Publications by authors named "Wolfgang Rathmann"

313 Publications

Incidence Rates and Predictors of Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes: Results from the Longitudinal Global DISCOVER Study.

Am Heart J 2021 Oct 16. Epub 2021 Oct 16.

Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.

Background: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications.

Methods: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up.

Results: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21-1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84-4.06).

Conclusion: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.
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http://dx.doi.org/10.1016/j.ahj.2021.10.181DOI Listing
October 2021

Association between hepatic fat and subclinical vascular disease burden in the general population.

BMJ Open Gastroenterol 2021 09;8(1)

Institute of Epidemiology, Helmholtz Center Munich German Research Center for Environmental Health, Neuherberg, Germany

Objective: It is still controversial if increased hepatic fat independently contributes to cardiovascular risk. We aimed to assess the association between hepatic fat quantified by MRI and various subclinical vascular disease parameters.

Design: We included two cross-sectional investigations embedded in two independent population-based studies (Study of Health in Pomerania (SHIP): n=1341; Cooperative Health Research in the Region of Augsburg (KORA): n=386). The participants underwent a whole-body MRI examination. Hepatic fat content was quantified by proton-density fat fraction (PDFF). Aortic diameters in both studies and carotid plaque-related parameters in KORA were measured with MRI. In SHIP, carotid intima-media thickness (cIMT) and plaque were assessed by ultrasound. We used (ordered) logistic or linear regression to assess associations between hepatic fat and subclinical vascular disease.

Results: The prevalence of fatty liver disease (FLD) (PDFF >5.6%) was 35% in SHIP and 43% in KORA. In SHIP, hepatic fat was positively associated with ascending (β, 95% CI 0.06 (0.04 to 0.08)), descending (0.05 (0.04 to 0.07)) and infrarenal (0.02 (0.01 to 0.03)) aortic diameters, as well as with higher odds of plaque presence (OR, 95% CI 1.22 (1.05 to 1.42)) and greater cIMT (β, 95% CI 0.01 (0.004 to 0.02)) in the age-adjusted and sex-adjusted model. However, further adjustment for additional cardiometabolic risk factors, particularly body mass index, attenuated these associations. In KORA, no significant associations were found.

Conclusions: The relation between hepatic fat and subclinical vascular disease was not independent of overall adiposity. Given the close relation of FLD with cardiometabolic risk factors, people with FLD should still be prioritised for cardiovascular disease screening.
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http://dx.doi.org/10.1136/bmjgast-2021-000709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487174PMC
September 2021

Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation.

Diabetes 2021 Aug 30. Epub 2021 Aug 30.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4 T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4 regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4 T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4 regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.
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http://dx.doi.org/10.2337/db21-0364DOI Listing
August 2021

Quantifying the underestimation of projected global diabetes prevalence by the International Diabetes Federation (IDF) Diabetes Atlas.

BMJ Open Diabetes Res Care 2021 08;9(1)

Institute for Biometrics and Epidemiology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

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http://dx.doi.org/10.1136/bmjdrc-2021-002122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370495PMC
August 2021

Effects of the COVID-19 lockdown on primary health care for persons with type 2 diabetes - Results from the German Disease Analyzer database.

Diabetes Res Clin Pract 2021 Sep 13;179:109002. Epub 2021 Aug 13.

Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Germany.

Objectives: To identify the effects of the first lockdown in Germany (March to May 2020) on glycemic control, BMI, and cardiovascular risk factors in persons with type 2 diabetes.

Methods: The nationwide Disease Analyzer database includes a representative panel of physicianś practices in Germany providing anonymized real-world patient data. For metabolic and renal factors, we estimated absolute changes of means comparing outcomes from June to November 2020 to outcomes in the same persons from June to November 2019, and June to November 2018, respectively.

Results: In 32,399 patients with type 2 diabetes, HbA1c change between 2019 and 2020 was + 0.04% (95 %CI: 0.03%; 0.05%) compared to -0.02% (95 %CI: -0.03%; -0.01%) between 2018 and 2019. Metabolic risk factors and creatinine changed only little between June to November 2019 and June to November 2020. The proportions of patients with BMI ≥ 30 kg/m were 56%, 55%, and 54% in June to November 2018, 2019, and 2020, respectively. The corresponding proportions for HbA1c > 53 mmol/mol Hb (>7.0%) were 39%, 39%, and 40%.

Conclusions: There is little evidence that the first COVID-19 lockdown in Germany had a short-term harmful influence on acute health care outcomes and vascular risk factors in people with type 2 diabetes.
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http://dx.doi.org/10.1016/j.diabres.2021.109002DOI Listing
September 2021

Longitudinal relationship of particulate matter and metabolic control and severe hypoglycaemia in children and adolescents with type 1 diabetes.

Environ Res 2021 Aug 10;203:111859. Epub 2021 Aug 10.

Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Germany; German Centre for Diabetes Research (DZD), München-Neuherberg, Germany.

