Publications by authors named "Andreas Fritsche"

380 Publications

A newly developed and externally validated non-clinical score accurately predicts 10-year cardiovascular disease risk in the general adult population.

Sci Rep 2021 Oct 4;11(1):19609. Epub 2021 Oct 4.

Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.

Inclusion of clinical parameters limits the application of most cardiovascular disease (CVD) prediction models to clinical settings. We developed and externally validated a non-clinical CVD risk score with a clinical extension and compared the performance to established CVD risk scores. We derived the scores predicting CVD (non-fatal and fatal myocardial infarction and stroke) in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 25,992, cases = 683) using competing risk models and externally validated in EPIC-Heidelberg (n = 23,529, cases = 692). Performance was assessed by C-indices, calibration plots, and expected-to-observed ratios and compared to a non-clinical model, the Pooled Cohort Equation, Framingham CVD Risk Scores (FRS), PROCAM scores, and the Systematic Coronary Risk Evaluation (SCORE). Our non-clinical score included age, gender, waist circumference, smoking, hypertension, type 2 diabetes, CVD family history, and dietary parameters. C-indices consistently indicated good discrimination (EPIC-Potsdam 0.786, EPIC-Heidelberg 0.762) comparable to established clinical scores (thereof highest, FRS: EPIC-Potsdam 0.781, EPIC-Heidelberg 0.764). Additional clinical parameters slightly improved discrimination (EPIC-Potsdam 0.796, EPIC-Heidelberg 0.769). Calibration plots indicated very good calibration with minor overestimation in the highest decile of predicted risk. The developed non-clinical 10-year CVD risk score shows comparable discrimination to established clinical scores, allowing assessment of individual CVD risk in physician-independent settings.
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http://dx.doi.org/10.1038/s41598-021-99103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490374PMC
October 2021

Editorial: Intermittent Fasting - Mechanisms and Clinical Usefulness.

Front Endocrinol (Lausanne) 2021 14;12:757539. Epub 2021 Sep 14.

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

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http://dx.doi.org/10.3389/fendo.2021.757539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476899PMC
September 2021

Diabetes detection from whole-body magnetic resonance imaging using deep learning.

JCI Insight 2021 Sep 30. Epub 2021 Sep 30.

Department of Internal Medicine, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.

HypothesisObesity is one of the main drivers of type 2 diabetes (T2D), but not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown features of body fat distribution which could additionally contribute to the disease.MethodsWe used machine learning with dense convolutional neural networks (DCNN) to detect diabetes related variables from 2,371 T1-weighted whole-body magnetic resonance imaging (MRI) datasets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c and prediabetes or incident diabetes. The results were compared to conventional models.ResultsThe Area Under the Receiver Operator Characteristic curve was 87% for the T2D discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk.InterpretationOur results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization unravels plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.
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http://dx.doi.org/10.1172/jci.insight.146999DOI Listing
September 2021

Different effects of lifestyle intervention in high- and low-risk prediabetes.

Diabetes 2021 Sep 16. Epub 2021 Sep 16.

German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.

Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested if prediabetic individuals with low risk benefit from conventional LI and individuals with high risk benefit from an intensification of LI in a multi-center randomized controlled intervention over 12 months with 2 years follow up. 1105 prediabetic individuals based on ADA glucose criteria were stratified into a high- and low-risk phenotype, based on previously described thresholds of insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI according to the DPP protocol or control (1:1), high-risk individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In high-risk individuals, the difference between conventional and intensified LI in post-challenge glucose change was -0.29 mmol/l [CI:-0.54;-0.04], p=0.025. Liver fat (-1.34 percentage points [CI:-2.17;-0.50], p=0.002) and cardiovascular risk (-1.82[CI:-3.13-0.50],p=0.007) underwent larger reductions with intensified than with conventional LI. During a follow up of 3 years, intensified compared to conventional LI had a higher probability to normalize glucose tolerance (p=0.008). In conclusion, it is possible in high-risk individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk-phenotype-based LI may be beneficial for the prevention of diabetes.
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http://dx.doi.org/10.2337/db21-0526DOI Listing
September 2021

Switching the basal insulin to insulin glargine 300 U/ml in people with type 2 diabetes under basal insulin supported oral therapy: Observational trial on effectiveness and safety.

Diabetes Obes Metab 2021 Sep 13. Epub 2021 Sep 13.

Medical Clinic I, Evang. Bethesda-Hospital Duisburg, Duisburg, Germany.

Aims: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D).

Materials And Methods: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target.

Results: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged.

