Publications by authors named "Dan Ziegler"

138 Publications

Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study.

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

Department of Internal Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.

Introduction: Distal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system. However, available studies have mainly investigated circulating immune mediators, whereas the role of immune cells remains unclear. Therefore, we aimed to test whether leukocyte subsets are associated with NCV.

Research Design And Methods: This cross-sectional study analyzed data from 850 individuals (of whom 252 and 118 had type 2 diabetes and pre-diabetes, respectively) of the Maastricht Study. NCV was measured in the peroneal and tibial motor nerves and the sural sensory nerve and summed to calculate a standardized NCV sum score. Associations between percentages of leukocyte subsets and NCV sum scores were estimated using linear regression models adjusted for demographic, lifestyle, metabolic and clinical covariates.

Results: After adjustment for covariates, higher percentages of basophils and CD4 T cells were associated with lower NCV (p=0.014 and p=0.005, respectively). The percentage of CD8 T cells was positively associated with NCV (p=0.022). These associations were not modified by glucose metabolism status (all p >0.05). No associations were found for monocytes, eosinophils, neutrophils, lymphocytes, total T cells, Treg cells and B cells.

Conclusions: The associations of basophils, CD4 and CD8 T cells with NCV suggest that cell types from both innate and adaptive immunity may be implicated in the development of DSPN.
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http://dx.doi.org/10.1136/bmjdrc-2020-001698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802711PMC
January 2021

Reduced Muscle Strength Associates with Insulin Resistance in Type 2 Diabetes Patients with Osteoarthritis.

J Clin Endocrinol Metab 2020 Dec 31. Epub 2020 Dec 31.

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

Context: Type 2 diabetes associates with greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear.

Objective: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles.

Design, Participants & Methods: Participants of the German Diabetes Study with type 2 diabetes (T2D, n=39) or normal glucose tolerance (CON, n=27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamps tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using WOMAC questionnaire, serum arthritis-related microRNA using qPCR.

Results: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4±2.0 vs. 5.7±3.0 mg*kg -¹*min -¹) and in CON+OA vs CON-OA (8.1±2.0 vs. 12.0±2.6 mg*kg -¹*min -¹, both p<0.05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both p<0.05). Insulin sensitivity correlated positively with KES (r=0.41, p<0.05) among T2D, and negatively with symptom severity in CON and T2D (r=-0.60 and r=-0.46, respectively, p<0.05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (p<0.05), and did not differ between T2D+OA and T2D-OA.

Conclusions: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.Clinicaltrials.gov (Identifier number: NCT01055093).
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http://dx.doi.org/10.1210/clinem/dgaa912DOI Listing
December 2020

Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study.

Environ Health Perspect 2020 12 23;128(12):127013. Epub 2020 Dec 23.

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

Background: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity.

Objectives: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity.

Methods: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62-81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013-2014). Associations of annual average air pollutant concentrations at participants' residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders.

Results: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, , , , and ) and gaseous (, ) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); ]. With the exception of , corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with [e.g., for PNC, (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); ].

Discussion: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311.
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http://dx.doi.org/10.1289/EHP7311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757787PMC
December 2020

Cumulative long-term recurrence of diabetic foot ulcers in two cohorts from centres in Germany and the Czech Republic.

Diabetes Res Clin Pract 2020 Dec 13;172:108621. Epub 2020 Dec 13.

Institute for Health Services Research and Health Economics, German Diabetes Center, Düsseldorf, Germany; German Centre for Diabetes Research (DZD), Neuherberg, Germany; Institute for Health Services Research and Health Economics, Faculty of Medicine, Heinrich-Heine- University, Düsseldorf, Germany.

Aims: Our aim was to comprehensively estimate the incidence of diabetic foot ulcer (DFU) recurrence and corresponding risk factors in two cohorts.

Methods: Prospective data from patients with active DFU from two diabetes centres in Germany (GER, n = 222) and the Czech Republic (CZ, n = 99) were analysed. Crude cumulative incidences were obtained. Additionally, time to recurrence and risk factors were investigated using multivariate Cox models.