Background: Evidence for the metabolic impact of long-term exposure to air pollution on diabetes is lacking. We investigated the association of particulate matter <10 μm (PM) and <2.5 μm (PM) with yearly averages of HbA1c, daily insulin dose (IU/kg) and rates of severe hypoglycaemia in type 1 diabetes (T1D).

Methods: We studied data of 44,383 individuals with T1D < 21 years which were documented in 377 German centres within the diabetes prospective follow-up registry (DPV) between 2009 and 2018. Outcomes were aggregated by year and by patient. PM-and PM-yearly averages prior to the respective treatment year were linked to individuals via the five-digit postcode areas of residency. Repeated measures linear and negative binomial regression were used to study the association between PM-quartiles (Q1 lowest, Q4 highest concentration) and yearly averages of HbA1c, daily insulin dose and rates of severe hypoglycaemia (confounders: sex, time-dependent age, age at diabetes onset, time-dependent type of treatment, migratory background, degree of urbanisation and socioeconomic index of deprivation).

Results: Adjusted mean HbA1c increased with PM (Q1: 7.96% [95%-CI: 7.95-7.98], Q4: 8.03% [8.02-8.05], p-value<0.001) and with PM (Q1: 7.97% [7.95-7.99], Q4: 8.02% [8.01-8.04], p < 0.001). Changes in daily insulin dose were inversely related to PM (PM and PM: Q1 0.85 IU/kg [0.84-0.85], Q4: 0.83 IU/kg [0.82-0.83], p < 0.001). Adjusted rates of severe hypoglycaemia increased with PM-quartile groups (PM Q1:11.2 events/100 PY [10.9-11.5], PM Q4: 15.3 [14.9-15.7], p < 0.001; PM Q1: 9.9 events/100 PY [9.6-10.2], PM Q4: 14.2 [13.9-14.6], p < 0.001).

Discussion: Air pollution was associated with higher HbA1c levels and increased risk of severe hypoglycaemia in people with T1D, consequently indicating a higher risk of diabetes complications. Further studies are needed to explore causal pathways of the observed associations.
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http://dx.doi.org/10.1016/j.envres.2021.111859DOI Listing
August 2021

Health-related quality of life in patients with type 2 diabetes initiating a second-line glucose-lowering therapy: The DISCOVER study.

Diabetes Res Clin Pract 2021 Jul 22;180:108974. Epub 2021 Jul 22.

Peking University People's Hospital, Beijing, China.

Aim: To investigate factors associated with health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (T2D) at initiation of second-line glucose-lowering therapy.

Methods: DISCOVER is a 3-year, prospective observational study of patients with T2D initiating second-line glucose-lowering therapy, conducted in 38 countries. HRQoL at baseline was assessed using the physical and mental component summary (PCS; MCS) scores of the 36-Item Short Form Health Survey version 2 (SF-36v2) in 31 countries (n = 8309) and the Hypoglycaemia Fear Survey-II (HFS-II) in 23 countries (n = 6516). Factors associated with differences in HRQoL were assessed using multivariable hierarchical regression models.

Results: Mean PCS and MCS scores were 48.0 (standard deviation [SD]: 7.8) and 45.5 (SD: 10.4), respectively. Factors associated with significantly lower SF-36v2 scores included being female, having a history of macrovascular complications and first-line treatment with oral combinations (vs metformin monotherapy). Mean HFS-II behaviour and worry scores were 8.2 (SD: 9.9) and 7.3 (SD: 11.8), respectively. Increased fear of hypoglycaemia was significantly associated with lower SF-36v2 scores.

Conclusions: Several patient-, disease- and treatment-related characteristics correlated with HRQoL, indicating that a multifactorial approach is needed to maintain HRQoL in patients with T2D.
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http://dx.doi.org/10.1016/j.diabres.2021.108974DOI Listing
July 2021

Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs.

Clin Epigenetics 2021 Jul 22;13(1):143. Epub 2021 Jul 22.

Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Pirkanmaa Hospital District and Fimlab Laboratories, Tampere, Finland.

Background: Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines.

Results: We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood.

Conclusions: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.
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http://dx.doi.org/10.1186/s13148-021-01132-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296652PMC
July 2021

Dietary habits and the presence and degree of asymptomatic diverticular disease by magnetic resonance imaging in a Western population: a population-based cohort study.

Nutr Metab (Lond) 2021 Jul 16;18(1):73. Epub 2021 Jul 16.

Department of Neuroradiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

Background: Despite the worldwide burden of diverticular disease, the connections between diverticular disease and dietary habits remain poorly understood, particularly in an asymptomatic representative sample. We investigated the association between asymptomatic diverticular disease as assessed by magnetic resonance imaging (MRI) and dietary habits in a Western study cohort.

Methods: Participants from a cross-sectional sample of a population-based cohort study underwent whole-body 3T-MRI including an isotropic VIBE-Dixon sequence. The presence and extent of diverticular disease was assessed in blinded fashion. Habitual dietary intake was recorded using a blended approach, applying 24-h food lists and a food-frequency questionnaire. Traditional cardiometabolic risk factors were obtained by interviews and medical examination. Univariate and multivariate associations were calculated.

