Hyperthyroxinemia is positively associated with prevalent and incident type 2 diabetes mellitus in two population-based samples from Northeast Germany and Denmark.

BACKGROUND AND AIMS: A potential causal relationship between thyroid function and type 2 diabetes mellitus is currently under debate, but the current state of research is limited. Our aim was to investigate the association of thyroid hormone levels with prevalent and incident type 2 diabetes mellitus (T2DM) in two representative studies. METHODS AND RESULTS: Analyses are based on data from the Study of Health in Pomerania (SHIP), a German population based cohort with 4308 individuals at baseline and 3300 individuals at a five-year follow-up, and from INTER99, a Danish population-based randomized controlled trial with 6784 individuals at baseline and 4516 individuals at the five-year-follow-up. Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentrations were measured in both studies, while free triiodothyronine was measured in SHIP only. T2DM was defined by self report or intake of anti-diabetic medication. Neither in SHIP nor in INTER99 we detected significant associations of serum TSH levels with prevalent or incident T2DM. Serum fT4 levels were significantly positively associated with prevalent T2DM in SHIP and INTER99. In longitudinal analyses baseline levels of fT4 were significantly positively associated with incident T2DM in SHIP (RR per pmol/L = 1.07; 95%-CI = 1.05-1.10), while this association barely missed statistical significance in INTER99 (RR per pmol/L = 1.03; 95%-CI = 0.99-1.06). In SHIP baseline fT3 levels were significantly associated with incident T2DM (RR per pmol/L = 1.21; 95%-CI = 1.16-1.27). CONCLUSION: We demonstrated positive associations of thyroid hormones with prevalent and incident type 2 diabetes mellitus suggesting that hyperthyroxinemia may contribute to the pathogenesis of this condition.

Prediabetes is associated with microalbuminuria, reduced kidney function and chronic kidney disease in the general population: The KORA (Cooperative Health Research in the Augsburg Region) F4-Study.

BACKGROUND AND AIMS: We investigated the associations of serum fasting (FG) and 2-h postload (2HG) glucose from an oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), fasting insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) with urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). METHODS AND RESULTS: We performed cross-sectional analyses of 2713 subjects (1429 women; 52.7%) without known type 2 diabetes, aged 31-82 years, from the KORA (Cooperative Health Research in the Augsburg Region) F4-Study. FG, 2HG, HbA1c, fasting insulin, HOMA-IR and glucose tolerance categories were analyzed for association with ACR and eGFR in multivariable adjusted linear and median regression models, and with isolated microalbuminuria (i-MA), isolated reduced kidney function (i-RKF) and chronic kidney disease (CKD, defined as MA and/or RKF) in multivariable adjusted logistic regression models. Among the 2713 study participants, 28% revealed prediabetes (isolated impaired fasting glucose [i-IFG], isolated glucose tolerance [i-IGT] or both by American Diabetes Association definition), 4.2% had unknown type 2 diabetes, 6.5% had i-MA, 3.1% i-RKF and 10.9% CKD. In multivariable adjusted analysis, all continuous variables (FG, 2HG, HbA1c, fasting insulin and HOMA-IR) were associated with i-MA, i-RKF and CKD. The odds ratios (ORs) for i-MA and CKD were 1.54 (95% confidence interval: 1.02-2.33) and 1.58 (1.10-2.25) for individuals with i-IFG. Moreover, the OR for i-RKF was 2.57 (1.31-5.06) for individuals with IFG + IGT. CONCLUSION: Our findings suggest that prediabetes might have harmful effects on the kidney.

Cardiopulmonary fitness is strongly associated with body cell mass and fat-free mass: The Study of Health in Pomerania (SHIP).