Conclusions: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain.
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http://dx.doi.org/10.1111/dom.14549DOI Listing
September 2021

Determinants of elevated chemerin as a novel biomarker of immunometabolism: data from a large population-based cohort.

Endocr Connect 2021 Sep 20;10(9):1200-1211. Epub 2021 Sep 20.

Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany.

Objective: Chemerin is a novel inflammatory biomarker suggested to play a role in the development of metabolic disorders, providing new avenues for treatment and prevention. Little is known about the factors that predispose elevated chemerin concentrations. We therefore aimed to explore a range of lifestyle-associated, dietary, and metabolic factors as potential determinants of elevated chemerin concentrations in asymptomatic adults.

Design: We used cross-sectional data from a random subsample of 2433 participants (1494 women and 939 men) aged 42-58 years of the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort.

Methods: Random forest regression (RFR) was applied to explore the relative importance of 32 variables as statistical predictors of elevated chemerin concentrations overall and by sex. Multivariable-adjusted linear regression was applied to evaluate associations between selected predictors and chemerin concentrations.

Results: Results from RFR suggested BMI, waist circumference, C-reactive protein, fatty liver index, and estimated glomerular filtration rate as the strongest predictors of chemerin concentrations. Additional predictors included sleeping duration, alcohol, red and processed meat, fruits, sugar-sweetened beverages (SSB), vegetables, dairy, and refined grains. Collectively, these factors explained 32.9% variation of circulating chemerin. Multivariable-adjusted analyses revealed linear associations of elevated chemerin with metabolic parameters, obesity, longer sleep, higher intakes of red meat and SSB, and lower intakes of dairy.

Conclusions: These findings come in support of the role of chemerin as a biomarker characterizing inflammatory and metabolic phenotypes in asymptomatic adults. Modifiable dietary and lifestyle-associated determinants of elevated chemerin concentrations require further evaluation in a prospective study setting.
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http://dx.doi.org/10.1530/EC-21-0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494416PMC
September 2021

Free fatty acids, glicentin and glucose-dependent insulinotropic polypeptide as potential major determinants of fasting substrate oxidation.

Sci Rep 2021 08 17;11(1):16642. Epub 2021 Aug 17.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body β-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (all p ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.
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http://dx.doi.org/10.1038/s41598-021-95750-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371005PMC
August 2021

Diabetes in the Hospital.

Dtsch Arztebl Int 2021 06;118(24):407-412

Institute of Epidemiology and Medical Biometry, ZIBMT, Medical Faculty of the University Ulm, Ulm, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany; Institute of Health Services Research and Health Economics, Center for Health and Society, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Health Services Research and Health Economics, German Diabetes Center (DDZ), Düsseldorf, Germany; Department of Gastroenterology, Diabetology, Endocrinology, and Nutritional Medicine, St. Josefskrankenhaus Heidelberg, Heidelberg, Germany; Department of Psychiatry and Psychotherapy II, University Hospital Ulm, Um, Germany; Division of Endocrinology and Diabetes, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Comprehensive data on the frequency of diabetes mellitus among hospitalized patients in Germany have not been published to date.

Methods: Among all inpatient cases aged ≥20 years that were documented in the German DRG statistics for 2015-2017, we analyzed the frequencies of five types of diabetes (type 1, type 2, other/pancreatic diabetes, "rare diabetes" with an ICD code of E12 or E14, gestational diabetes) and of prediabetes, stratified by sex and age group. The presence of any of these conditions was ascertained from the corresponding ICD-10 code among the main diagnoses (reasons for admission) or secondary diagnoses. We also compared the length of hospital stay, in-hospital mortality, and the frequency of various categories of main diagnosis in cases with and without diabetes in each age group.

Results: In the period 2015-2017, approximately 18% of the 16.4 to 16.7 million inpatient cases carried a main or secondary diagnosis of diabetes (in 2017: type 2, 17.1%; type 1, 0.5%). Diabetes was more common in male cases than in female cases (in 2017: type 2, 19.7% vs. 14.8%; type 1, 0.5% vs. 0.4%). In 2017, the greatest difference in length of hospital stay between patients with and without diabetes was for patients with type 1 diabetes aged 40-49 (7.3 vs. 4.5 days), while the greatest difference in in-hospital mortality was for patients with type 2 diabetes aged 70-79 (3.7% vs. 2.8%). From the age of 30 (age category 30-39), diseases of the cardiovascular system, and from the age of 50 (age category 50-59), diseases of the respiratory or urogenital systems were more frequently listed as a reason for admission in cases with than in those without diabetes.

