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Article: Lower serum extracellular superoxide dismutase levels are associated with polyneuropathy in recent-onset diabetes

Roden, Michael / Ziegler, Dan

Experimental & molecular medicine, 49:e394

2017

Abstract: Increased oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but translational evidence in recent-onset diabetes is scarce. We aimed to determine whether markers of systemic oxidative stress are associated with ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	Increased oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but translational evidence in recent-onset diabetes is scarce. We aimed to determine whether markers of systemic oxidative stress are associated with diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. In this cross-sectional study, we measured serum concentrations of extracellular superoxide dismutase (SOD3), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) in 107 type 1 and 215 type 2 diabetes patients from the German Diabetes Study baseline cohort and 37 glucose-tolerant individuals (controls). DSPN was defined by electrophysiological and clinical criteria (Toronto Consensus, 2011). SOD3 and GSH concentrations were lower in individuals with type 1 and type 2 diabetes compared with concentrations in controls (P<0.0001). In contrast, the TBARS concentration was higher in participants with type 1 diabetes and type 2 diabetes compared with levels in controls (P<0.0001). In addition, the SOD3 concentration was higher in participants with type 1 diabetes compared to concentrations in those with type 2 diabetes (P<0.0001). A low SOD3 concentration was associated with DSPN in individuals with type 1 diabetes (β=−0.306, P=0.002), type 2 diabetes (β=−0.164, P=0.017), and in both groups combined (β=−0.206, P=0.0003). Lower SOD3 concentrations were associated with decreased motor nerve conduction velocity (NCV) in men and, to a lesser degree, with reduced sensory NCV in women with diabetes. In conclusion, several biomarkers of oxidative stress are altered in recent-onset diabetes, with only a lower SOD3 concentration being linked to the presence of DSPN, suggesting a role for reduced extracellular antioxidative defense against superoxide in the early development of DSPN.
Keywords	Diabetes complications ; Predictive markers
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Spatial analysis improves the detection of early corneal nerve fiber loss in patients with recently diagnosed type 2 diabetes

Ziegler, Dan / PAPANAS, NIKOLAOS / Roden, Michael

PLOS ONE, 12(3):e0173832

2017

Abstract: Corneal confocal microscopy (CCM) has revealed reduced corneal nerve fiber (CNF) length and density (CNFL, CNFD) in patients with diabetes, but the spatial pattern of CNF loss has not been studied. We aimed to determine whether spatial analysis of the ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	Corneal confocal microscopy (CCM) has revealed reduced corneal nerve fiber (CNF) length and density (CNFL, CNFD) in patients with diabetes, but the spatial pattern of CNF loss has not been studied. We aimed to determine whether spatial analysis of the distribution of corneal nerve branching points (CNBPs) may contribute to improving the detection of early CNF loss. We hypothesized that early CNF decline follows a clustered rather than random distribution pattern of CNBPs. CCM, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed in a cross-sectional study including 86 patients recently diagnosed with type 2 diabetes and 47 control subjects. In addition to CNFL, CNFD, and branch density (CNBD), CNBPs were analyzed using spatial point pattern analysis (SPPA) including 10 indices and functional statistics. Compared to controls, patients with diabetes showed lower CNBP density and higher nearest neighbor distances, and all SPPA parameters indicated increased clustering of CNBPs (all P<0.05). SPPA parameters were abnormally increased >97.5th percentile of controls in up to 23.5% of patients. When combining an individual SPPA parameter with CNFL, ≥1 of 2 indices were >99th or <1st percentile of controls in 28.6% of patients compared to 2.1% of controls, while for the conventional CNFL/CNFD/CNBD combination the corresponding rates were 16.3% vs 2.1%. SPPA parameters correlated with CNFL and several NCS and QST indices in the controls (all P<0.001), whereas in patients with diabetes these correlations were markedly weaker or lost. In conclusion, SPPA reveals increased clustering of early CNF loss and substantially improves its detection when combined with a conventional CCM measure in patients with recently diagnosed type 2 diabetes.
Keywords	Cornea ; Diabetes mellitus ; Morphometry ; Neuropathy ; Nerve fibers ; Spatial analysis ; Permutation ; Type 2 diabetes
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article: Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism

Bierwagen, Alessandra / Ziegler, Dan / Roden, Michael

Molecular metabolism, 7:71-79

2017

Abstract: OBJECTIVE: Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	OBJECTIVE: Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2). METHODS: Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. RESULTS: taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. CONCLUSION: Non-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.
Keywords	Hepatic energy metabolism ; Hepatic insulin sensitivity ; Liver fat content ; Vagus nerve stimulation
Language	English
Document type	Article
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Article ; Online: Pharmacogenetic Implementation Lessons From the "Real World".