Peak oxygen uptake (VO2peak) is commonly indexed by total body weight (TBW) to determine cardiopulmonary fitness (CPF). This approach may lead to misinterpretation, particularly in obese subjects. We investigated the normalization of VO2peak by different body composition markers. We analyzed combined data of 3848 subjects (1914 women; 49.7%), aged 20-90, from two independent cohorts of the population-based Study of Health in Pomerania (SHIP-2 and SHIP-TREND). VO2peak was assessed by cardiopulmonary exercise testing. Body cell mass (BCM), fat-free mass (FFM), and fat mass (FM) were determined by bioelectrical impedance analysis. The suitability of the different markers as a normalization variable was evaluated by taking into account correlation coefficients (r) and intercept (α-coefficient) values from linear regression models. A combination of high r and low α values was considered as preferable for normalization purposes. BCM was the best normalization variable for VO2peak (r = .72; P ≤ .001; α-coefficient = 63.3 mL/min; 95% confidence interval [CI]: 3.48-123) followed by FFM (r = .63; P ≤ .001; α-coefficient = 19.6 mL/min; 95% CI: -57.9-97.0). On the other hand, a much weaker correlation and a markedly higher intercept were found for TBW (r = .42; P ≤ .001; α-coefficient = 579 mL/min; 95% CI: 483 to 675). Likewise, FM was also identified as a poor normalization variable (r = .10; P ≤ .001; α-coefficient = 2133; 95% CI: 2074-2191). Sex-stratified analyses confirmed the above order for the different normalization variables. Our results suggest that BCM, followed by FFM, might be the most appropriate marker for the normalization of VO2peak when comparing CPF between subjects with different body shape.

Prediabetes is associated with lower brain gray matter volume in the general population. The Study of Health in Pomerania (SHIP).

BACKGROUND AND AIMS: We investigated the associations of fasting (FG) and 2-h postload (2HG) plasma glucose from oral glucose tolerance test (OGTT) with gray (GMV) and white (WMV) matter volume. METHODS AND RESULTS: We analyzed data from 1330 subjects without known diabetes mellitus, aged 21 to 81, from the second cohort (SHIP-Trend-0) of the population-based Study of Health in Pomerania (SHIP). Following the OGTT, individuals were classified in five groups (according to the American Diabetes Association criteria): normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) and unknown type 2 diabetes mellitus (UDM). GMV and WMV were determined by magnetic resonance imaging. FG, 2HG and OGTT groups were associated with GMV and WMV by linear regression models adjusted for confounders. FG and 2HG were inversely associated with GMV. The adjusted mean GMV, when compared with the NGT group (584 ml [95% CI: 581 to 587]), was significantly lower in the groups i-IFG (578 ml [95% CI: 573 to 582]; p = 0.035) and UDM (562 ml [95% CI: 551 to 573]; p < 0.001), but not different in the i-IGT (586 ml [95% CI: 576 to 596]; p = 0.688) and IFG + IGT (579 ml [95% CI: 571 to 586]; p = 0.209) groups. There were no associations of FG, 2HG and OGTT parameters with WMV. CONCLUSION: Our findings suggest that elevated FG levels, even within the prediabetic range, might already have some harmful effects on GMV.

Association of neighbourhood unemployment rate with incident Type 2 diabetes mellitus in five German regions.

AIM: To analyse the association of neighbourhood unemployment with incident self-reported physician-diagnosed Type 2 diabetes in a population aged 45-74 years from five German regions. METHODS: Study participants were linked via their addresses at baseline to particular neighbourhoods. Individual-level data from five population-based studies were pooled and combined with contextual data on neighbourhood unemployment. Type 2 diabetes was assessed according to a self-reported physician diagnosis of diabetes. We estimated proportional hazard models (Weibull distribution) in order to obtain hazard ratios and 95% CIs of Type 2 diabetes mellitus, taking into account interval-censoring and clustering. RESULTS: We included 7250 participants residing in 228 inner city neighbourhoods in five German regions in our analysis. The incidence rate was 12.6 per 1000 person-years (95% CI 11.4-13.8). The risk of Type 2 diabetes mellitus was higher in men [hazard ratio 1.79 (95% CI 1.47-2.18)] than in women and higher in people with a low education level [hazard ratio 1.55 (95% CI 1.18-2.02)] than in those with a high education level. Independently of individual-level characteristics, we found a higher risk of Type 2 diabetes mellitus in neighbourhoods with high levels of unemployment [quintile 5; hazard ratio 1.72 (95% CI 1.23-2.42)] than in neighbourhoods with low unemployment (quintile 1). CONCLUSIONS: Low education level and high neighbourhood unemployment were independently associated with an elevated risk of Type 2 diabetes mellitus. Studies examining the impact of the residential environment on Type 2 diabetes mellitus will provide knowledge that is essential for the identification of high-risk populations.

Long-term changes in body weight are associated with changes in blood pressure levels.