Conclusion: The fact that diabetes is twice as prevalent in hospitalized cases as in the general population underscores the high morbidity associated with the disease and the greater need of persons with diabetes for in-hospital care, as the population of multimorbid diabetes patients continues to grow older.
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http://dx.doi.org/10.3238/arztebl.m2021.0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380837PMC
June 2021

Systematic, Modifying Group-Assisted Strategy Expanding Coverage of Metabolite Annotation in Liquid Chromatography-Mass Spectrometry-Based Nontargeted Metabolomics Studies.

Anal Chem 2021 08 30;93(31):10916-10924. Epub 2021 Jul 30.

CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

From microbes to human beings, nontargeted metabolic profiling by liquid chromatography (LC)-mass spectrometry (MS) has been commonly used to investigate metabolic alterations. Still, a major challenge is the annotation of metabolites from thousands of detected features. The aim of our research was to go beyond coverage of metabolite annotation in common nontargeted metabolomics studies by an integrated multistep strategy applying data-dependent acquisition (DDA)-based ultrahigh-performance liquid chromatography (UHPLC)-high-resolution mass spectrometry (HRMS) analysis followed by comprehensive neutral loss matches for characteristic metabolite modifications and database searches in a successive manner. Using pooled human urine as a model sample for method establishment, we found 22% of the detected compounds having modifying structures. Major types of metabolite modifications in urine were glucuronidation (33%), sulfation (20%), and acetylation (6%). Among the 383 annotated metabolites, 100 were confirmed by standard compounds and 50 modified metabolites not present in common databases such as human metabolite database (HMDB) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were structurally elucidated. Practicability was tested by the investigation of urines from pregnant women diagnosed with gestational diabetes mellitus vs healthy controls. Overall, 83 differential metabolites were annotated and 67% of them were modified metabolites including five previously unreported compounds. To conclude, the systematic modifying group-assisted strategy can be taken as a useful tool to extend the number of annotated metabolites in biological and biomedical nontargeted studies.
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http://dx.doi.org/10.1021/acs.analchem.1c01715DOI Listing
August 2021

Influence of Spinal Cord Stimulation on Insulin Sensitivity in Chronic Pain Patients.

Exp Clin Endocrinol Diabetes 2021 Jul 12. Epub 2021 Jul 12.

Medical Clinic IV, University of Tübingen, Tübingen, Germany.

Background And Objective: This prospective, sham-controlled, randomized, cross-over study (NCT03637075), was designed to test the hypothesis that spinal cord stimulation (SCS) for the treatment of pain can also improve glucose metabolism and insulin sensitivity when compared to sham stimulation.

Methods: Ten non-diabetic participants (5 females, mean age 48.8 years) who had an SCS system implanted for the treatment of chronic neuropathic pain were studied. Whilst applying a hyperinsulinemic-euglycemic clamp, sham-stimulation and tonic stimulation were performed for 45 min (n=4) or 60 min (n=6) in each case randomly. The insulin sensitivity index and pain levels were determined. A second investigation, BurstDR stimulation was also conducted and the result was compared to that of sham stimulation (cross-over design).

Results: The insulin sensitivity improved significantly under the tonic stimulation when compared to the sham stimulation (p=0.037). BurstDR stimulation independently did not lead to a significantly improved insulin sensitivity compared to that after sham stimulation (p=0.16). We also examined the pain during the test and found no significant difference between sham and tonic stimulation (p=0.687).

Conclusion: The results of this study show that tonic stimulation used for the treatment of pain could also improve glucose metabolism and insulin sensitivity. Further investigations are required to investigate the clinical relevance of the role of glucose metabolism in diabetic chronic pain participants and its underlying mechanisms.
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http://dx.doi.org/10.1055/a-1525-3339DOI Listing
July 2021

Central Insulin Modulates Dopamine Signaling in the Human Striatum.

J Clin Endocrinol Metab 2021 Sep;106(10):2949-2961

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany.

Objective: Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive.

Research Design And Methods: We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial.

Results: In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin.

Conclusions: This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.
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http://dx.doi.org/10.1210/clinem/dgab410DOI Listing
September 2021

Hemostatic alterations linked to body fat distribution, fatty liver, and insulin resistance.

Mol Metab 2021 May 31;53:101262. Epub 2021 May 31.

Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Objective: Obesity, in particular visceral obesity, and insulin resistance emerged as major risk factors for severe coronavirus disease 2019 (COVID-19), which is strongly associated with hemostatic alterations. Because obesity and insulin resistance predispose to thrombotic diseases, we investigated the relationship between hemostatic alterations and body fat distribution in participants at risk for type 2 diabetes.