Roden, D M

Clinical pharmacology and therapeutics

2017 Volume 102, Issue 1, Page(s) 25–27

Abstract: The manuscript "Anticoagulation Endpoints With Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real- World Setting: A Proposal for a New Pharmacogenetic Dosing Approach" describes process outcomes in an institutional program to use ... ...

Abstract	The manuscript "Anticoagulation Endpoints With Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real- World Setting: A Proposal for a New Pharmacogenetic Dosing Approach" describes process outcomes in an institutional program to use pharmacogenetic testing to optimize warfarin dose in a cohort of 257 patients of diverse ancestries. The strengths and weaknesses of the approach and program are discussed, along with the current and potential future status of warfarin as a model for pharmacogenetic testing.
MeSH term(s)	Algorithms ; Anticoagulants ; Humans ; Pharmacogenetics ; Pharmacogenomic Testing ; Warfarin
Chemical Substances	Anticoagulants ; Warfarin (5Q7ZVV76EI)
Language	English
Publishing date	2017-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.584
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Article: Cohort profile: the German Diabetes Study (GDS)

Herder, Christian / Icks, Andrea / Kuss, Oliver / Ziegler, Dan / Roden, Michael

Cardiovascular diabetology, 15:59

2016

Abstract: BACKGROUND: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	BACKGROUND: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. STUDY DESIGN AND METHODS: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.
Keywords	Beta cell function ; Diabetes comorbidities ; Insulin resistance ; Magnetic resonance spectroscopy ; Metabolic phenotyping
Language	English
Document type	Article
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Article ; Online: The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.

Wada, Yuko / Wang, Lili / Hall, Lynn D / Yang, Tao / Short, Laura L / Solus, Joseph F / Glazer, Andrew M / Roden, Dan M

Cardiovascular research

2024

Abstract: Aims: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes.: Methods and results: ... ...

Abstract	Aims: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. Methods and results: We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss of function KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 loss of function allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug.In control cells, a small IKs was readily recorded but pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). By contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (μM) of moxifloxacin required to prolong APD90 100 msec was 237.4 (median, IQR 100.6-391.6, n = 7) in population cells versus 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300μM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs, and markedly prolonged APD90. Conclusion: Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs. Translational perspective: Mutations in KCNQ1 - whose expression generates IKs - are the major cause of long QT syndrome. We report here that while pharmacologic IKs block in human cardiomyocytes generates minimal change in repolarization, suppressing KCNQ1 expression markedly increases both baseline repolarization duration and sensitivity to some (but not all) specific IKr blockers. Thus, beyond simply generating IKs, KCNQ1 subserves critical additional role(s) in repolarization control at baseline and in response to IKr block. Our findings imply that assessment of arrhythmic risk in individual patients and by drugs requires a framework that extends beyond a simple one gene-one ion current paradigm.
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvae042
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Article: Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes.

Davogustto, Giovanni / Zhao, Shilin / Li, Yajing / Farber-Eger, Eric / Lowery, Brandon D / Shaffer, Lauren Lee / Mosley, Jonathan D / Shoemaker, M Benjamin / Xu, Yaomin / Roden, Dan M / Wells, Quinn S

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with ... ...