BACKGROUND AND AIMS: Hypertension and obesity are highly prevalent in Western societies. We investigated the associations of changes in body weight with changes in blood pressure and with incident hypertension, incident cardiovascular events, or incident normalization of blood pressure in patients who were hypertensive at baseline, over a 5-year period. METHODS AND RESULTS: Data of men and women aged 20-81 years of the Study of Health in Pomerania were used. Changes in body weight were related to changes in blood pressure by linear regression (n = 1875) adjusted for cofounders. Incident hypertension, incident cardiovascular events, or incident blood pressure normalization in patients who were hypertensive at baseline were investigated using Poisson regression (n = 3280) models. A change of 1 kg in body weight was positively associated with a change of 0.45 mm Hg (95% confidence interval (CI): 0.34-0.55 mm Hg) in systolic blood pressure, 0.32 mm Hg (95% CI: 0.25-0.38 mm Hg) in diastolic blood pressure, and 0.36 mm Hg (95% CI: 0.29-0.43 mm Hg) in mean arterial pressure (all p-values <0.001). A 5% weight loss reduced the relative risk (RR) of incident hypertension (RRs 0.84 (95% CI: 0.79-0.89)) and incident cardiovascular events (RRs 0.81 (95% CI: 0.68-0.98)) and increased the chance of incident blood pressure normalization in patients who were hypertensive at baseline by 15% (95% CI: 7-23%). CONCLUSIONS: Absolute and relative changes in body weight are positively associated with changes in blood pressure levels and also affect the risk of cardiovascular events.

[The design of a nationwide cohort study in Germany : the pretest studies of the German National Cohort (GNC)]. / Das Design der Machbarkeitsstudien für eine bundesweite Kohortenstudie in Deutschland : Die Pretests der Nationalen Kohorte (NAKO).

The German National Cohort (GNC) is the largest population-based cohort study in Germany. Beginning in 2014, a total of 200,000 women and men aged 20-69 years will be examined in 18 study centers. The aim of the study is to investigate the etiology of chronic diseases in relation to lifestyle, genetic, socioeconomic, and environmental factors and to develop appropriate methods for early diagnosis and prevention of diseases such as cardiovascular and respiratory diseases, cancer, diabetes, neurodegenerative/psychiatric diseases, as well as musculoskeletal and infectious diseases. Pretest studies (phase 1 and 2) were conducted to select methods, instruments, and procedures for the main study, to develop standard operating procedures, and to design and test the examination program according to acceptance, expected duration, and feasibility. The pretest studies included testing of interviews, questionnaires, anthropometric measurements, several medical examinations, and the collection of biosamples. In addition, the logistic, technical, and personnel infrastructure for the main study could be established including the study centers, the central infrastructure for data management, processes to coordinate the study, and data protection and quality management concepts. The examination program for the main phase of the GNC was designed and optimized based on the results of the pretest studies. The GNC is a population-based, highly standardized and excellently phenotyped cohort that will be the basis for new strategies for risk assessment and identification, early diagnosis, and prevention of multifactorial diseases.

The impact of regional deprivation and individual socio-economic status on the prevalence of Type 2 diabetes in Germany. A pooled analysis of five population-based studies.

AIM: Our objective was to test the hypothesis that the prevalence of Type 2 diabetes increases with increasing regional deprivation even after controlling for individual socio-economic status. METHODS: We pooled cross-sectional data from five German population-based studies. The data set contained information on n = 11,688 study participants (men 50.1%) aged 45-74 years, of whom 1008 people had prevalent Type 2 diabetes (men 56.2%). Logistic multilevel regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for diabetes prevalence. We controlled for sex, age and lifestyle risk factors, individual socio-economic status and regional deprivation, based on a new small-area deprivation measure, the German Index of Multiple Deprivation. RESULTS: Adjusted for sex, age, body mass index (BMI), physical activity, smoking status and alcohol consumption, the prevalence of Type 2 diabetes showed a stepwise increase in risk with increasing area deprivation [OR 1.88 (95% CI 1.16-3.04) in quintile 4 and OR 2.14 (95% CI 1.29-3.55) in quintile 5 compared with the least deprived quintile 1], even after controlling for individual socio-economic status. Focusing on individual socio-economic status alone, the risk of having diabetes was significantly higher for low compared with medium or high educational level [OR 1.46 (95% CI 1.24-1.71)] and for the lowest compared with the highest income group [OR 1.53 (95% CI 1.18-1.99)]. CONCLUSION: Regional deprivation plays a significant part in the explanation of diabetes prevalence in Germany independently of individual socio-economic status. The results of the present study could help to target public health measures in deprived regions.

Health-related quality of life in subjects with and without Type 2 diabetes: pooled analysis of five population-based surveys in Germany.