Subjects: Body fat distribution (visceral and subcutaneous abdominal adipose tissue) and liver fat content of 150 participants - with impaired glucose tolerance and/or impaired fasting glucose - were determined using magnetic resonance imaging and spectroscopy. Participants underwent precise metabolic characterization and major hemostasis parameters were analyzed.

Results: Procoagulant factors (FII, FVII, FVIII, and FIX) and anticoagulant proteins (antithrombin, protein C, and protein S) were significantly associated with body fat distribution. In patients with fatty liver, fibrinogen (298 mg/dl vs. 264 mg/dl, p = 0.0182), FVII (99% vs. 90%, p = 0.0049), FVIII (114% vs. 90%, p = 0.0098), protein C (124% vs. 111%, p = 0.0006), and protein S (109% vs. 89%, p < 0.0001) were higher than in controls. In contrast, antithrombin (97% vs. 102%, p = 0.0025) was higher in control patients. In multivariate analyses controlling for insulin sensitivity, body fat compartments, and genotype variants (PNPLA3/TM6SF2), only protein C and protein S remained significantly increased in fatty liver.

Conclusions: Body fat distribution is significantly associated with alterations of procoagulant and anticoagulant parameters. Liver fat plays a key role in the regulation of protein C and protein S, suggesting a potential counteracting mechanism to the prothrombotic state in subjects with prediabetes and fatty liver.
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http://dx.doi.org/10.1016/j.molmet.2021.101262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165974PMC
May 2021

Fully Automated and Standardized Segmentation of Adipose Tissue Compartments via Deep Learning in 3D Whole-Body MRI of Epidemiologic Cohort Studies.

Radiol Artif Intell 2020 Nov 28;2(6):e200010. Epub 2020 Oct 28.

Department of Diagnostic and Interventional Radiology, Medical Image and Data Analysis, University Hospital Tübingen, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany (T.K., T.H., M.F., K.N., S.G.); Department of Signal Processing and System Theory, University of Stuttgart, Stuttgart, Germany (T.K., M.F., M.S., B.Y.); School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, England (T.K.); Department of Empirical Inference, Max-Planck Institute for Intelligent Systems, Tübingen, Germany (T.H.); Department of Diagnostic and Interventional Radiology, Section of Experimental Radiology, University Hospital Tübingen, Tübingen, Germany (M.F., M.S., F.S., J.M.); Department of Internal Medicine IV, Eberhard Karls University, Tübingen, Germany (A.F.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany (A.F., F.S., J.M.); German Center for Diabetes Research (DZD), Tübingen, Germany (A.F., H.U.H., F.S., J.M.); and Department of Diagnostic and Interventional Radiology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany (F.B.).

Purpose: To enable fast and reliable assessment of subcutaneous and visceral adipose tissue compartments derived from whole-body MRI.

Materials And Methods: Quantification and localization of different adipose tissue compartments derived from whole-body MR images is of high interest in research concerning metabolic conditions. For correct identification and phenotyping of individuals at increased risk for metabolic diseases, a reliable automated segmentation of adipose tissue into subcutaneous and visceral adipose tissue is required. In this work, a three-dimensional (3D) densely connected convolutional neural network (DCNet) is proposed to provide robust and objective segmentation. In this retrospective study, 1000 cases (average age, 66 years ± 13 [standard deviation]; 523 women) from the Tuebingen Family Study database and the German Center for Diabetes research database and 300 cases (average age, 53 years ± 11; 152 women) from the German National Cohort (NAKO) database were collected for model training, validation, and testing, with transfer learning between the cohorts. These datasets included variable imaging sequences, imaging contrasts, receiver coil arrangements, scanners, and imaging field strengths. The proposed DCNet was compared to a similar 3D U-Net segmentation in terms of sensitivity, specificity, precision, accuracy, and Dice overlap.

Results: Fast (range, 5-7 seconds) and reliable adipose tissue segmentation can be performed with high Dice overlap (0.94), sensitivity (96.6%), specificity (95.1%), precision (92.1%), and accuracy (98.4%) from 3D whole-body MRI datasets (field of view coverage, 450 × 450 × 2000 mm). Segmentation masks and adipose tissue profiles are automatically reported back to the referring physician.

Conclusion: Automated adipose tissue segmentation is feasible in 3D whole-body MRI datasets and is generalizable to different epidemiologic cohort studies with the proposed DCNet.© RSNA, 2020.
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http://dx.doi.org/10.1148/ryai.2020200010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082356PMC
November 2020

Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study.

Metabolism 2021 06 20;119:154776. Epub 2021 Apr 20.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address:

Aims/hypothesis: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome.

Methods: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes).

