TY - JOUR A1 - Wittenbecher, Clemens A1 - Kuxhaus, Olga A1 - Boeing, Heiner A1 - Stefan, Norbert A1 - Schulze, Matthias Bernd T1 - Associations of short stature and components of height with incidence of type 2 diabetes BT - mediating effects of cardiometabolic risk factors JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers. Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions. Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women. Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile. KW - Adult height KW - Blood pressure KW - Diabetes incidence KW - Leg length KW - Liver fat KW - Short stature KW - Trunk length Y1 - 2019 U6 - https://doi.org/10.1007/s00125-019-04978-8 SN - 0012-186X SN - 1432-0428 VL - 62 IS - 12 SP - 2211 EP - 2221 PB - Springer CY - New York ER - TY - JOUR A1 - Kroeger, Janine A1 - Meidtner, Karina A1 - Stefan, Norbert A1 - Guevara, Marcela A1 - Kerrison, Nicola D. A1 - Ardanaz, Eva A1 - Aune, Dagfinn A1 - Boeing, Heiner A1 - Dorronsoro, Miren A1 - Dow, Courtney A1 - Fagherazzi, Guy A1 - Franks, Paul W. A1 - Freisling, Heinz A1 - Gunter, Marc J. A1 - Maria Huerta, Jose A1 - Kaaks, Rudolf A1 - Key, Timothy J. A1 - Khaw, Kay Tee A1 - Krogh, Vittorio A1 - Kuehn, Tilman A1 - Mancini, Francesca Romana A1 - Mattiello, Amalia A1 - Nilsson, Peter M. A1 - Olsen, Anja A1 - Overvad, Kim A1 - Palli, Domenico A1 - Ramon Quiros, J. A1 - Rolandsson, Olov A1 - Sacerdote, Carlotta A1 - Sala, Nuria A1 - Salamanca-Fernandez, Elena A1 - Sluijs, Ivonne A1 - Spijkerman, Annemieke M. W. A1 - Tjonneland, Anne A1 - Tsilidis, Konstantinos K. A1 - Tumino, Rosario A1 - van der Schouw, Yvonne T. A1 - Forouhi, Nita G. A1 - Sharp, Stephen J. A1 - Langenberg, Claudia A1 - Riboli, Elio A1 - Schulze, Matthias Bernd A1 - Wareham, Nicholas J. T1 - Circulating Fetuin-A and Risk of Type 2 Diabetes BT - a mendelian randomization analysis JF - Diabetes : a journal of the American Diabetes Association N2 - Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. Weaimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mu g/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population. Y1 - 2018 U6 - https://doi.org/10.2337/db17-1268 SN - 0012-1797 SN - 1939-327X VL - 67 IS - 6 SP - 1200 EP - 1205 PB - American Diabetes Association CY - Alexandria ER - TY - JOUR A1 - Birukov, Anna A1 - Polemiti, Elli A1 - Jaeger, Susanne A1 - Stefan, Norbert A1 - Schulze, Matthias Bernd T1 - Fetuin-A and risk of diabetes-related vascular complications BT - a prospective study JF - Cardiovascular diabetology N2 - Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease. KW - Fetuin-A KW - biomarkers KW - epidemiology KW - Type 2 diabetes KW - vascular disease; KW - vascular calcification KW - microvascular complications Y1 - 2022 U6 - https://doi.org/10.1186/s12933-021-01439-8 SN - 1475-2840 VL - 21 IS - 1 PB - BMC CY - London ER - TY - JOUR A1 - Lehn-Stefan, Angela A1 - Peter, Andreas A1 - Machann, Jürgen A1 - Schick, Fritz A1 - Randrianarisoa, Elko A1 - Heni, Martin A1 - Wagner, Robert A1 - Birkenfeld, Andreas L. A1 - Fritsche, Andreas A1 - Schulze, Matthias Bernd A1 - Stefan, Norbert A1 - Kantartzis, Konstantinos T1 - Impaired metabolic health and low cardiorespiratory fitness independently associate with subclinical atherosclerosis in obesity JF - The journal of clinical endocrinology & metabolism N2 - Context For a given body mass index (BMI), both impaired metabolic health (MH) and reduced cardiorespiratory fitness (CRF) associate with increased risk of cardiovascular disease (CVD). Objective It remains unknown whether both risk phenotypes relate to CVD independently of each other, and whether these relationships differ in normal weight, overweight, and obese subjects. Methods Data from 421 participants from the Tubingen Diabetes Family Study, who had measurements of anthropometrics, metabolic parameters, CRF (maximal aerobic capacity [VO2max]) and carotid intima-media thickness (cIMT), an early marker of atherosclerosis, were analyzed. Subjects were divided by BMI and MH status into 6 phenotypes. Results In univariate analyses, older age, increased BMI, and a metabolic risk profile correlated positively, while insulin sensitivity and VO2max negatively with cIMT. In multivariable analyses in obese subjects, older age, male sex, lower VO2max (std. ss -0.21, P = 0.002) and impaired MH (std. ss 0.13, P = 0.02) were independent determinants of increased cIMT. After adjustment for age and sex, subjects with metabolically healthy obesity (MHO) had higher cIMT than subjects with