Results: A total of 308 subjects were included in this analysis (56% male, 56.4 ± 9.1 years). 39.9% had any form of diverticular disease and 15.3% had advanced asymptomatic diverticular disease. After adjustment for age, sex and total energy intake a higher intake of fiber and vegetables was associated with a lower odds for asymptomatic diverticular disease (fiber: OR 0.68 95% CI [0.48, 0.95]; vegetables: OR 0.72 95% CI [0.53, 0.97]) and an increased intake of meat was associated with an approximately two-fold higher odds for advanced asymptomatic diverticular disease (OR 1.84 95% CI [1.13, 2.99]). However, after additional adjustment for body-mass-index (BMI), alcohol consumption, smoking behavior and physical activity only a high fiber and vegetables intake remained significantly associated with lower odds of asymptomatic diverticular disease.

Conclusion: Our results indicate that a high-fiber diet and increased intake of vegetables is associated with lower odds of having asymptomatic diverticular disease, independent of age, sex, total energy intake, BMI and other life-style factors.
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http://dx.doi.org/10.1186/s12986-021-00599-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283990PMC
July 2021

Association between type 2 diabetes and chronic low back pain in general practices in Germany.

BMJ Open Diabetes Res Care 2021 07;9(1)

Epidemiology, IQVIA, Frankfurt, Germany

Introduction: There are conflicting results on the association between type 2 diabetes and chronic low back pain (CLBP). Therefore, the goal was to investigate the relationship between type 2 diabetes and CLBP in individuals followed in general practices in Germany.

Research Design And Methods: Adults diagnosed for the first time with type 2 diabetes in 809 general practices in Germany between 2005 and 2018 (index date) were included. Adults without type 2 diabetes were matched (1:1) to those with type 2 diabetes by sex, age, index year, and the annual number of medical consultations (index date: a randomly selected visit date). The association between type 2 diabetes and the 10-year incidence of CLBP was analyzed in conditional Cox regression models adjusted for a wide range of comorbidities, including hypertension, lipid metabolism disorders, and obesity.

Results: There were 139 002 individuals included in this study (women: 58.0%; mean (SD) age 62.5 (13.4) years). There was a positive association between type 2 diabetes and the incidence of CLBP in the overall sample (HR=1.23, 95% CI: 1.13 to 1.35). Sex-stratified analyses showed a higher risk of CLBP in women (HR=1.68, 95% CI: 1.43 to 1.90) and a lower risk in men with than in their counterparts without type 2 diabetes (HR=0.83, 95% CI: 0.71 to 0.97).

Conclusions: Newly diagnosed type 2 diabetes was associated with an increased risk of CLBP. There were important sex differences in the type 2 diabetes-CLBP relationship, and more research is warranted to investigate the underlying factors explaining these differences.
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http://dx.doi.org/10.1136/bmjdrc-2021-002426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286747PMC
July 2021

Early versus late intensification of glucose-lowering therapy in patients with type 2 diabetes: Results from the DISCOVER study.

Diabetes Res Clin Pract 2021 Aug 10;178:108947. Epub 2021 Jul 10.

Juntendo University, Tokyo, Japan.

Aims: To assess the effects of glycated haemoglobin (HbA) levels at time of glucose-lowering treatment intensification in DISCOVER, a global observational study of patients with type 2 diabetes (T2D) initiating second-line therapy. Outcomes of interest were glycaemic control, hypoglycaemia, and need for further intensification during 3 years of follow-up.

Methods: We included patients who intensified treatment (add-on or insulin initiation) upon initiation of second-line therapy (baseline). Outcomes were assessed according to baseline HbA: HbA ≤ 7·5% (early intensification) or HbA > 7·5% (late intensification). Factors associated with early or late intensification were assessed using multivariate logistic regression.

Results: Of the 9575 patients included, 3275 (34·2%) intensified treatment early and 6300 (65·8%) intensified treatment late. During follow-up, mean (SD) HbA was lower in the early- than in the late-intensification group (6·9% [0·95%] vs 7·5% [1·28%] at 36 months). More patients had HbA < 7·0% in the early- than in the late-intensification group (61·8% vs 37·9% at 36 months; p < 0·001). The risk of further intensification was higher in the late-intensification group (hazard ratio 1·88 [95% confidence interval 1·68-2·09]). Occurrence of hypoglycaemia was similar in both groups.

Conclusions: Late intensification of glucose-lowering therapy after first-line treatment failure reduces the likelihood of reaching recommended treatment goals.
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http://dx.doi.org/10.1016/j.diabres.2021.108947DOI Listing
August 2021

Serum uromodulin is inversely associated with biomarkers of subclinical inflammation in the population-based KORA F4 study.

Clin Kidney J 2021 Jun 6;14(6):1618-1625. Epub 2020 Sep 6.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU, München, Germany.