Results: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (N = 1054, N = 2254; N = 1985, N = 2251). BMI-related SNPs were causally associated with HIC (N = 2772, N = 2259, p < 0.001) but not waist circumference-SNPs (N = 2751, N = 2280). Genetically determined insulin sensitivity was not causally related to HIC (N = 2752, N = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (N = 2660, N = 2240; N = 2694, N = 2275).

Conclusions: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.
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http://dx.doi.org/10.1016/j.metabol.2021.154776DOI Listing
June 2021

Low-Density Lipoprotein Cholesterol Is Associated With Insulin Secretion.

J Clin Endocrinol Metab 2021 05;106(6):1576-1584

Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, 72076 Tübingen, Germany.

Context: Pharmacological lowering of low-density lipoprotein (LDL) cholesterol potently reduces cardiovascular risk while concurrently increasing type 2 diabetes risk.

Objective: The aim of this study was to investigate the relationship between LDL cholesterol concentrations and insulin secretion and glucagon levels.

Methods: A total of 3039 individuals without cholesterol-lowering therapy, but with increased risk for diabetes, underwent routine blood tests and a 5-point oral glucose tolerance test (OGTT). Glucagon concentrations, insulin secretion, and insulin clearance indices were derived from the OGTT.

Results: There was no association between LDL cholesterol and fasting glucagon (P = .7, β = -.01) or post-glucose load glucagon levels (P = .7, β = -.07), but we detected significant positive associations of LDL cholesterol and C-peptide-based indices of insulin secretion (area under the curve [AUC]C-Peptide(0-30min)/AUCGlucose(0-30min): P < .001, β = .06; AUCC-Peptide(0-120min) /AUCGlucose(0-120min): P < .001, β = -.08). In contrast, we found a negative association of insulin-based insulin secretion indices with LDL concentrations (insulinogenic index: P = .01, β = -.04; disposition index: P < .001, β = -.06). LDL cholesterol levels, however, were positively associated with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state and post-glucose load (P < .001, β = .09 and P < .001, β = .06, respectively).

Conclusion: As C-peptide based indices reflect insulin secretion independent of hepatic clearance, our results indicate lower insulin secretion in case of lesser LDL cholesterol. This could explain deteriorating glycemic control in response to cholesterol-lowering drugs.
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http://dx.doi.org/10.1210/clinem/dgab147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118579PMC
May 2021

Diabetes in the Hospital—A Nationwide Analysis of all Hospitalized Cases in Germany With and Without Diabetes, 2015-2017.

Dtsch Arztebl Int 2021 06 18;118(Forthcoming). Epub 2021 Jun 18.

Background: Comprehensive data on the frequency of diabetes mellitus among hospitalized patients in Germany have not been published to date.

Methods: Among all inpatient cases aged ≥20 years that were documented in the German DRG statistics for 2015-2017, we analyzed the frequencies of five types of diabetes (type 1, type 2, other/pancreatic diabetes, "rare diabetes" with an ICD code of E12 or E14, gestational diabetes) and of prediabetes, stratified by sex and age group. The presence of any of these conditions was ascertained from the corresponding ICD-10 code among the main diagnoses (reasons for admission) or secondary diagnoses. We also compared the length of hospital stay, in-hospital mortality, and the frequency of various categories of main diagnosis in cases with and without diabetes in each age group.

Results: In the period 2015-2017, approximately 18% of the 16.4 to 16.7 million inpatient cases carried a main or secondary diagnosis of diabetes (in 2017: type 2, 17.1%; type 1, 0.5%). Diabetes was more common in male cases than in female cases (in 2017: type 2, 19.7% vs. 14.8%; type 1, 0.5% vs. 0.4%). In 2017, the greatest difference in length of hospital stay between patients with and without diabetes was for patients with type 1 diabetes aged 40-49 (7.3 vs. 4.5 days), while the greatest difference in in-hospital mortality was for patients with type 2 diabetes aged 70-79 (3.7% vs. 2.8%). From the age of 30 (age category 30-39), diseases of the cardiovascular system, and from the age of 50 (age category 50-59), diseases of the respiratory or urogenital systems were more frequently listed as a reason for admission in cases with than in those without diabetes.

Conclusion: The fact that diabetes is twice as prevalent in hospitalized cases as in the general population underscores the high morbidity associated with the disease and the greater need of persons with diabetes for in-hospital care, as the population of multimorbid diabetes patients continues to grow older.
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http://dx.doi.org/10.3238/arztebl.m2021.0151DOI Listing
June 2021

Body composition in term offspring after maternal gestational diabetes does not predict postnatal hypoglycemia.

