TY - JOUR AB - The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D. AU - Lernmark, * AU - Akolkar, B.* AU - Hagopian, W.* AU - Krischer, J.* AU - McIndoe, R.* AU - Rewers, M.* AU - Toppari, J.* AU - Vehik, K.* AU - Ziegler, A.-G. C1 - 67774 C2 - 54252 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 145-158 TI - Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes. JO - J. Intern. Med. VL - 294 IS - 2 PB - Wiley PY - 2023 SN - 0954-6820 ER - TY - JOUR AB - BACKGROUND: Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline-recommended mineralocorticoid receptor antagonist (MRA) treatment. OBJECTIVES: To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well-being. METHODS: A total of 41 patients with PA on a stable antihypertensive regimen-including MRA-followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well-being by validated questionnaires. RESULTS: Dietary salt intake significantly decreased from 9.1 to 5.2 g/d at the end of the study. In parallel, systolic (130 vs. 121 mm Hg) and diastolic blood pressure (BP) (84 vs. 81 mm Hg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4 g/d). Salt restriction entailed a significant weight loss of 1.4 kg, improvement in pulse pressure (46 vs. 40 mm Hg) and normalization of depressive symptoms (PHQD scale, p < 0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin-angiotensin-aldosterone-system (RAAS) blockers were independently associated with BP reduction. CONCLUSION: A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk. AU - Schneider, H.* AU - Sarkis, A.L.* AU - Sturm, L.* AU - Britz, V.* AU - Lechner, A. AU - Potzel, A. AU - Müller, L.M.* AU - Heinrich, D.A.* AU - Künzel, H.* AU - Nowotny, H.F.* AU - Seiter, T.M.* AU - Kunz, S.* AU - Bidlingmaier, M.* AU - Reincke, M.* AU - Adolf, C.* C1 - 67703 C2 - 54010 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 47-57 TI - Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial. JO - J. Intern. Med. VL - 294 IS - 1 PB - Wiley PY - 2023 SN - 0954-6820 ER - TY - JOUR AB - Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. Whilst surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5-10%. An emerging class of multi-agonist drugs may eventually bridge this gap. This new class of specially tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action. Successful examples of this strategy include multi-agonist drugs targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon and the glucose-dependent insulinotropic polypeptide (GIP). Due to the simultaneous activity at several metabolically relevant receptors, these multi-agonists offer improved body weight loss and glucose tolerance relative to their constituent monotherapies. Further advancing this concept, chimeras were generated that covalently link nuclear acting hormones such as oestrogen, thyroid hormone (T-3) or dexamethasone to peptide hormones such as GLP-1 or glucagon. The benefit of this strategy is to restrict the nuclear hormone action exclusively to cells expressing the peptide hormone receptor, thereby maximizing combinatorial metabolic efficacy of both drug constituents in the target cells whilst preventing the nuclear hormone cargo from entering and acting on cells devoid of the peptide hormone receptor, in which the nuclear hormone might have unwanted effects. Many of these multi-agonists are in preclinical and clinical development and may represent new and effective tools in the fight against obesity and its comorbidities. AU - Brandt, S. AU - Müller, T.D. AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - Stemmer, K. C1 - 54822 C2 - 45845 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 581-602 TI - Peptide-based multi-agonists: A new paradigm in metabolic pharmacology. JO - J. Intern. Med. VL - 284 IS - 6 PB - Wiley PY - 2018 SN - 0954-6820 ER - TY - JOUR AB - BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and antioxidative glycoprotein. Plasma apoA-IV levels are elevated in patients with primary chronic kidney disease (CKD) or renal failure. The association between apoA-IV and kidney function has not been investigated in the general population; therefore, we analysed this relationship in two large population-based cohorts. METHODS: Plasma apoA-IV concentrations were measured in the Cooperative Health Research in the Region of Augsburg (KORA) F3 (n = 3159) and KORA F4 (n = 3061) studies. CKD was defined by the serum creatinine-estimated glomerular filtration rate (eGFR) and/or urine albumin-to-creatinine ratio. RESULTS: Mean (±SD) apoA-IV concentration was 17.3 ± 4.7 mg dL(-1) in KORA F3 and 15.3 ± 4.3 mg dL(-1) in KORA F4. Fully adjusted linear mixed models revealed a significant association between apoA-IV concentration and lower eGFR in the third and fourth versus the first quartile of apoA-IV (β = -1.78 mL min(-1) /1.73 m², P = 0.0003 and β = -5.09 mL min(-1) /1.73 m², P = 2.83 × 10(-23) , respectively). ApoA-IV was significantly associated with an eGFR of <60 mL min(-1) /1.73 m², which was observed in 601 of the 6220 study participants [odds ratio (OR) 1.46, P = 0.03 and OR 3.47, P = 6.84 × 10(-15) for the third and fourth vs. the first quartile of apoA-IV, respectively]. Adding apoA-IV (fourth vs. first quartile) to the fully adjusted model significantly improved discrimination of eGFR <60 mL min(-1) /1.73 m² in KORA F3 [integrated discrimination improvement (IDI) 0.03, P = 1.30 × 10(-7) ] and KORA F4 (IDI 0.04, P = 1.32 × 10(-9) ) beyond classical risk factors for CKD. CONCLUSION: The present analysis in two population-based cohorts revealed that high plasma apoA-IV concentrations are strongly associated with low kidney function defined by eGFR independent of major CKD risk factors. ApoA-IV appears to be an early marker of impaired kidney function. AU - Stangl, S.* AU - Kollerits, B.* AU - Lamina, C.* AU - Meisinger, C. AU - Huth, C. AU - Stöckl, A.* AU - Dähnhardt, D.* AU - Böger, C.A.* AU - Krämer, B.K.* AU - Peters, A. AU - Kronenberg, F.* C1 - 45109 C2 - 37228 CY - Hoboken SP - 410-423 TI - Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: Results from the KORA studies. JO - J. Intern. Med. VL - 278 IS - 4 PB - Wiley-blackwell PY - 2015 SN - 0954-6820 ER - TY - JOUR AB - BACKGROUND: Metabolomics is a versatile unbiased method to search for biomarkers of human disease. In particular, one approach in cancer therapy is to promote apoptosis in tumour cells; this could be improved with specific biomarkers of apoptosis for monitoring treatment. We recently observed specific metabolic patterns in apoptotic cell lines; however, in that study, apoptosis was only induced with one pro-apoptotic agent, staurosporine. OBJECTIVE: The aim of this study was to find novel biomarkers of apoptosis by verifying our previous findings using two further pro-apoptotic agents, 5-fluorouracil and etoposide, that are commonly used in anticancer treatment. METHODS: Metabolic parameters were assessed in HepG2 and HEK293 cells using the newborn screening assay adapted for cell culture approaches, quantifying the levels of amino acids and acylcarnitines with mass spectrometry. RESULTS: We were able to identify apoptosis-specific changes in the metabolite profile. Moreover, the amino acids alanine and glutamate were both significantly up-regulated in apoptotic HepG2 and HEK293 cells irrespective of the apoptosis inducer. CONCLUSION: Our observations clearly indicate the potential of metabolomics in detecting metabolic biomarkers applicable in theranostics and for monitoring drug efficacy. AU - Halama, A. AU - Riesen, N. AU - Hrabě de Angelis, M. AU - Adamski, J. C1 - 27861 C2 - 32839 CY - Hoboken SP - 425-439 TI - Identification of biomarkers for apoptosis in cancer cell lines using metabolomics: Tolls for individualized medicine. JO - J. Intern. Med. VL - 274 IS - 5 PB - Wiley-Blackwell PY - 2013 SN - 0954-6820 ER - TY - JOUR AB - Aims.  Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Myeloperoxidase (MPO) is a marker of oxidative stress. We prospectively investigated whether an increased serum concentration of MPO is associated with an increased risk of incident coronary heart disease (CHD). Methods.  We conducted a population-based case-cohort study in middle-aged, healthy men and women within the MONICA/KORA Augsburg studies. Serum levels of MPO were measured in 333 subjects with (cases) and 1727 without (noncases) incident CHD. Mean follow-up time was 10.8 ± 4.6 years. Results.  