Results: 69%(154) of patients in GER and 70%(69) in CZ experienced at least one DFU recurrence; 25%(56) in DEU and 15%(15) in CZ died; 5%(11) and 9%(9) were lost to follow-up. The crude cumulative incidence in the first year was 28% in GER and 25% in CZ; 68%/70% within ten years, and 69%/70% in 15 years. In GER, renal replacement therapy was associated with shorter time to recurrence (HR = 3.71, 95%CI:1.26-10.87); no history of DFU before the index lesion with longer time to recurrence (HR = 0.62, 0.42-0.92). In CZ, type 2 diabetes (HR = 2.57, 1.18-5.62) and index ulcer treatment by minor amputation (HR = 2.11, 1.03-4.33) were associated with shorter time to recurrence.

Conclusions: Cumulative DFU recurrence was approximately 70% in 15 years in both cohorts. We found a significantly higher risk of future recurrence in patients having a consecutive ulcer compared with the first ever ulcer.
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http://dx.doi.org/10.1016/j.diabres.2020.108621DOI Listing
December 2020

Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models.

Mol Metab 2021 Jan 6;43:101114. Epub 2020 Nov 6.

Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. Electronic address:

Objective: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy.

Methods: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium.

Results: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation.

Conclusions: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.
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http://dx.doi.org/10.1016/j.molmet.2020.101114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704399PMC
January 2021

Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes.

Diabetologia 2021 Feb 21;64(2):458-468. Epub 2020 Oct 21.

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

Aims/hypothesis: Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes.

Methods: We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic-euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years.

Results: In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = -0.242 to r = -0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered.

Conclusions/interpretation: Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05310-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801358PMC
February 2021

Treatment with benfotiamine in patients with diabetic sensorimotor polyneuropathy: A double-blind, randomized, placebo-controlled, parallel group pilot study over 12 months.

J Diabetes Complications 2020 Dec 7;34(12):107757. Epub 2020 Oct 7.

Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, USA.

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http://dx.doi.org/10.1016/j.jdiacomp.2020.107757DOI Listing
December 2020

Current concepts in the management of diabetic polyneuropathy.

J Diabetes Investig 2020 Sep 12. Epub 2020 Sep 12.

Diabetes and Endocrinology Unit, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand.

Diabetic sensorimotor polyneuropathy (DSPN) is encountered in approximately one-third of people with diabetes. This, in turn, might markedly impoverish their quality of life, mainly owing to neuropathic pain and foot ulcerations. Painful DSPN might be as frequent as 25% in diabetes patients. Symptoms as a result of DSPN typically comprise pain, paresthesia and numbness in the distal lower limbs. Asymptomatic DSPN might reach 50% among patients with this condition. Unfortunately, DSPN is still not adequately diagnosed and treated. Its management has three priorities: (i) lifestyle improvement, near-normoglycemia and multifactorial cardiovascular risk intervention; (ii) pathogenesis-oriented pharmacotherapy; and (iii) symptomatic alleviation of pain. Intensive diabetes therapy showed evidence for favorable effects on the incidence and deterioration of DSPN in type 1 diabetes, but not type 2 diabetes. Among pathogenesis-oriented treatments, α-lipoic acid, actovegin, benfotiamine and epalrestat are currently authorized to treat DSPN in several countries. Symptomatic therapy uses analgesics, notably antidepressants, opioids and anticonvulsants, reducing pain by ≥50% in approximately 50% of individuals, but might be limited, particularly by central nervous system-related adverse events. Local treatment with the capsaicin 8% patch might offer an alternative. In addition to pain relief, therapy should improve sleep, mobility and quality of life. In conclusion, multimodal treatment of DSPN should consider the individual risk profile, pathogenetic treatment and pain management using pharmacotherapy (combinations, if required), as well as non-pharmacological options.
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http://dx.doi.org/10.1111/jdi.13401DOI Listing
September 2020

Evaluation of molecular inversion probe versus TruSeq® custom methods for targeted next-generation sequencing.

PLoS One 2020 2;15(9):e0238467. Epub 2020 Sep 2.

Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, the Netherlands.

Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238467PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467307PMC
October 2020

Double-blind, randomized, placebo-controlled crossover trial of alpha-lipoic acid for the treatment of fibromyalgia pain: the IMPALA trial.

Pain 2021 Feb;162(2):561-568

Gray Research Consulting, Pharmacy Research Services, EpiPharm Consultants, Joyceville, ON, Canada.

Abstract: Fibromyalgia is a common and challenging chronic pain disorder with few, if any, highly effective and well-tolerated treatments. Alpha-lipoic acid (ALA) is a nonsedating antioxidant with evidence of efficacy in the treatment of symptomatic diabetic neuropathy that has not been evaluated in the setting of fibromyalgia treatment. Thus, we conducted a single-centre, proof-of-concept, randomized, placebo-controlled, crossover trial of ALA for the treatment of fibromyalgia. Twenty-seven participants were recruited, and 24 participants completed both treatment periods of the trial. The median maximal tolerated dose of ALA in this trial was 1663 mg/day. Treatment-emergent adverse events with ALA were infrequent and not statistically different from placebo. For the primary outcome of pain intensity, and for several other validated secondary outcomes, there were no statistically significant differences between placebo and ALA. A post hoc exploratory subgroup analysis showed a significant interaction between gender and treatment with a significant favourable placebo-ALA difference in pain for men, but not for women. Overall, the results of this trial do not provide any evidence to suggest promise for ALA as an effective treatment for fibromyalgia, which is predominantly prevalent in women. This negative clinical trial represents an important step in a collective strategy to identify new, better tolerated and more effective treatments for fibromyalgia.
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http://dx.doi.org/10.1097/j.pain.0000000000002028DOI Listing
February 2021

Polyneuropathy is inadequately treated despite increasing symptom intensity in individuals with and without diabetes (PROTECT follow-up study).

J Diabetes Investig 2020 Sep 9;11(5):1272-1277. Epub 2020 May 9.

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

Aims/introduction: Despite its major clinical impact, distal symmetric polyneuropathy remains frequently undiagnosed and undertreated in clinical practice. We previously reported in the PROTECT Study that 70% of type 2 diabetes patients with distal symmetric polyneuropathy were unaware of having the latter condition.

Materials And Methods: In the present follow up after 2.5 ± 0.7 years, 122 and 85 participants with and without type 2 diabetes, respectively, completed questionnaires to obtain information about the further course of disease and its management.

Results: At follow up, 49 and 48% of the respondents with type 2 diabetes and without diabetes, respectively, reported that the intensity of paresthesia or numbness in the feet increased, whereas for burning and pain in the feet the corresponding percentages were 56 and 61%. However, 33 and 40% of the respondents with type 2 diabetes and without diabetes, respectively, reporting neuropathic symptoms at follow up did not receive any pharmacotherapy. Pharmacotherapy of neuropathic symptoms at follow up among participants with type 2 diabetes and without diabetes included mainly World Health Organization Step 1 analgesics (17% each; excluding acetylsalicylic acid), pregabalin/gabapentin (20 and 12%), vitamin B complex (13 and 22%), benfotiamine (13 and 2%), opioids (7 and 12%), antidepressants (4 and 5%) and α-lipoic acid (4 and 2%).

Conclusions: These findings point to insufficient care, inadequate treatment adherence or limited efficacy of treatments in patients with polyneuropathy, suggesting that effective measures should be implemented to correct these healthcare deficits.
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http://dx.doi.org/10.1111/jdi.13267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477515PMC
September 2020

Vitamin B12 and Folate Concentrations in Recent-onset Type 2 Diabetes and the Effect of Metformin Treatment.

J Clin Endocrinol Metab 2020 06;105(6)

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany.

Context: Vitamin B12 and folate deficiency are not only linked to hematological, neurological, and cardiovascular diseases, but are also associated with insulin resistance. Metformin can decrease vitamin B12 and folate concentrations.

Objective: To examine (1) effects of short-term metformin treatment on serum holotranscobalamin (holoTC) and folate and (2) their association with insulin sensitivity in recent-onset type 2 diabetes.

