)), the preoperative, inadequately low T(4) and free T(4) remained, while increasing the l-T(4) dosage led to T(3) serum concentrations above the normal range. Conclusions Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities. AU - Wirth, E.K.* AU - Sheu, S.Y.* AU - Chiu-Ugalde, J.* AU - Sapin, R.* AU - Klein, M.O.* AU - Mossbrugger, I. AU - Quintanilla-Martinez, L. AU - Hrabě de Angelis, M. AU - Krude, H.* AU - Riebel, T.* AU - Rothe, K.* AU - Köhrle, J.* AU - Schmid, K.W.* AU - Schweizer, U.* AU - Grüters, A.* C1 - 6575 C2 - 28929 SP - 555-561 TI - Monocarboxylate transporter 8 deficiency: Altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy. JO - Eur. J. Endocrinol. VL - 165 IS - 4 PB - European Society of Endocrinology PY - 2011 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: Analysis of salivary cortisol concentrations and derived indices is increasingly used in clinical and scientific medicine. However, comprehensive data on these parameters in the general population are scarce. The aim of this study was to evaluate the concentrations of salivary cortisol in a large middle-aged community sample and to identify major factors associated with altered hormone levels. DESIGN: We conducted a cross-sectional study within the Cooperative Health Research in the Region of Augsburg (KORA)-F3 study. A total of 1484 participants aged 50-69 years (52% women) had agreed to provide four saliva samples during a regular weekday. METHODS: We measured salivary cortisol concentrations at wake-up (F0), (1/2) h (F(1/2)), 8 h (F8), and 14 h (F14) after waking. We calculated cortisol awakening response (CAR), slope, and area under the curve (AUC(G)) of the circadian cortisol secretion. Sociodemographic and clinical characteristics were evaluated by interview and questionnaires, sampling conditions by protocol. In total, 1208 participants returned saliva samples, exclusion criteria left 990 subjects for final analyses. RESULTS: Salivary cortisol levels were (means+/-s.d.) F0=13.7+/-7.6, F(1/2)=20.5+/-9.8, F8=5.4+/-3.3, and F14=2.0+/-1.8 nmol/l. Earlier sampling times were associated with higher CAR and smaller slope. Cortisol secretion was also influenced by gender and smoking habits. Higher perceived social support was associated with lower AUC(G) and smaller slope. CONCLUSIONS: We provide data on salivary cortisol concentrations in a large middle-aged community sample. Gender, sampling time, smoking habits, and perceived social support appeared as determinants of cortisol secretion. AU - Lederbogen, F.* AU - Kühner, C.* AU - Kirschbaum, C.* AU - Meisinger, C. AU - Lammich, J.* AU - Holle, R. AU - Krumm, B.* AU - von Lengerke, T.* AU - Wichmann, H.-E. AU - Deuschle, M.* AU - Ladwig, K.-H. C1 - 5758 C2 - 27546 SP - 443-451 TI - Salivary cortisol in a middle-aged community sample: Results from 990 men and women of the KORA-F3 Augsburg study. JO - Eur. J. Endocrinol. VL - 163 IS - 3 PB - Bioscientifica Ltd. PY - 2010 SN - 0804-4643 ER - TY - JOUR AB - OBJECTIVE: In the past 20 years, obesity has become a major health problem due to associated diseases like type 2 diabetes mellitus. The gastric inhibitory polypeptide receptor (GIPR) modulates body weight and glucose homeostasis and, therefore, represents an interesting candidate gene for obesity and the comorbidity impaired glucose homeostasis. Recently, a GIPR variation was found to be associated with impaired insulin response in humans. In this study, we screened the GIPR gene for mutations and examined the association between three single-nucleotide polymorphisms (SNPs; rs8111428, rs2302382, rs1800437) and childhood obesity, as well as impaired glucose homeostasis. METHODS: The coding region of the GIPR was screened for mutations by direct sequencing. We genotyped three known SNPs in 2280 healthy normal weight (1696) and obese (584) children and adolescents. Genotyping was performed using the SNaPshot protocol, the iplex, and matrix-assisted laser desorption ionization time-of-flight spectrometry technique. Obesity was defined by a body mass index SDS above 2; homeostatic model assessment was calculated. RESULTS: No evidence for an association was found between the SNPs and the obesity phenotype. Significant association was found between the minor allele C of the SNP rs1800437 and elevated homeostasis model of insulin resistance values (P=0.001). No further sequence variations in the GIPR were found to be associated with childhood obesity. CONCLUSION: Variations of the GIPR sequence are not associated with childhood obesity. This study points to a potential role for rs1800437 in glucose homeostasis. Further studies are necessary to confirm these results. AU - Sauber, J.