Background: Uromodulin is a kidney-specific glycoprotein synthesized in tubular cells of Henle's loop exerting nephroprotective and immunomodulatory functions in the urinary tract. A small amount of uromodulin is also released into the systemic circulation, where its physiological role is unknown. Serum uromodulin (sUmod) has been associated with metabolic risk factors and with cardiovascular events and mortality, where these associations were partly stronger in men than in women. In this study, we investigated the associations of sUmod with biomarkers of subclinical inflammation in a population-based sample of women and men.

Methods: Associations of sUmod with 10 biomarkers of subclinical inflammation were assessed in 1065 participants of the Cooperative Health Research in the Region of Augsburg (KORA) F4 study aged 62-81 years using linear regression models adjusted for sex, age, body mass index, estimated glomerular filtration rate and diabetes. Analyses were performed in the total study sample and stratified by sex.

Results: sUmod was inversely associated with white blood cell count, high-sensitive C-reactive protein, interleukin (IL)-6, tumour necrosis factor-α, myeloperoxidase, superoxide dismutase-3, IL-1 receptor antagonist and IL-22 after multivariable adjustment and correction for multiple testing (P < 0.001 for each observation). There was a trend towards a stronger association of sUmod with pro-inflammatory markers in men than in women, with a significant P for sex interaction (<0.001) regarding the relation of sUmod with IL-6.

Conclusions: sUmod was inversely associated with biomarkers of subclinical inflammation in older participants of the KORA F4 study. The association of sUmod with IL-6 differed between women and men. Future research should focus on whether the immunomodulatory properties of sUmod are one explanation for the association of sUmod with cardiovascular outcomes and mortality.
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http://dx.doi.org/10.1093/ckj/sfaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248959PMC
June 2021

Prediction of type 2 diabetes mellitus based on nutrition data.

J Nutr Sci 2021;10:e46. Epub 2021 Jun 21.

Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

Numerous predictive models for the risk of type 2 diabetes mellitus (T2DM) exist, but a minority of them has implemented nutrition data so far, even though the significant effect of nutrition on the pathogenesis, prevention and management of T2DM has been established. Thus, in the present study, we aimed to build a predictive model for the risk of T2DM that incorporates nutrition data and calculates its predictive performance. We analysed cross-sectional data from 1591 individuals from the population-based Cooperative Health Research in the Region of Augsburg (KORA) FF4 study (2013-14) and used a bootstrap enhanced elastic net penalised multivariate regression method in order to build our predictive model and select among 193 food intake variables. After selecting the significant predictor variables, we built a logistic regression model with these variables as predictors and T2DM status as the outcome. The values of area under the receiver operating characteristic (ROC) curve, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of our predictive model were calculated. Eleven out of the 193 food intake variables were selected for inclusion in our model, which yielded a value of area under the ROC curve of 0⋅79 and a maximum PPV, NPV and accuracy of 0⋅37, 0⋅98 and 0⋅91, respectively. The present results suggest that nutrition data should be implemented in predictive models to predict the risk of T2DM, since they improve their performance and they are easy to assess.
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http://dx.doi.org/10.1017/jns.2021.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223171PMC
June 2021

Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

J Clin Med 2021 Jun 22;10(13). Epub 2021 Jun 22.

German Center for Diabetes Research (DZD), München, 85764 Neuherberg, Germany.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65-90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts ( = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) ( = 82, 10.8%) ( = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.
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http://dx.doi.org/10.3390/jcm10132751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267679PMC
June 2021

Genetic Variation and Cardiovascular Risk Factors: A Cohort Study on Migrants from the Former Soviet Union and a Native German Population.

Int J Environ Res Public Health 2021 06 8;18(12). Epub 2021 Jun 8.

Institute for Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Resettlers are a large migrant group of more than 2 million people in Germany who migrated mainly from the former Soviet Union to Germany after 1989. We sought to compare the distribution of the major risk factors for cardiovascular disease (CVD) and to investigate the overall genetic differences in a study population which consisted of resettlers and native (autochthone) Germans. This was a joint analysis of two cohort studies which were performed in the region of Augsburg, Bavaria, Germany, with 3363 native Germans and 363 resettlers. Data from questionnaires and physical examinations were used to compare the risk factors for cardiovascular diseases between the resettlers and native Germans. A population-based genome-wide association analysis was performed in order to identify the genetic differences between the two groups. The distribution of the major risk factors for CVD differed between the two groups. The resettlers lead a less active lifestyle. While female resettlers smoked less than their German counterparts, the men showed similar smoking behavior. SNPs from three genes (BTNL2, DGKB, TGFBR3) indicated a difference in the two populations. In other studies, these genes have been shown to be associated with CVD, rheumatoid arthritis and osteoporosis, respectively.
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http://dx.doi.org/10.3390/ijerph18126215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227685PMC
June 2021

White matter hyperintensity volume in pre-diabetes, diabetes and normoglycemia.

BMJ Open Diabetes Res Care 2021 06;9(1)

Department of Radiology, University Hospital, LMU Munich, Munich, Germany

Introduction: As white matter hyperintensities (WMHs) of the brain are associated with an increased risk of stroke, cognitive decline, and depression, elucidating the associated risk factors is important. In addition to age and hypertension, pre-diabetes and diabetes may play important roles in the development of WMHs. Previous studies have, however, shown conflicting results. We aimed to investigate the effect of diabetes status and quantitative markers of glucose metabolism on WMH volume in a population-based cohort without prior cardiovascular disease.