BMC Pediatr 2021 03 6;21(1):111. Epub 2021 Mar 6.

Department of Neonatology, University Children's Hospital, Eberhard Karls University, Calwerstr. 7, 72076, Tuebingen, Germany.

Background: Offspring of mothers with gestational diabetes mellitus (GDM) have an increased risk of neonatal complications like birth trauma due to macrosomia or postnatal hypoglycemia, as well as long-term metabolic sequelae. Neonatal body composition may be a sensitive marker of metabolic effects on the fetus caused by suboptimal glycemic control during pregnancy.

Objective: To determine body composition in offspring of mothers with GDM compared to a reference cohort of healthy term neonates and to assess whether increased body fat would be associated with postnatal hypoglycemia.

Methods: This prospective, observational, cross-sectional study included 311 full-term, singleton infants born between June 2014 and July 2015. Body composition was measured within 96 h of birth using air displacement plethysmography. Results are indicated as median (1st Quartile - 3rd Quartile).

Results: Of 311 infants, 40 (12.9%) were born to mothers with GDM. Birth weight standard deviation scores (SDS) (0.24 vs. - 0.07, p = 0.04), fat mass (370 g vs. 333 g, p = 0.02) as well as fat mass/total body mass (BF%; 11.4% vs. 10.8%, p = 0.03) were significantly higher in infants following maternal GDM than in controls. In GDM offspring, anthropometric parameters, fat mass or BF% did not differ between infants with or without postnatal hypoglycemia. In this cohort, SDS for birth weight, fat mass, fat free mass, BF% or postnatal hypoglycemia were not associated with maternal blood glucose levels measured at an oral glucose tolerance test.

Conclusions: SDS for birth weight, neonatal fat mass, and BF% were significantly higher in newborns following maternal GDM. In these infants born to mothers with GDM, body composition did not differ between those with or without postnatal hypoglycemia.
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http://dx.doi.org/10.1186/s12887-021-02578-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936473PMC
March 2021

Lifestyle Intervention Improves Prothrombotic Coagulation Profile in Individuals at High Risk for Type 2 Diabetes.

J Clin Endocrinol Metab 2021 07;106(8):e3198-e3207

Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany.

Context: Patients with obesity and insulin resistance are at higher risk for arterial and venous thrombosis due to a prothrombotic state.

Objective: The present study addressed whether this is reversible by lifestyle intervention and elucidated potential underlying associations.

Methods: A total of 100 individuals with impaired glucose tolerance or impaired fasting plasma glucose participated in a 1-year lifestyle intervention, including precise metabolic phenotyping and MRS-based determination of liver fat content as well as a comprehensive analysis of coagulation parameters before and after this intervention.

Results: During the lifestyle intervention, significant reductions in coagulation factor activities (II, VII, VIII, IX, XI, and XII) were observed. Accordingly, prothrombin time (PT%) and activated partial thromboplastin time (aPTT) were slightly decreased and prolonged, respectively. Moreover, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and also protein C and protein S decreased. Fibrinogen, antithrombin, D-dimer, and FXIII remained unchanged. Searching for potential regulators, especially weight loss, but also liver fat reduction, improved insulin sensitivity, and decreased low-grade inflammation were linked to favorable changes in hemostasis parameters. Independent of weight loss, liver fat reduction (FII, protein C, protein S, PAI-1, vWF), improved insulin sensitivity (protein S, PAI-1), and reduced low-grade inflammation (PT%, aPTT, FVIII/IX/XI/XII, vWF) were identified as single potential regulators.

Conclusion: Lifestyle intervention is able to improve a prothrombotic state in individuals at high risk for type 2 diabetes. Besides body weight, liver fat content, insulin sensitivity, and systemic low-grade inflammation are potential mechanisms for improvements in hemostasis and could represent future therapeutic targets.
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http://dx.doi.org/10.1210/clinem/dgab124DOI Listing
July 2021

No Effect of Lifestyle Intervention during Third Trimester on Brain Programming in Fetuses of Mothers with Gestational Diabetes.

Nutrients 2021 Feb 8;13(2). Epub 2021 Feb 8.

Helmholtz Center Munich at the University of Tübingen/fMEG Center, Institute for Diabetes Research and Metabolic Diseases, 72076 Tübingen, Germany.