Abstract	Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear. Methods: We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping. The phenotypic architecture in the AF cohort was defined using principal component analysis of 35 expertly curated and uncorrelated clinical features. We applied an unsupervised co-clustering machine learning algorithm to the 35 features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention in the EHR. Polygenic risk scores (PRS) for AF and cytokine levels were used to assess genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from EHR up to the last medical contact. Results: The analysis included 23,271 subjects with AF, of which 6,023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal dysfunction, and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbid cluster, while there was no difference between groups in genetically predicted levels of inflammatory biomarkers. Subgroup assignment was associated with multiple clinical outcomes including mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis. Conclusion: Patient subgroups identified by unsupervised clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes. Polygenic liability to AF across clusters was greatest in the low comorbidity subgroup. Clinical inflammation, as reflected by measured biomarkers, was lowest in the subgroup with lowest comorbidities. However, there were no differences in genetically predicted levels of inflammatory biomarkers, suggesting associations between AF and inflammation is driven by acquired comorbidities rather than genetic predisposition.
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.13.24302788
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Article ; Online: Physical Activity and Incident Obesity Across the Spectrum of Genetic Risk for Obesity.

Brittain, Evan L / Han, Lide / Annis, Jeffrey / Master, Hiral / Hughes, Andrew / Roden, Dan M / Harris, Paul A / Ruderfer, Douglas M

JAMA network open

2024 Volume 7, Issue 3, Page(s) e243821

Abstract: ... The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5 ... those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d ... with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and ...

Abstract	Importance: Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity. Objective: To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity. Design, setting, and participants: In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis. Exposure: Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared. Main outcome and measures: Incident obesity (BMI ≥30). Results: A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d. Conclusions and relevance: In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.
MeSH term(s)	Female ; Humans ; Middle Aged ; Male ; Cohort Studies ; Retrospective Studies ; Population Health ; Obesity ; Exercise ; Genetic Risk Score
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Journal Article
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2024.3821
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Article ; Online: TAVI Under Pressure: Intra-balloon Pressure Profiles During Balloon-Expandable TAVR-First Data from a Feasibility Study.

Noterdaeme, Timothée / Marx, Nikolaus / Theiss, Hans / Orban, Martin / Roden, Daniel / Massberg, Steffen / Braun, Daniel

Journal of cardiovascular translational research

2022 Volume 16, Issue 1, Page(s) 152–154

Abstract: Our study investigated the feasibility to measure pressure profiles inside the inflation balloon during direct implantation of Edwards Sapien 3 ultra-prostheses using an additional syringe with a digital pressure read-out. Pressure profiles of 15 ... ...

Abstract	Our study investigated the feasibility to measure pressure profiles inside the inflation balloon during direct implantation of Edwards Sapien 3 ultra-prostheses using an additional syringe with a digital pressure read-out. Pressure profiles of 15 patients for 26 mm valve size were analyzed. Uniform patterns were found for 5 patients similar to those of previously acquired in vitro curves. 10 patients showed strikingly different pressure profiles compared to the above-mentioned group, marked by an earlier pressure increase, single or multiple pressure drops or higher overall pressure. Measuring the percentage of under-expansion of the prostheses, using calibrated angiographic projections revealed a significant difference between both groups. Our data raises the hypothesis that the acquisition of pressure profiles might help to better understand not only the implantation procedure itself but also the highly individual patient-device interaction, offering new information and a new perspective on optimization of TAVR implantation in the future.
MeSH term(s)	Humans ; Aortic Valve/surgery ; Transcatheter Aortic Valve Replacement ; Aortic Valve Stenosis/surgery ; Feasibility Studies ; Heart Valve Prosthesis ; Treatment Outcome ; Prosthesis Design
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2422411-X
ISSN	1937-5395 ; 1937-5387
ISSN (online)	1937-5395
ISSN	1937-5387
DOI	10.1007/s12265-022-10281-6
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Article ; Online: The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments.

Targher, Giovanni / Corey, Kathleen E / Byrne, Christopher D / Roden, Michael

Nature reviews. Gastroenterology & hepatology

2021 Volume 18, Issue 9, Page(s) 599–612

Abstract: Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical ... ...

Abstract	Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression.
MeSH term(s)	Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/physiopathology ; Humans ; Non-alcoholic Fatty Liver Disease/complications ; Non-alcoholic Fatty Liver Disease/physiopathology
Language	English
Publishing date	2021-05-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/s41575-021-00448-y
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