AIMS: To estimate population values of health-related quality of life (HRQL) in subjects with and without Type 2 diabetes mellitus across several large population-based survey studies in Germany. Systematic differences in relation to age and sex were of particular interest. METHODS: Individual data from four population-based studies from different regions throughout Germany and the nationwide German National Health Interview and Examination Survey (GNHIES98) were included in a pooled analysis of primary data (N = 9579). HRQL was assessed using the generic index instrument SF-36 (36-item Short Form Health Survey) or its shorter version, the SF-12 (12 items). Regression analysis was carried out to examine the association between Type 2 diabetes and the two component scores derived from the SF-36/SF-12, the physical component summary score (PCS-12) and the mental component summary score (MCS-12), as well as interaction effects with age and sex. RESULTS: The PCS-12 differed significantly by -4.1 points in subjects with Type 2 diabetes in comparison with subjects without Type 2 diabetes. Type 2 diabetes was associated with significantly lower MCS-12 in women only. Higher age was associated with lower PCS-12, but with an increase in MCS-12, for subjects with and without Type 2 diabetes. CONCLUSIONS: Pooled analysis of population-based primary data offers HRQL values for subjects with Type 2 diabetes in Germany, stratified by age and sex. Type 2 diabetes has negative consequences for HRQL, particularly for women. This underlines the burden of disease and the importance of diabetes prevention. Factors that disadvantage women with Type 2 diabetes need to be researched more thoroughly.

Regional differences in the prevalence of known Type 2 diabetes mellitus in 45-74 years old individuals: results from six population-based studies in Germany (DIAB-CORE Consortium).

AIM: In Germany, regional data on the prevalence of Type 2 diabetes mellitus are lacking for health-care planning and detection of risk factors associated with this disease. We analysed regional variations in the prevalence of Type 2 diabetes and treatment with antidiabetic agents. METHODS: Data of subjects aged 45-74 years from five regional population-based studies and one nationwide study conducted between 1997 and 2006 were analysed. Information on self-reported diabetes, treatment, and diagnosis of diabetes were compared. Type 2 diabetes prevalence estimates (95% confidence interval) from regional studies were directly standardized to the German population (31 December 2007). RESULTS: Of the 11,688 participants of the regional studies, 1008 had known Type 2 diabetes, corresponding to a prevalence of 8.6% (8.1-9.1%). For the nationwide study, a prevalence of 8.2% (7.3-9.2%) was estimated. Prevalence was higher in men (9.7%; 8.9-10.4%) than in women (7.6%; 6.9-8.3%). The regional standardized prevalence was highest in the east with 12.0% (10.3-13.7%) and lowest in the south with 5.8% (4.9-6.7%). Among persons with Type 2 diabetes, treatment with oral antidiabetic agents was more frequently reported in the south (56.9%) and less in the northeast (46.0%), whereas treatment with insulin alone was more frequently reported in the northeast (21.6%) than in the south (16.4%). CONCLUSION: The prevalence of known Type 2 diabetes showed a southwest-to-northeast gradient within Germany, which is in accord with regional differences in the distribution of risk factors for Type 2 diabetes. Furthermore, the treatment with antidiabetic agents showed regional differences.

[Directed acyclic graphs (DAGs) - the application of causal diagrams in epidemiology]. / Directed Acyclic Graphs (DAGs) - Die Anwendung kausaler Graphen in der Epidemiologie.

Causal graphs such as directed acyclic graphs (DAGs) are a novel approach in epidemiology to conceptualize confounding and other sources of bias. DAGs visually encode the causal relations based on a priori knowledge among the exposure of interest and the outcome while considering several covariates. The application of formal rules on these diagrams enables the identification of the causal and non-causal structures in the DAG. The causal effects are of interest and require no adjustment. Whereas the non-causal effects have to be checked for confounding and for which covariates adjustment is necessary. The identification of the adjustment set depends on the causal relations among the variables. The consideration of these relations is valuable because adjusting for more variables increases the risk of introducing bias. Considering every single path of a DAG allows the systematic identification of the causal structures in the DAG, and the determination of minimally sufficient adjustment sets for estimating the causal effect of the exposure on the outcome based on the underlying DAG. The aim of this paper is to provide an introduction to the basic assumptions as well as the steps for drawing and applying a DAG.

Smoking prevalence in Type 2 diabetes: results of the Study of Health in Pomerania (SHIP) and the German National Health Interview and Examination Survey (GNHIES).