Research Design And Methods: 400 participants underwent 3 T MRI. WMHs were manually segmented on 3D fluid-attenuated inversion recovery images. An oral glucose tolerance test (OGTT) was administered to all participants not previously diagnosed with diabetes to assess 2-hour serum glucose concentrations. Fasting glucose concentrations and glycated hemoglobin (HbA1c) levels were measured. Zero-inflated negative binomial regression analyses of WMH volume and measures of glycemic status were performed while controlling for cardiovascular risk factors and multiple testing.

Results: The final study population comprised 388 participants (57% male; age 56.3±9.2 years; n=98 with pre-diabetes, n=51 with diabetes). Higher WMH volume was associated with pre-diabetes (p=0.001) and diabetes (p=0.026) compared with normoglycemic control participants after adjustment for cardiovascular risk factors. 2-hour serum glucose (p<0.001), but not fasting glucose (p=0.389) or HbA1c (p=0.050), showed a significant positive association with WMH volume after adjustment for cardiovascular risk factors.

Conclusion: Our results indicate that high 2-hour serum glucose concentration in OGTT, but not fasting glucose levels, may be an independent risk factor for the development of WMHs, with the potential to inform intensified prevention strategies in individuals at risk of WMH-associated morbidity.
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http://dx.doi.org/10.1136/bmjdrc-2020-002050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240582PMC
June 2021

Association of hepatic steatosis derived from ultrasound and quantitative MRI with prediabetes in the general population.

Sci Rep 2021 06 24;11(1):13276. Epub 2021 Jun 24.

Institute for Community Medicine, University Medicine Greifswald, Walther Rathenau Str. 48, 17475, Greifswald, Germany.

The aim of our study was to investigate the association of hepatic steatosis derived from quantitative ultrasound and magnetic resonance imaging (MRI) with prediabetes in a large population-based study conducted in Northeast Germany. Hepatic steatosis was assessed through transabdominal ultrasound and quantitative MRI. For analysis we included 1622 subjects with MRI who participated in an oral glucose tolerance test and reported no known type 2 diabetes mellitus (T2DM). We classified participants as proposed by the American Diabetes Association: isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT), and undiagnosed T2DM. Regression models were adjusted for age, sex body mass index and alcohol consumption. We observed positive associations of hepatic steatosis with glycated hemoglobin, fasting glucose and insulin, 2-h glucose and insulin, as well as homeostasis model assessment-insulin resistance index. Similarly, individuals having hepatic steatosis as defined by MRI had a higher relative risk ratio (RR) to be in the prediabetes groups i-IFG (RR = 1.6; 95% confidence interval (CI) 1.2; 2.2), i-IGT (RR = 3.3, 95% CI 2.0; 5.6) and IFG + IGT (RR = 2.5, 95% CI 1.6; 3.9) or to have undiagnosed T2DM (RR = 4.8, 95% CI 2.6; 9.0). All associations were attenuated when defining hepatic steatosis by ultrasound. Hepatic steatosis is associated with prediabetes and undiagnosed T2DM in the general population. Quantitative liver MRI revealed stronger associations with prediabetes and undiagnosed T2DM compared to ultrasound, which indicates the higher sensitivity and specificity of MRI to determine hepatic steatosis.
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http://dx.doi.org/10.1038/s41598-021-92681-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225774PMC
June 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Association of persistent organic pollutants with sensorimotor neuropathy in participants with and without diabetes or prediabetes: Results from the population-based KORA FF4 study.

Int J Hyg Environ Health 2021 06 19;235:113752. Epub 2021 May 19.

Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Background: Concentrations of persistent organic pollutants (POPs) have been associated with an increased type 2 diabetes (T2D) risk. It remains unclear whether POPs are also associated with the risk of diabetes complications including neuropathy and evidence on this topic is scarce. We aimed to investigate the hypothesis that low-dose background concentrations of POPs were positively associated with distal sensorimotor polyneuropathy (DSPN).

Methods: This cross-sectional study was based on data from the second follow-up (FF4, 2013-2014, N = 2279) of the population-based KORA S4 study (Augsburg, Germany). The study sample consisted of 200 participants, including four groups of 50 persons each with known T2D, prediabetes, newly diagnosed diabetes, and normal glucose tolerance (NGT) based on an oral glucose tolerance test. We analyzed the association of six most abundant serum concentrations of POPs, including polychlorinated biphenyls (PCBs) as well as organochlorine (OC) pesticides, with DSPN by multivariable logistic regression adjusted for age, sex, glycaemic status, body mass index, physical activity, smoking and alcohol consumption. We assessed effect modification by age, sex, glycaemic status and obesity and conducted two-pollutant models to check the robustness of the estimates.