Baseline concentrations of MPO were higher in cases compared with noncases (P ≤ 0.001 in men; P = 0.131 in women). After adjustment for major cardiovascular risk factors, the hazard ratio (HR) with 95% confidence interval (CI) comparing the top with the two lower tertiles was 1.70 (95% CI, 1.25-2.30). After additional adjustment for markers of inflammation and endothelial dysfunction, the association was attenuated (HR 1.50; 95% CI, 1.08-2.09). There were no significant interactions of MPO with sex or increased weight on CHD risk. Conclusions.  Elevated concentrations of the oxidative stress marker MPO were independently associated with increased risk of incident CHD. This finding deserves detailed evaluation in further studies. AU - Karakas, M.* AU - Koenig, W.* AU - Zierer, A. AU - Herder, C.* AU - Rottbauer, W.* AU - Baumert, J.J. AU - Meisinger, C. AU - Thorand, B. C1 - 6886 C2 - 29396 SP - 43-50 TI - Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: Results from the MONICA/KORA Augsburg study. JO - J. Intern. Med. VL - 271 IS - 1 PB - Wiley-Blackwell PY - 2012 SN - 0954-6820 ER - TY - JOUR AB - OBJECTIVES: The early recognition of symptoms of myocardial infarction (MI) is crucial for patients with both ST-segment elevation (STEMI) and non-STEMI (NSTEMI). However, to date, only a few studies have examined the differences between patients with STEMI and NSTEMI with regard to the range of presenting MI symptoms. DESIGN: The study population comprised 889 individuals with STEMI and 1268 with NSTEMI, aged 25-74, hospitalized with a first-time MI between January 2001 and December 2006 recruited from a population-based MI registry. The occurrence of 13 symptoms was recorded during a standardized patient interview. RESULTS: Patients with STEMI were significantly younger, more likely to be smokers and less likely to have a history of hypertension or sleep disturbances prior to the acute MI (AMI) event than those with NSTEMI. A total of 50% of the patients attributed their experienced symptoms to the heart. Logistic regression modelling revealed that patients with STEMI were significantly more likely than patients with NSTEMI to complain of vomiting [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.76-3.05], dizziness (OR 1.63, 95% CI 1.30-2.03) and diaphoresis (OR 1.49, 95% CI 1.23-1.81). Furthermore, patients with STEMI were less likely to experience dyspnoea (OR 0.81, 95% CI 0.68-0.98) or pain in the throat/jaw (OR 0.80, 95% CI 0.66-0.98).CONCLUSIONS:Only half of all patients correctly attributed their symptoms to the heart. Patients with STEMI and NSTEMI showed differences regarding several presenting symptoms. Further research is needed to replicate our results, and public awareness of AMI symptoms needs to be improved. AU - Kirchberger, I. AU - Meisinger, C. AU - Heier, M. AU - Kling, B.* AU - Wende, R.* AU - Greschik, C. AU - von Scheidt, W.* AU - Kuch, B.* C1 - 3969 C2 - 29400 SP - 58-64 TI - Patient-reported symptoms in acute myocardial infarction: Differences related to ST-segment elevation: The MONICA/KORA Myocardial Infarction Registry. JO - J. Intern. Med. VL - 270 IS - 1 PB - Wiley-Blackwell PY - 2011 SN - 0954-6820 ER - TY - JOUR AB - OBJECTIVE: Later life weight change and mortality amongst elders. DESIGN: Nested case-control study. SETTING: Six countries from the European Investigation into Cancer and nutrition-Elderly, Network on Ageing and Health. SUBJECTS: A total of 1712 deceased (cases) and 4942 alive (controls) were selected from 34,239 participants, > or = 60 years at enrolment (1992-2000) who were followed-up until March 2007. Annual weight change was estimated as the weight difference from recruitment to the most distant from-date-of-death re-assessment, divided by the respective time. OUTCOME MEASURES: Mortality in relation to weight change was examined using conditional logistic regression. RESULTS: Weight loss > 1 kg year(-1) was associated with statistically significant increased death risk (OR = 1.65; 95% CI: 1.41-1.92) compared to minimal weight change (+/-1 kg year(-1)). Weight gain > 1 kg year(-1) was also associated with increased risk of death (OR = 1.15; 95% CI: 0.98-1.37), but this was evident and statistically significant only amongst overweight/obese (OR = 1.55; 95% CI: 1.17-2.05). In analyses by time interval since weight re-assessment, the association of mortality with weight loss was stronger for the interval proximal (< 1 year) to death (OR = 3.10; 95% CI: 2.03-4.72). The association of mortality with weight gain was stronger at the interval of more than 3 years and statistically significant only amongst overweight/obese (OR = 1.58; 95% CI: 1.07-2.33). Similar patterns were observed regarding death from circulatory diseases and cancer. CONCLUSIONS: In elderly, stable body weight is a predictor of lower subsequent mortality. Weight loss is associated with increased mortality, particularly short-term, probably reflecting underlying nosology. Weight gain, especially amongst overweight/obese elders, is also associated with increased mortality, particularly longer term. AU - Bamia, C.