metabolically healthy normal weight (MHNW; 0.59 +/- 0.009 vs 0.52 +/- 0.01 mm; P < 0.05). When VO2max was additionally included in this model, the difference in cIMT between MHO and MHNW groups became statistically nonsignificant (0.58 +/- 0.009 vs 0.56 +/- 0.02 mm; P > 0.05). Conclusion These data suggest that impaired MH and low CRF independently determine increased cIMT in obese subjects and that low CRF may explain part of the increased CVD risk observed in MHO compared with MHNW. KW - Metabolically healthy obesity KW - cardiorespiratory fitness KW - subclinical KW - atherosclerosis KW - obesity KW - carotid intima-media thickness KW - cardiovascular KW - disease Y1 - 2022 U6 - https://doi.org/10.1210/clinem/dgac091 SN - 0021-972X SN - 1945-7197 VL - 107 IS - 6 SP - E2417 EP - E2424 PB - Endocrine Society CY - Washington ER - TY - JOUR A1 - Willmann, Caroline A1 - Heni, Martin A1 - Linder, Katarzyna A1 - Wagner, Robert A1 - Stefan, Norbert A1 - Machann, Jürgen A1 - Schulze, Matthias Bernd A1 - Joost, Hans-Georg A1 - Haring, Hans-Ulrich A1 - Fritsche, Andreas T1 - Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content BT - a randomized and controlled dietary intervention study JF - The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc. N2 - Background: Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk. Objectives: We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes. Methods: This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy. Results: Participants in all groups lost weight (mean 3.3 +/- 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r(2) = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084). Conclusions: Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839. KW - type 2 diabetes KW - prevention KW - randomized controlled intervention study KW - nutritional factors KW - fiber KW - red meat Y1 - 2019 U6 - https://doi.org/10.1093/ajcn/nqy307 SN - 0002-9165 SN - 1938-3207 VL - 109 IS - 2 SP - 288 EP - 296 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Eckel, Nathalie A1 - Li, Yanping A1 - Kuxhaus, Olga A1 - Stefan, Norbert A1 - Hu, Frank B. A1 - Schulze, Matthias Bernd T1 - Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study) BT - 30 year follow-up from a prospective cohort study JF - The lancet diabetes & endocrinology N2 - Background Cardiovascular disease risk among individuals across different categories of BMI might depend on their metabolic health. It remains unclear to what extent metabolic health status changes over time and whether this affects cardiovascular disease risk. In this study, we aimed to examine the association between metabolic health and its change over time and cardiovascular disease risk across BMI categories. Findings During 2 127 391 person-years of follow-up with a median follow-up of 24 years, we documented 6306 cases of cardiovascular disease including 3304 myocardial infarction cases and 3080 strokes. Cardiovascular disease risk of women with metabolically healthy obesity was increased compared with women with metabolically healthy normal weight (HR 1.39, 95% CI 1.15-1.68), but risk was considerably higher in women with metabolically unhealthy normal weight (2.43, 2.19-2.68), overweight (2.61, 2.36-2.89) and obesity (3.15, 2.83-3.50). The majority of metabolically healthy women converted to unhealthy phenotypes (2555 [84%] of 3027 women with obesity, 22 215 [68%] of 32 882 women with normal-weight after 20 years). Women who maintained metabolically healthy obesity during follow-up were still at a higher cardiovascular disease risk compared with women with stable healthy normal weight (HR 1.57, 1.03-2.38), yet this risk was lower than for initially metabolically healthy women who converted to an unhealthy phenotype (normal-weight 1.90, 1.66-2.17 vs obesity 2.74, 2.30-3.27). Particularly incident diabetes and hypertension increased the risk among women with initial metabolic health. Interpretation Even when metabolic health is maintained during long periods of time, obesity remains a risk factor for cardiovascular disease. However, risks are highest for metabolically unhealthy women across all BMI categories. A large proportion of metabolically healthy women converted to an unhealthy phenotype over time across all BMI categories, which is associated with an increased cardiovascular disease risk. Copyright (C) 2018 Elsevier Ltd. All rights reserved. Y1 - 2018 U6 - https://doi.org/10.1016/S2213-8587(18)30137-2 SN - 2213-8587 VL - 6 IS - 9 SP - 714 EP - 724 PB - Elsevier CY - New York ER -