* AU - Grothe, J.* AU - Behm, M.* AU - Scherag, A.* AU - Grallert, H. AU - Illig, T. AU - Hinney, A.* AU - Hebebrand, J.* AU - Wiegand, S.* AU - Grüters, A.* AU - Krude, H.* AU - Biebermann, H.* C1 - 4659 C2 - 27550 SP - 259-264 TI - Association of variants in gastric inhibitory polypeptide receptor gene with impaired glucose homeostasis in obese children and adolescents from Berlin. JO - Eur. J. Endocrinol. VL - 163 IS - 2 PB - Bioscientifica Ltd. PY - 2010 SN - 0804-4643 ER - TY - JOUR AB - Objectives: Chemerin is a recently discovered adipokine that regulates adipocyte differentiation and modulates chemotaxis and activation of dendritic cells and macrophages. Given the convergence of adipocyte and macrophage function, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis in humans. We sought to examine the relationship of 1) chemerin and markers of inflammation, 2) chemerin and components of the metabolic syndrome, and 3) chemerin and coronary atherosclerotic plaque burden and morphology. Design: Serum chemerin levels were determined in 303 patients with stable typical or atypical chest pain who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. Results: Chemerin levels were highly correlated with hsCRP (r=0.44, p<0.0001), IL-6 (r=0.18, p=0.002), TNF-{alpha} (r=0.24, p<0.0001), resistin (r=0.28, p<0.0001) and leptin (r=0.36, p<0.0001) concentrations. Furthermore, chemerin was associated with components of the metabolic syndrome including BMI (r=0.23, p=0.0002), triglycerides (r=0.29, p<0.0001), HDL-C (r=-0.18, p=0.003) and hypertension (p<0.0001). In bivariate analysis, chemerin levels weakly correlated with coronary plaque burden (r=0.16, p=0.006) and the number of non-calcified plaques (r=0.14, p=0.02). These associations, however, were lost after adjusting for established cardiovascular risk factors (OR 1.17, 95%CI 0.97 to 1.41, p=0.11 for coronary plaque burden; OR 1.06, 95%CI 0.96 to 1.17, p=0.22 for non-calcified plaques). Conclusions: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome. Chemerin, however, does not predict coronary atherosclerosis. AU - Lehrke, M.* AU - Becker, A.* AU - Greif, M.* AU - Stark, R.G. AU - Laubender, R.P. AU - von Ziegler, F.* AU - Lebherz, C.* AU - Tittus, J.* AU - Reiser, M.* AU - Becker, C. AU - Göke, B.* AU - Leber, A.W.* AU - Parhofer, K.G.* AU - Broedl, U.C.* C1 - 24 C2 - 26786 SP - 339-344 TI - Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. JO - Eur. J. Endocrinol. VL - 161 IS - 2 PY - 2009 SN - 0804-4643 ER - TY - JOUR AB - Objective: The prevalence of type 2 diabetes mellitus escalates with aging although P-cell mass. a primary parameter of beta-cell function, is subject to compensatory regulation. So far it is unclear whether the proliferative capacity of pancreatic islets is restricted by senescence. Materials and methods: Human pancreatic tissue from n = 20 non-diabetic organ donors with a mean age of 50.2 +/- 3.5 years (range 7-66 years) and mean body mass index of 25.7 +/- 0.9 kg/m(2) (17.2-33.1 kg/m(2)) was morphometrically analyzed to determine beta-cell volume. beta-cell replication. beta-cell apoptosis, islet neogenesis, and pancreatic duodenal homeobox-1 (PDX-1) expression. Results: Relative beta-cell volume in human pancreata (mean 2.3 +/- 0.2%) remains constant with aging (r=0.26, P=ns). beta-cell replication (r=0.71, P=0.0004) decreases age-dependently, while beta-cell apoptosis does not change significantly (r=0.42. P=0.08). Concomitantly, PDX-1 expression is downregulated with age in human pancreatic tissue (r=0.65, P=0.002). The rate of islet neogenesis is not affected by aging (r=0.13, P=ns). Conclusions: In non-diabetic humans, aging is linked with impaired islet turnover possibly due to reduced PDX-1 expression. As P-cell replication is considered to be the main mechanism responsible for beta-cell regeneration, these changes restrict the flexibility of the aging human pancreas to adapt to changing demands for insulin secretion and increase the risk for the development of diabetes mellitus in older subjects. AU - Reers, C.