Maternal metabolism and intrauterine conditions influence development of health and disease in offspring, leading to metabolic, physiologic, and/or epigenetic adaptation of the fetus. Maternal gestational diabetes (GDM) leads to higher incidence of obesity and type 2 diabetes in offspring. We have previously shown that fetuses of insulin-resistant mothers with GDM have a delayed reaction to auditory stimuli in the postprandial state, indicating a fetal central insulin resistance. We tested whether this effect could be influenced by a lifestyle intervention in mothers with GDM, including diet counselling and regular blood glucose measurements. We measured fetal brain activity over the course of a maternal glucose challenge, at two measurement time points (baseline at an average of 29 weeks of gestation and follow-up after 4 weeks) in mothers with GDM and mothers with normal glucose tolerance (NGT). Data from eight mothers were able to be included. Fetuses of GDM mothers showed longer latencies than those of NGT mothers postprandially at both measurement time points during the third trimester and did not show a difference in response patterns between baseline and after 4 weeks. Maternal postprandial blood glucose and insulin values did not change from baseline to follow-up either. While the overall intervention seems to have been effective, it does not appear to have influenced the fetal postprandial brain responses. This might have been because interventions for GDM take place relatively late in pregnancy. Future research should focus on maternal lifestyle interventions as early as possible during gestation, or even prenatally.
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http://dx.doi.org/10.3390/nu13020556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915982PMC
February 2021

Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes.

Nat Med 2021 01 4;27(1):49-57. Epub 2021 Jan 4.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.
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http://dx.doi.org/10.1038/s41591-020-1116-9DOI Listing
January 2021

Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus.

Sci Rep 2020 12 31;10(1):22453. Epub 2020 Dec 31.

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Hyperglycemia and insulin resistance contribute to vascular damage and are regulated by different pathophysiological processes. The aim of the study was to systematically investigate the relative contributions of multiple fasting state- and oral glucose tolerance test (oGTT)-derived glycemic traits to carotid intima-media thickness (cIMT), a surrogate parameter of subclinical atherosclerosis, in individuals with increased risk for type 2 diabetes mellitus (T2D). 667 volunteers (417 women and 250 men, mean age 44.1 years), who were free of cardiovascular disease (CVD), were included in this cross-sectional study. Glucose tolerance, insulin sensitivity, insulin secretion and insulin clearance were assessed by frequently sampled 75 g oGTT. CIMT was measured by high-resolution ultrasound. Insulin clearance was associated with cIMT in univariate analysis (ß = - 0.17, p < 0.0001) and in a stepwise regression analysis on 15 variables possibly affecting cIMT, age (r = 0.3923, p < 0.0001), insulin clearance (r = 0.4564, p < 0.0001), systolic blood pressure (r = 0.4733, p < 0.0001), body mass index (BMI) (r = 0.4804, p = 0.002), gender (r = 0.4831, p = 0.013), and fasting insulin clearance (r = 0.4857, p = 0.030) turned out to be significant determinants of cIMT. In a cross-validated model resulting from this analysis, insulin clearance was found to be an independent determinant of cIMT (ß = - 0.16, p < 0.0001) even after adjusting for traditional CVD risk factors. Reduced insulin clearance may be an early marker of damage on the vasculature, independent of classical CVD risk factors. Reduced insulin clearance should be considered with regard to vascular insulin resistance.
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http://dx.doi.org/10.1038/s41598-020-80581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775444PMC
December 2020

Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.

J Clin Endocrinol Metab 2021 01;106(2):e982-e989

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany.

Objective: Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis.

Methods: Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT).

Results: Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05).

Conclusions: Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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http://dx.doi.org/10.1210/clinem/dgaa898DOI Listing
January 2021

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men.

Sci Rep 2020 11 24;10(1):20466. Epub 2020 Nov 24.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.
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http://dx.doi.org/10.1038/s41598-020-77430-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686306PMC
November 2020

Insulin sensitivity predicts cognitive decline in individuals with prediabetes.

BMJ Open Diabetes Res Care 2020 11;8(2)

Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany

Introduction: Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).

Research Design And Methods: We investigated longitudinal data from participants of the 'Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration' Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer's Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1-3: 2.2-4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%-6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.

Results: Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.

Conclusions: Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2020-001741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674089PMC
November 2020

Ectopic fat accumulation in human astrocytes impairs insulin action.

R Soc Open Sci 2020 Sep 16;7(9):200701. Epub 2020 Sep 16.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.
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http://dx.doi.org/10.1098/rsos.200701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540778PMC
September 2020

Investigating obesity-associated brain inflammation using quantitative water content mapping.