Results: For all pollutants, the main models indicated no significant association of having DSPN but pointed to rather decreased odds for DSPN. Two-pollutant models supported these findings, though only the association between the combination of PCB-138 and beta-hexachlorocyclohexane (β-HCH) (OR: 0.59; 95% CI: 0.35-0.99) with DSPN became significant. No effect modification was found by age, sex, glycaemic status and obesity.

Conclusion: Low-dose concentrations of POPs were not associated with increased odds of having DSPN in T2D, prediabetes and NGT.
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http://dx.doi.org/10.1016/j.ijheh.2021.113752DOI Listing
June 2021

Metabolic syndrome and the plasma proteome: from association to causation.

Cardiovasc Diabetol 2021 05 20;20(1):111. Epub 2021 May 20.

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Background: The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering.

Methods: Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization.

Results: Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04).

Conclusions: Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.
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http://dx.doi.org/10.1186/s12933-021-01299-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138979PMC
May 2021

Inappropriate intensification of glucose-lowering treatment in older patients with type 2 diabetes: the global DISCOVER study.

BMJ Open Diabetes Res Care 2021 05;9(1)

Institute for Biometrics and Epidemiology, German Diabetes Center Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Dusseldorf, Germany.

Introduction: Although individualized target glycated hemoglobin (HbA) levels are recommended in older people with type 2 diabetes, studies report high levels of potential overtreatment. We aimed to investigate the proportion of older patients (aged ≥65 years) who potentially received an inappropriately intensive treatment (HbA level <7.0% (53.0 mmol/mol)) in a global study. Factors associated with intensive glycemic management and using glucose-lowering medications associated with a high risk of hypoglycemia (high-risk medications (insulin, sulfonylureas, and meglitinides)) were also assessed.

Research Design And Methods: DISCOVER is a 3-year observational study program of 15 992 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. Data were collected at baseline (initiation of second-line therapy) and at 6, 12, and 24 months. Factors associated with an inappropriately intensive treatment or using high-risk medications were assessed using a hierarchical regression model.

Results: Of the 3344 older patients with baseline HbA data in our analytic cohort, 23.5% received inappropriate treatment intensification. Among those who had follow-up HbA data, 55.2%, 54.2%, and 53.5% were inappropriately tightly controlled at 6, 12, and 24 months, respectively, with higher proportions in high-income than in middle-income countries. The proportion of patients receiving high-risk medications was higher in middle-income countries than in high-income countries. Gross national income (per US$5000 increment) was associated with increased odds of inappropriately intensive treatment but with decreased odds of receiving high-risk medications.

Conclusions: A large proportion of older DISCOVER patients received an inappropriately intensive glucose-lowering treatment across the 2 years of follow-up, with substantial regional variation. The use of high-risk medications in these patients is particularly concerning.
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http://dx.doi.org/10.1136/bmjdrc-2020-001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098925PMC
May 2021

Significant Impact of Coffee Consumption on MR-Based Measures of Cardiac Function in a Population-Based Cohort Study without Manifest Cardiovascular Disease.

Nutrients 2021 Apr 13;13(4). Epub 2021 Apr 13.

Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany.

Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume ( < 0.01 each), and ejection fraction ( < 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors ( < 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.
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http://dx.doi.org/10.3390/nu13041275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069927PMC
April 2021

Distribution patterns of intramyocellular and extramyocellular fat by magnetic resonance imaging in subjects with diabetes, prediabetes and normoglycaemic controls.

Diabetes Obes Metab 2021 08 17;23(8):1868-1878. Epub 2021 May 17.

Department of Diagnostic and Interventional Radiology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Aim: To evaluate the distribution of intramyocellular lipids (IMCLs) and extramyocellular lipids (EMCLs) as well as total fat content in abdominal skeletal muscle by magnetic resonance imaging (MRI) using a dedicated segmentation algorithm in subjects with type 2 diabetes (T2D), prediabetes and normoglycaemic controls.

Materials And Methods: Subjects from a population-based cohort were classified with T2D, prediabetes or as normoglycaemic controls. Total myosteatosis, IMCLs and EMCLs were quantified by multiecho Dixon MRI as proton-density fat-fraction (in %) in abdominal skeletal muscle.

Results: Among 337 included subjects (median age 56.0 [IQR: 49.0-64.0] years, 56.4% males, median body mass index [BMI]: 27.2 kg/m ), 129 (38.3%) were classified with an impaired glucose metabolism (T2D: 49 [14.5%]; prediabetes: 80 [23.7%]). IMCLs were significantly higher than EMCLs in subjects without obesity (5.7% [IQR: 4.8%-7.0%] vs. 4.1% [IQR: 2.7%-5.8%], P < .001), whereas the amounts of IMCLs and EMCLs were shown to be equal and significantly higher in subjects with obesity (both 6.7%, P < .001). Subjects with prediabetes and T2D had significantly higher amounts of IMCLs and EMCLs compared with normoglycaemic controls (P < .001). In univariable analysis, prediabetes and T2D were significantly associated with both IMCLs (prediabetes: β: 0.76, 95% CI: 0.28-1.24, P = .002; T2D: β: 1.56, 95% CI: 0.66-2.47, P < .001) and EMCLs (prediabetes: β: 1.54, 95% CI: 0.56-2.51, P = .002; T2D: β: 2.15, 95% CI: 1.33-2.96, P < .001). After adjustment for age and gender, the association of IMCLs with prediabetes attenuated (P = 0.06), whereas for T2D, both IMCLs and EMCLs remained significantly and positively associated (P < .02).