* AU - Erbel, S.* AU - Esposito, I. AU - Schmied, B.* AU - Büchler, M.W.* AU - Nawroth, P.P.* AU - Ritzel, R.A.* C1 - 2055 C2 - 26797 SP - 185-191 TI - Impaired islet turnover in human donor pancreata with aging. JO - Eur. J. Endocrinol. VL - 160 IS - 2 PB - Bio Scientifica PY - 2009 SN - 0804-4643 ER - TY - JOUR AB - Regulated on activation, normal T-cell expressed and secreted (RANTES)/chemokine(C-C motif) ligand (CCL5) is expressed by adipocytes, and serum levels of RANTES are increased in obesity and type 2 diabetes. The aim of this study was to test the hypothesis that RANTES is involved in the pathogenesis of type 2 diabetes by analyzing the triangular association between CCL5 gene polymorphisms, systemic RANTES concentrations, and incident type 2 diabetes in a large prospective study. SUBJECTS AND METHODS: The study is based on 502 individuals (293 men and 209 women) and 1632 individuals (859 men and 773 women) with and without incident type 2 diabetes from the population-based MONItoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) case-cohort study respectively (mean follow-up time+/-s.d. 10.1+/-4.9 years). CCL5 genotypes and RANTES serum concentrations were determined and associations between genotypes, haplotypes, serum levels, and incident type 2 diabetes were assessed. Results Minor alleles of four single nucleotide polymorphisms were associated with lower RANTES levels (P(additive) between 1.2 x 10(-9) and 3.1 x 10(-8)), but neither genotypes, haplotypes, nor serum levels were associated with incident type 2 diabetes. CONCLUSIONS: Our data suggest that RANTES/CCL5 gene variants and serum levels are not causally related with type 2 diabetes and that elevated RANTES levels in patients with type 2 diabetes may be a consequence of hyperglycemia. However, our findings cannot preclude a local role in adipose tissue where RANTES expression may contribute to leukocyte infiltration and a proinflammatory state. AU - Herder, C.* AU - Illig, T. AU - Baumert, J.J. AU - Müller, M. AU - Klopp, N. AU - Khuseyinova, N.* AU - Meisinger, C. AU - Poschen, U.* AU - Martin, S.* AU - Koenig, W.* AU - Thorand, B. C1 - 3659 C2 - 25264 SP - R1-R5 TI - RANTES/CCL5 gene polymorphisms, serum concentrations, and incident type 2 diabetes: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Eur. J. Endocrinol. VL - 158 IS - 5 PB - BioScientifica Ltd. PY - 2008 SN - 0804-4643 ER - TY - JOUR AB - Objective: Upstream transcription factor 1 (USF1) regulates genes of glucose and lipid metabolism. Polymorphisms in the USF1 gene showed association with familial combined hyperlipidemia and lipid parameters. The aim of our study was to examine the associations between USF1 polymorphisms and lipid parameters as well as incident type 2 diabetes mellitus (T2DM) in German Caucasians. Design: We genotyped eight polymorphisms in the USF1 gene in 2067 middle-aged (35–74 years) individuals including 498 incident T2DM cases and 1569 non-cases of the population-based case–cohort study from the MONICA/KORA Augsburg project. Methods: Six polymorphisms and their haplotypes were analyzed using multivariable linear regression and Cox proportional hazards models. Results: Polymorphism rs3737787 was inversely associated with incident T2DM in women with decreased risk for female heterozygotes compared with women homozygous for the major allele (Hazard ratio=0.57; 95% confidence intervals: 0.38–0.87; P=0.008). After correction for multiple testing, significance remained. Polymorphisms rs3813609 and rs1556259 were significantly associated with reduction in low-density lipoprotein (LDL) cholesterol (pNOM=0.001; pNOM=0.00002) in women. Analyses also indicated associations of haplotypes with LDL cholesterol in women, but the association lost statistical significance after correction for multiple testing. Total serum cholesterol (TC) and high-density lipoprotein (HDL) cholesterol were weakly associated (P<0.05) with USF1 polymorphisms in women. No significant associations were found in men. Conclusions: In this large population-based study, statistically significant associations of USF1 polymorphisms with incident T2DM and LDL cholesterol were found in women, but not in men. Genetic variants in the USF1 gene showed weak or no associations with TC and HDL cholesterol AU - Holzapfel, C. AU - Baumert, J.J. AU - Grallert, H. AU - Müller, A.M. AU - Thorand, B.