J Neuroendocrinol 2020 12 6;32(12):e12907. Epub 2020 Oct 6.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

There is growing evidence that obesity is associated with inflammation in the brain, which could contribute to the pathogenesis of obesity. In humans, it is challenging to detect brain inflammation in vivo. Recently, quantitative magnetic resonance imaging (qMRI) has emerged as a tool for characterising pathophysiological processes in the brain with reliable and reproducible measures. Proton density imaging provides quantitative assessment of the brain water content, which is affected in different pathologies, including inflammation. We enrolled 115 normal weight, overweight and obese men and women (body mass index [BMI] range 20.1-39.7 kg m , age range 20-75 years, 60% men) to acquire cerebral water content mapping in vivo using MRI at 3 Tesla. We investigated potential associations between brain water content with anthropometric measures of obesity, body fat distribution and whole-body metabolism. No global changes in water content were associated with obesity. However, higher water content values in the cerebellum, limbic lobe and sub-lobular region were detected in participants with higher BMI, independent of age. More specifically, the dorsal striatum, hypothalamus, thalamus, fornix, anterior limb of the internal capsule and posterior thalamic radiation showed the strongest relationship with BMI, independent of age. In a subgroup with available measurements (n = 50), we identified visceral adipose tissue to be the strongest tested link between higher water content values and obesity. Individuals with metabolic syndrome had the highest water content values in the hypothalamus and the fornix. There is accumulating evidence that inflammation of the hypothalamus contributed to obesity-associated insulin resistance in that area. Whether brain inflammation is a cause or consequence of obesity in humans still needs to be investigated using a longitudinal study design. Using qMRI, we were able to detect marked water content changes in young and older obese adults, which is most likely the result of chronic low-grade inflammation.
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http://dx.doi.org/10.1111/jne.12907DOI Listing
December 2020

Pregnant women do not display impaired memory formation across one night of sleep.

J Sleep Res 2021 06 28;30(3):e13204. Epub 2020 Sep 28.

Institute of Medical Psychology and Behavioural Neurobiology, University of Tübingen, Tübingen, Germany.

Forgetfulness is a common complaint of pregnant women, who also often report impaired nocturnal sleep. Considering sleep's well-known beneficial role in consolidating newly encoded memory content, we hypothesized that pregnant women would display detrimental changes in objective sleep measures and associated memory deficits. We compared the consolidation of declarative as well as procedural memory across sleep in 21 healthy, third-trimester pregnant women versus 20 matched non-pregnant controls. Subjects encoded and were tested on visuospatial and procedural memory tasks before and after, respectively, a night of sleep spent at home. The emergence of gist-based memories was tested with the Deese-Roediger-McDermott (DRM) paradigm. Sleep was polysomnographically recorded and subjective sleep quality was assessed with questionnaires. Although pregnant in comparison to non-pregnant women reported markedly impaired subjective sleep quality and efficiency, quantitative changes were limited to increases in wakefulness after sleep onset and reductions in rapid eye movement (REM) sleep. Retention of newly learned memory contents, which is believed to reflect sleep-associated memory consolidation, was comparable between groups, as was the formation of gist-based memories. The findings indicate that subjective deteriorations in sleep quality experienced by pregnant women are not necessarily linked to objective impairments. They raise the possibility that sufficient slow wave sleep towards the end of pregnancy allows for normal sleep-related memory consolidation. Although these results were obtained in a small number of pregnant women in very good health and should be corroborated in larger samples, they challenge the assumption of poor sleep and impaired memory as hallmarks of the "pregnancy brain".
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http://dx.doi.org/10.1111/jsr.13204DOI Listing
June 2021

Considering Insulin Secretory Capacity as Measured by a Fasting C-Peptide/Glucose Ratio in Selecting Glucose-Lowering Medications.

Exp Clin Endocrinol Diabetes 2020 Sep 18. Epub 2020 Sep 18.

German Center for Diabetes Research (DZD), Neuherberg.

Type 2 diabetes mellitus is a heterogeneous disease. Recently introduced new subclassifications promise more efficacious, tailored treatments which could complement current guidelines. In the differentiation of the new diabetes subphenotypes, assessment of insulin secretion is one of the essential components. Based on a large number of insulin secretion measurements, we propose fasting C-peptide/glucose ratio (CGR) as an adequate and practicable estimate of insulin secretion. CGR discriminates insulin deficiency from insulin hypersecretion. We suggest using insulin secretion, determined from CGR, as an essential input for therapeutic decisions at the beginning or modification of diabetes treatment. Furthermore, we propose 3 practical steps to guide decisions in the subtype-specific therapy of diabetes mellitus. The first step consists of detecting insulin deficiency indicated by a low CGR with the need for immediate insulin therapy. The second step is related to high CGR and aims at lowering cardiovascular risk associated with diabetes. The third step is the consideration of a de-escalation of glucose-lowering therapy in individuals with mild diabetes subphenotypes.
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http://dx.doi.org/10.1055/a-1242-9809DOI Listing
September 2020
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