Conclusion: There are significant differences in the amount and distribution ratio of IMCLs and EMCLs between subjects with T2D, prediabetes and normoglycaemic controls. Therefore, these patterns of intramuscular fat distribution by MRI might serve as imaging biomarkers in both normal and impaired glucose metabolism.
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http://dx.doi.org/10.1111/dom.14413DOI Listing
August 2021

Generalized anxiety disorder symptoms and type 2 diabetes onset: Findings from the Prospective Cooperative Health Research in the Region of Augsburg F4 and FF4 studies.

J Psychosom Res 2021 06 30;145:110480. Epub 2021 Mar 30.

Department of Psychosomatic Medicine and Psychotherapy, University of Gießen and Marburg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Partner Helmholtz Zentrum München, Germany. Electronic address:

Objective: To investigate the association of generalized anxiety disorder (GAD) symptomology on the incidence of type 2 diabetes.

Research Design & Methods: Participants from the prospective KORA F4/FF4 German cohort were followed for a mean of 6.5 years. Generalized Anxiety Disorder Scale-7 (GAD-7) was used to assess GAD symptoms and incident type 2 diabetes cases were confirmed using a standard oral glucose tolerance test. Multivariate logistic regression models were used to estimate the effect of GAD symptoms on the incidence of type 2 diabetes.

Results: The present study included 1694 participants (51.8% women, 48.2% men) with a mean age of 51.2 years, among whom 113 (6.7%) had high GAD symptoms. During the follow-up period (11,102 person/years), 113 (6.5%) type 2 diabetes cases were confirmed. Participants with GAD symptoms had 2-fold higher incidence of type 2 diabetes than participants without GAD (17.7 vs. 8.7 cases/1000 person-years). Correspondingly, GAD symptoms independently increased the risk of type 2 diabetes by an odds ratio of 2.09 [95%CI 1.02-4.32, p = 0.04] after adjustment for concurrent sociodemographic, lifestyle and cardiometabolic risk factors, high sensitivity C-reactive protein, depression, and the use of antidepressant medications. Additionally, GAD symptoms had an even larger impact on the onset of type 2 diabetes incidence following additional adjustment for prediabetes at baseline (2.68 [1.23-5.88], p=0.01).

Conclusions: Participants with GAD symptoms had 2-times higher odds of type 2 diabetes incidence during 6.5 years of follow-up, highlighting the significant role of dysregulated stress mechanisms in the pathway to developing type 2 diabetes.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110480DOI Listing
June 2021

Associations between second-line glucose-lowering combination therapies with metformin and HbA1c, body weight, quality of life, hypoglycaemic events and glucose-lowering treatment intensification: The DISCOVER study.

Diabetes Obes Metab 2021 08 3;23(8):1823-1833. Epub 2021 May 3.

AstraZeneca, Gaithersburg, Maryland, USA.

Aim: To explore the effects of second-line combination therapies with metformin on body weight, HbA1c and health-related quality of life, as well as the risks of hypoglycaemia and further treatment intensification in the DISCOVER study, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy.

Materials And Methods: Adjusted changes from baseline in weight, HbA1c and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24 and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses.

Results: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor (8.3%) or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8%-1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor or a GLP-1 receptor agonist was associated with greater weight loss (1.9, 2.9 and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < .0001). Proportions of further treatment intensification were similar across combinations (19.9%-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9%-6.4%, P < .0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU.

Conclusions: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia and lower SF-36v2 scores.
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http://dx.doi.org/10.1111/dom.14400DOI Listing
August 2021

Prevalence and progression of chronic kidney disease among patients with type 2 diabetes: Insights from the DISCOVER study.

Diabetes Obes Metab 2021 08 3;23(8):1956-1960. Epub 2021 May 3.

Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA.

We report the prevalence and change in severity of chronic kidney disease (CKD) in DISCOVER, a global, 3-year, prospective, observational study of patients with type 2 diabetes (T2D) initiating second-line glucose-lowering therapy. CKD stages were defined according to estimated glomerular filtration rate (eGFR). Overall, 7843 patients from 35 countries had a baseline serum creatinine measurement. Of these (56.7% male; mean age: 58.1 years; mean eGFR: 87.5 mL/min/1.73 m ), baseline prevalence estimates for stage 0-1, 2, 3 and 4-5 CKD were 51.4%, 37.7%, 9.4% and 1.4%, respectively. A total of 5819 patients (74.2%) also had at least one follow-up serum creatinine measurement (median time between measurements: 2.9 years, interquartile range: 1.9-3.0 years). Mean eGFR decreased slightly to 85.7 mL/min/1.73 m over follow-up. CKD progression (increase of ≥1 stage) occurred in 15.7% of patients, and regression (decrease of ≥1 stage) in 12.0%. In summary, a substantial proportion of patients with T2D developed CKD or had CKD progression after the initiation of second-line therapy. Renal function should be regularly monitored in these patients, to ensure early CKD diagnosis and treatment.
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http://dx.doi.org/10.1111/dom.14401DOI Listing
August 2021

Associations between habitual diet, metabolic disease, and the gut microbiota using latent Dirichlet allocation.