* AU - Khuseyinova, N.* AU - Herder, C.* AU - Meisinger, C. AU - Hauner, H.* AU - Wichmann, H.-E. AU - Koenig, W.* AU - Illig, T. AU - Klopp, N. C1 - 4285 C2 - 25994 SP - 407-416 TI - Genetic variants in the USF1 gene are associated with lowdensity lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Eur. J. Endocrinol. VL - 159 IS - 4 PB - BioScientifica Ltd. PY - 2008 SN - 0804-4643 ER - TY - JOUR AB - he aim of our study was to determine the variant pattern of the leukemia-associated Rho guanine nucleotide exchange factor (LARG, or ARHGEF12) gene and investigate whether LARG variants are associated with diabetes mellitus type 2 (T2DM), the metabolic syndrome (MetS), or related parameters such as insulin sensitivity in German Caucasians. DESIGN: We analyzed single nucleotide polymorphisms (SNPs) in the LARG gene in the 55-74-year-old individuals of the population-based German Caucasian Cooperative Health Research in the region of Augsberg (KORA) survey 4 (S4). METHODS: Sequencing of Tyr1306Cys, which was of functional relevance in Pima Indians, in 48 randomly selected individuals and genotyping of 11 additional LARG SNPs in 1653 subjects were performed. Four linkage disequilibrium (LD) blocks (r(2)> or =0.8) were established and each block was statistically analyzed for association with metabolic traits. The association with T2DM and the MetS was analyzed by logistic regression in 1462 subjects, and HOMA-IR (homeostasis model assessment of insulin resistance) as a measure of insulin sensitivity was analyzed by the Kruskal-Wallis test in 1346 fasting subjects. RESULTS: The polymorphism Tyr1306Cys, which was significantly associated with insulin sensitivity in Pima Indians, was not found in the KORA S4 population. Statistical analysis yielded no significant associations (P>0.05) between the analyzed LARG variants and T2DM, the MetS, or related parameters such as insulin sensitivity. CONCLUSIONS: Caucasian individuals and Pima Indians differ in their genetic variance pattern in the LARG gene region. There is no evidence in the Caucasian KORA study that variants of the LARG gene confer susceptibility for T2DM, insulin sensitivity, or the MetS. AU - Holzapfel, C. AU - Klopp, N. AU - Grallert, H. AU - Huth, C. AU - Gieger, C. AU - Meisinger, C. AU - Strassburger, K.* AU - Giani, G.* AU - Wichmann, H.-E. AU - Laumen, H.* AU - Hauner, H.* AU - Herder, C.* AU - Rathmann, W.* AU - Illig, T. C1 - 2735 C2 - 24918 SP - R1-R5 TI - Genetic variants in the leukemia-associated Rho guanine nucleotide exchange factor (ARHGEF12) gene are not associated with T2DM and related parameters in Caucasians (KORA study). JO - Eur. J. Endocrinol. VL - 157 IS - 3 PB - BioScientifica Ltd. PY - 2007 SN - 0804-4643 ER - TY - JOUR AB - BJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors. SUBJECTS AND METHODS: The population-based study sample comprised 1630 subjects aged 55-74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products. RESULTS: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height. CONCLUSIONS: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS. AU - Sedlmeier, E.-M. AU - Grallert, H. AU - Huth, C. AU - Löwel, H. AU - Herder, C.* AU - Strassburger, K.* AU - Giani, G.* AU - Wichmann, H.-E. AU - Hauner, H.* AU - Illig, T. AU - Rathmann, W.* C1 - 4138 C2 - 24508 SP - 377-385 TI - Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg. JO - Eur. J. Endocrinol. VL - 156 IS - 3 PB - BioScientifica Ltd. PY - 2007 SN - 0804-4643 ER - TY - JOUR AU - Herder, C.* AU - Müller-Scholze, S.* AU - Rating, P.* AU - König, W.* AU - Thorand, B. AU - Haastert, B.* AU - Holle, R. AU - Illig, T. AU - Rathmann, W.* AU - Seissler, J.* AU - Wichmann, H.