AIMS: Smoking contributes to the development of diabetes and diabetes-related complications. Currently, data on smoking prevalence in subjects with diabetes in Germany are lacking. The aim of our analysis was to determine smoking prevalence in adults with Type 2 diabetes mellitus using data from the two population-based studies in Germany. METHODS: From the Study of Health in Pomerania (SHIP) (n = 4283) and the 1998 German National Health Interview and Examination Survey (GNHIES 98) (n = 6663) subjects aged 20-79 years were investigated. Descriptive statistics on smoking prevalence and behaviours were calculated for Type 2 diabetes mellitus and compared with the general population using weightings reflecting the European adult population. RESULTS: Overall, the prevalence of current smokers was lower among persons with than without Type 2 diabetes mellitus in SHIP (17.3% vs. 38.0%) and in GNHIES 98 (24.7% vs. 32.1%). Only in men, there were more former smokers in Type 2 diabetic patients than in subjects without diabetes in both studies. Among current and former smokers, the number of cigarettes smoked was higher among persons with than without Type 2 diabetes mellitus. For men, this finding was consistent in SHIP and GNHIES 98, while in women, this difference was only observed in GNHIES 98. CONCLUSIONS: The associations between smoking and Type 2 diabetes mellitus are likely to reflect behavioural changes secondary to illness or medical counselling. The high proportion of current smokers among Type 2 diabetic patients, particularly men, should be monitored in repeated surveys following the introduction of disease management programmes.

Changes in body weight and obesity status in German adults: results of seven population-based prospective studies.

BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time.

Health-related quality of life in women and men with type 2 diabetes: a comparison across treatment groups.

AIM: This study compares health-related quality of life (HRQL) in patients with type 2 diabetes (T2DM) across treatment groups and explores gender differences. METHODS: Four regional surveys (KORA, CARLA, SHIP, DHS) and a national survey (GNHIES98) were pooled at individual level. HRQL was assessed with the SF-12/-36v1. Linear regression models were used to assess the effect of T2DM by treatment type (no medication; oral; oral/insulin combination; insulin) on the physical (PCS-12) and mental summary score (MCS-12) and the SF-6D, controlling for age, sex, study and covariates. We also performed an explanatory analysis of single items. RESULTS: PCS-12 scores and treatment type were associated (P-value 0.006), with lowest values for insulin treatment (-4.44 vs. oral; -4.41 vs. combination). MCS-12 scores were associated with treatment type and gender (P-value <0.012), with lower scores for women undergoing oral (-4.25 vs. men) and combination treatment (-6.99 vs. men). Similar results were observed for SF-6D utilities and single items, related to mental health, social functioning, vitality and role limitation (emotional). Comorbidities were predictors of lower PCS-12 and SF-6D scores. CONCLUSIONS: T2DM treatment impacts differently on physical and mental HRQL and on women and men. Further studies of gender-specific perceptions of T2DM treatment regimens are needed.

Risk factors associated with the metabolic syndrome in abdominal obesity.

Obesity is associated with the metabolic syndrome. However, not all obese individuals have cardiovascular risk factors (CVRF). It is not clear how many abdominally obese individuals are free of CVRF and what distinguishes them from the group of obese individuals with CVRF. In this study, we aimed to assess the associated factors and prevalence of abdominal obesity without CVRF. In our cross-sectional analysis, we included n = 4244 subjects from the Study of Health in Pomerania (SHIP), a population-based study and n = 6671 subjects from the Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study, a representative primary care study in Germany. We defined abdominal obesity by waist-to-height ratio (WHtR) of 0.5 or greater. We assessed how many subjects with abdominal obesity had CVRF based on the definition of the metabolic syndrome. We analysed which conditions were associated with the absence of CVRF in abdominal obesity. In SHIP and DETECT, 2652 (62.5%) and 5126 (76.8%) subjects had a WHtR ≥ 0.5. Among those with a WHtR ≥ 0.5, 9.0% and 13.8% were free of CVRF and 49.9% and 52.7% had at least two CVRF in SHIP and DETECT, respectively. In both studies, after backward elimination, age, male sex, body mass index and high liver enzymes and unemployment were consistently inversely associated with the absence of CVRF. Among abdominally obese subjects, the prevalence of metabolically healthy subjects is low. Conditions consistently associated with the absence of CVRF in abdominal obesity are younger age, female sex, low BMI, and normal liver enzymes, the latter likely reflecting the absence of steatohepatitis.