Microbiome 2021 03 16;9(1):61. Epub 2021 Mar 16.

Independent Research Unit Clinical Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.

Background: The gut microbiome impacts human health through various mechanisms and is involved in the development of a range of non-communicable diseases. Diet is a well-known factor influencing microbe-host interaction in health and disease. However, very few findings are based on large-scale analysis using population-based studies. Our aim was to investigate the cross-sectional relationship between habitual dietary intake and gut microbiota structure in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 study.

Results: Fecal microbiota was analyzed using 16S rRNA gene amplicon sequencing. Latent Dirichlet allocation (LDA) was applied to samples from 1992 participants to identify 20 microbial subgroups within the study population. Each participant's gut microbiota was subsequently described by a unique composition of these 20 subgroups. Associations between habitual dietary intake, assessed via repeated 24-h food lists and a Food Frequency Questionnaire, and the 20 subgroups, as well as between prevalence of metabolic diseases/risk factors and the subgroups, were assessed with multivariate-adjusted Dirichlet regression models. After adjustment for multiple testing, eight of 20 microbial subgroups were significantly associated with habitual diet, while nine of 20 microbial subgroups were associated with the prevalence of one or more metabolic diseases/risk factors. Subgroups 5 (Faecalibacterium, Lachnospiracea incertae sedis, Gemmiger, Roseburia) and 14 (Coprococcus, Bacteroides, Faecalibacterium, Ruminococcus) were particularly strongly associated with diet. For example, participants with a high probability for subgroup 5 were characterized by a higher Alternate Healthy Eating Index and Mediterranean Diet Score and a higher intake of food items such as fruits, vegetables, legumes, and whole grains, while participants with prevalent type 2 diabetes mellitus were characterized by a lower probability for subgroup 5.

Conclusions: The associations between habitual diet, metabolic diseases, and microbial subgroups identified in this analysis not only expand upon current knowledge of diet-microbiota-disease relationships, but also indicate the possibility of certain microbial groups to be modulated by dietary intervention, with the potential of impacting human health. Additionally, LDA appears to be a powerful tool for interpreting latent structures of the human gut microbiota. However, the subgroups and associations observed in this analysis need to be replicated in further studies. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00969-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967986PMC
March 2021

Hepatic steatosis and hepatic iron overload modify the association of iron markers with glucose metabolism disorders and metabolic syndrome.

Liver Int 2021 08 22;41(8):1841-1852. Epub 2021 Mar 22.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Background: Iron status has been linked with impaired glucose metabolism (IGM), type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MetS), but the role of hepatic steatosis or iron overload on these associations remains uncertain.

Methods: We analysed data from 2310 participants without known T2DM of the population-based Study of Health in Pomerania (SHIP-TREND, Germany) through logistic regression models. We tested additive and multiplicative interactions between ferritin and hepatic steatosis or iron overload.

Results: Serum ferritin was positively associated with IGM (OR per 100 µg/L: 1.11 [1.01, 1.23]), T2DM (OR per 100 µg/L: 1.20 [1.06, 1.36]) and MetS (OR per 100 µg/L: 1.11 [1.02, 1.20]) in the total population as well as in participants without hepatic iron overload. However, the synergistic effect of higher ferritin concentrations and hepatic iron overload showed stronger associations with IGM and T2DM. Similarly, while ferritin was positively associated with T2DM and MetS even in the absence of hepatic steatosis, the synergistic effect of higher ferritin concentrations and hepatic steatosis showed stronger associations with IGM, T2DM and MetS. Transferrin was associated with isolated impaired glucose tolerance but not with T2DM and MetS.

Conclusions: Our study suggests that ferritin may be associated with glucose metabolism disorders and MetS even in people without hepatic steatosis or iron overload. However, in individuals with higher ferritin concentrations, the presence of hepatic steatosis may indicate stronger risk for glucose metabolism disorders and MetS, while the presence of hepatic iron overload may indicate stronger risk only for glucose metabolism disorders.
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http://dx.doi.org/10.1111/liv.14868DOI Listing
August 2021

Revealing the role of the human blood plasma proteome in obesity using genetic drivers.

Nat Commun 2021 02 24;12(1):1279. Epub 2021 Feb 24.

Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.

Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies.
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http://dx.doi.org/10.1038/s41467-021-21542-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904950PMC
February 2021

Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes.

Diabetes 2021 05 19;70(5):1198-1208. Epub 2021 Feb 19.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g., lower CASP8, EN-RAGE, and IL-6 in SIDD vs. all other subgroups, all < 0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.
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http://dx.doi.org/10.2337/db20-1054DOI Listing
May 2021
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