-E. C1 - 3490 C2 - 23703 SP - 311-317 TI - Systemic monocyte chemoattractant protein-1 concentrations are independent of type 2 diabetes or parameters of obesity: Results from the Cooperative Health Research in the Region of Augsburg survey S4 (KORA S4). JO - Eur. J. Endocrinol. VL - 154 PY - 2006 SN - 0804-4643 ER - TY - JOUR AB - Objective: The importance of the melanin-concentrating hormone (MCH) system for regulation of energy homeostasis and body weight has been demonstrated in rodents. We analysed the human MCH receptor 1 gene (MCHR1) with respect to human obesity. Design: This consisted of genomic screening of 13.4 kb encompassing the MCHR1 in extremely obese German children and adolescents and association analyses for two coding single nucleotide polymorphisms (SNPs). To confirm initial positive association results, additional association studies and transmission disequilibrium tests in further German, Danish, French and American samples were conducted. Selected SNPs were investigated using functional in vitro studies and reporter gene assays. Methods: Single-stranded conformation polymorphism analysis, re-sequencing, PCR-restriction fragment length polymorphism analyses, tetra-primer amplification refractory mutation systems, matrix-assisted laser desorption/ionization time of flight mass spectrometry and reporter gene assays were carried out as well as measuring inositol phosphate formation, inhibition of cAMP formation and activation of p42/44 MAP kinase. Results: We identified 11 infrequent variations and two SNPs in the MCHR1 coding sequence and 18 SNPs (eight novel) in the flanking sequence. Association and transmission disequilibrium with obesity were detected for several SNPs in independent study groups of German obese children and adolescents and controls. In two German samples, encompassing 4056 and 295 individuals, trends towards association with obesity were detected. Findings in a second epidemiological German sample and in Danish, French and American samples were negative. Functional in vitro studies as well as reporter gene assays revealed no significant results. Conclusion: Our initial association of MCHR1 alleles/haplotype detected might be related to juvenile-onset obesity, conditional on a particular genetic and/or environmental background. Alternatively, we could not exclude the possibility that the initially detected association represented a false positive finding. © 2005 Society of the European Journal of Endocrinology. AU - Wermter, A.K.* AU - Reichwald, K.* AU - Buch, T.* AU - Geller, F.* AU - Platzer, C.* AU - Huse, K.* AU - Hess, C.* AU - Remschmidt, H.* AU - Gudermann, T.* AU - Preibisch, G.* AU - Siegfried, W.* AU - Goldschmidt, H.P.* AU - Li, W.D.* AU - Price, R.A.* AU - Biebermann, H.* AU - Krude, H.* AU - Vollmert, C. AU - Wichmann, H.-E. AU - Illig, T. AU - Sørensen, T.I.* AU - Astrup, A.* AU - Larsen, L.H.* AU - Pedersen, O.* AU - Eberle, D.* AU - Clément, K.* AU - Blundell, J.* AU - Wabitsch, M.* AU - Schäfer, H.* AU - Platzer, M.* AU - Hinney, A.* AU - Hebebrand, J.* C1 - 5518 C2 - 22983 SP - 851-862 TI - Mutation analysis of the MCHR1 gene in human obesity. JO - Eur. J. Endocrinol. VL - 152 IS - 6 PY - 2005 SN - 0804-4643 ER - TY - JOUR AB - Pax2 is a paired box transcription factor expressed in a spatially and temporally restricted manner and its absence results in major developmental defects of the central nervous system, eyes, ears and urogenital system. We recently reported that Pax2 is expressed in pancreatic endocrine cell lines and adult islets of Langerhans and activates glucagon gene expression. We have shown here that the Pax2 gene is expressed during pancreas development as early as embryonic day 10.5. Its absence, as assessed in Pax2(1Neu) mutant mice, results in a two- to threefold increase in the average pancreas volume occupied by the islets in both heterozygous and homozygous mutant mice with a gene-dependent dosage effect. This increase, which is due to a change in the number of islets per unit pancreas volume and in the size of individual islets, is not accompanied by significant modification in the insulin or glucagon content of the pancreas, indicating that the content of these hormones per cell is decreased. We have concluded that Pax2 may be implicated in the prenatal determination of the relative proportion of the endocrine and exocrine tissues of the pancreas. AU - Zaiko, M.* AU - Estreicher, A.* AU - Ritz-Laser, B.* AU - Herrera, P.* AU - Favor, J. AU - Meda, P.* AU - Philippe, J.* C1 - 2970 C2 - 22165 SP - 389-395 TI - Pax2 mutant mice display increased number and size of islets of Langerhans but no change in insulin and glucagon content. JO - Eur. J. Endocrinol. VL - 150 PY - 2004 SN - 0804-4643 ER -