* AU - Halkjaer, J.* AU - Lagiou, P.* AU - Trichopoulos, D.* AU - Tjønneland, A.* AU - Berentzen, T.L.* AU - Overvad, K.* AU - Clavel-Chapelon, F.* AU - Boutron-Ruault, M.-C.* AU - Rohrmann, S.* AU - Linseisen, J. AU - Steffen, A.* AU - Boeing, H.* AU - May, A.M.* AU - Peeters, P.H.* AU - Bas Bueno-de-Mesquita, H.* AU - van den Berg, S.W.* AU - Dorronsoro, M.* AU - Barricarte, A.* AU - Rodriguez Suarez, L.* AU - Navarro, C.* AU - González, C.A.* AU - Boffetta, P.* AU - Pala, V.* AU - Hallmans, G.* AU - Trichopoulou, A.* C1 - 2816 C2 - 27385 SP - 133-144 TI - Weight change in later life and risk of death amongst the elderly: The European Prospective Investigation into Cancer and Nutrition-Elderly Network on Ageing and Health Study. JO - J. Intern. Med. VL - 268 IS - 2 PB - Wiley-Blackwell Publishing PY - 2010 SN - 0954-6820 ER - TY - JOUR AB - OBJECTIVES: To examine the extent to which evidence-based beneficial therapy is applied in practice, whether this is changing over time and is associated with improved outcomes. BACKGROUND: Randomized trials have proved efficacy of several treatments for acute myocardial infarction (AMI) with ST-elevation (STEMI), non-ST-elevation (NSTEMI) and bundle branch block (BBB). DESIGN AND SETTING: We prospectively examined all 6748 consecutive patients with AMI aged 25-74 years hospitalized in the study region's major clinic stratified into four time-periods: 1985-1989 (n = 1622), 1990-1994 (n = 1588), 1995-1999 (n = 1450) and 2000-2004 (n = 2088). RESULTS: The increase in numbers of AMI in the last period was mainly, but not exclusively driven by NSTEMI cases. Evidence-based pharmacological therapy increased steeply over time. Invasive procedures increased mainly in the last period with percutaneous coronary intervention and coronary artery bypass graft performed in 30% and 15% in 1998 and 66.0% and 22%, respectively, in 2004. In-hospital complications and 28-day-case fatality decreased significantly from period 1 to period 4 in all patients with AMI. Marked reductions in 28-day-case fatality were mostly seen in BBB patients during the last period (25.3% vs. 10.3%, P < 0.001). Of interest, the odds in 28-day-case fatality reduction was diminished after correction for recanalization therapy (from 0.35, 95% CI: 0.16-0.74 to 0.52, 95% CI: 0.19-1.45). CONCLUSIONS: Over the past 20 years, there were substantial changes in pharmacological and interventional therapies in AMI accompanied by reductions in in-hospital complications and 28-day-case fatality in all infarction types with marked reductions in 28-day-case fatality in BBB patients. The latter observation may mainly be because of the increased use of interventional therapy. AU - Kuch, B.* AU - Heier, M. AU - von Scheidt, W.* AU - Kling, B.* AU - Hoermann, A. AU - Meisinger, C. C1 - 2523 C2 - 25958 SP - 254-264 TI - 20-year trends in clinical characteristics, therapy and short-term prognosis in acute myocardial infarction according to presenting electrocardiogram: The MONICA/KORA AMI Registry (1985-2004). JO - J. Intern. Med. VL - 264 IS - 3 PB - Wiley-Blackwell PY - 2008 SN - 0954-6820 ER - TY - JOUR AU - Meisinger, C. AU - Löwel, H. AU - Heier, M. AU - Schneider, A.E. AU - Thorand, B. C1 - 1895 C2 - 23278 SP - 527-535 TI - Serum g-glutamyltransferase and risk of type 2 diabetes mellitus in men and women from the general population. JO - J. Intern. Med. VL - 258 PY - 2005 SN - 0954-6820 ER - TY - JOUR AU - Koenig, W. AU - Sund, M. AU - Ernst, E. AU - Hehr, R. AU - Binner, L. AU - Rosenthal, J. AU - Hombach, V. C1 - 19640 C2 - 12759 SP - 533-538 TI - Effects of Felodipine ER and Hydrochlorothiazide on Blood Rheology in Essential Hypertension - a Randomized Double-Blind, Crossover Study. JO - J. Intern. Med. VL - 229 PY - 1991 SN - 0954-6820 ER -