Design: This cross-sectional analysis comprised patients (known disease duration <12 months) on metformin monotherapy (MET, n = 123, 81 males, 53 ± 12 years) or nonpharmacological treatment (NPT, n = 126, 77 males, 54 ± 11 years) of the German Diabetes Study.

Main Outcome Measures: HoloTC (enzyme-linked immunosorbent assay), cobalamin, and folate (electrochemiluminescence); beta-cell function and whole-body insulin sensitivity, measured during fasting (HOMA-B, HOMA-IR) and intravenous glucose tolerance tests combined with hyperinsulinemic-euglycemic clamp tests.

Results: HoloTC (105.4 [82.4, 128.3] vs 97 [79.7, 121.9] pmol/L) and folate concentrations (13.4 [9.3, 19.3] vs 12.7 [9.3, 22.0] nmol/L) were similar in both groups. Overall, holoTC was not associated with fasting or glucose-stimulated beta-cell function and insulin-stimulated glucose disposal. Cobalamin measurements yielded similar results in representative subgroups. In NPT but not MET, folate levels were inversely correlated with HOMA-IR (r = -0.239, P = .007). Folate levels did not relate to insulin sensitivity or insulin secretion in the whole cohort and in each group separately after adjustment for age, body mass index, and sex.

Conclusions: Metformin does not affect circulating holoTC and folate concentrations in recent-onset type 2 diabetes, rendering monitoring of vitamin B12 and folate dispensable, at least during the first 6 months after diagnosis or initiation of metformin.
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http://dx.doi.org/10.1210/clinem/dgaa150DOI Listing
June 2020

Impairment in Baroreflex Sensitivity in Recent-Onset Type 2 Diabetes Without Progression Over 5 Years.

Diabetes 2020 05 21;69(5):1011-1019. Epub 2020 Feb 21.

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

Impaired baroreflex sensitivity (BRS) predicts cardiovascular mortality and is prevalent in long-term diabetes. We determined spontaneous BRS in patients with recent-onset diabetes and its temporal sequence over 5 years by recording beat-to-beat blood pressure and R-R intervals over 10 min. Four time domain and four frequency domain BRS indices were computed in participants from the German Diabetes Study baseline cohort with recent-onset type 1/type 2 diabetes ( = 206/381) and age-matched glucose-tolerant control subjects (control 1/control 2: = 65/83) and subsets of consecutive participants with type 1/type 2 diabetes who reached the 5-year follow-up ( = 84/137). Insulin sensitivity (M-value) was determined using a hyperinsulinemic-euglycemic clamp. After appropriate adjustment, three frequency domain BRS indices were reduced in type 2 diabetes compared with control 2 and were positively associated with the M-value and inversely associated with fasting glucose and HbA ( < 0.05), whereas BRS was preserved in type 1 diabetes. After 5 years, a decrease in one and four BRS indices was observed in patients with type 1 and type 2 diabetes, respectively ( < 0.05), which was explained by the physiologic age-dependent decline. Unlike patients with well-controlled recent-onset type 1 diabetes, those with type 2 diabetes show early baroreflex dysfunction, likely due to insulin resistance and hyperglycemia, albeit without progression over 5 years.
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http://dx.doi.org/10.2337/db19-0990DOI Listing
May 2020

NADPH Oxidase Inhibition: Preclinical and Clinical Studies in Diabetic Complications.

Antioxid Redox Signal 2020 08 6;33(6):415-434. Epub 2020 Mar 6.

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

Oxidative stress plays a critical role in the development and progression of serious micro- and macrovascular complications of diabetes. Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) significantly contribute to oxidative stress-associated inflammatory pathways that lead to tissue damage of different organs, including the kidneys, retina, brain, nerves, and the cardiovascular system. Preclinical studies, including genetic-modified mouse models or cell culture models, have revealed the role of specific NOX isoforms in different diabetic complications, and suggested them as a promising target for the treatment of these diseases. In this review, we provide an overview of the role of ROS and oxidative stress in macrovascular complications, such as stroke, myocardial infarction, coronary artery disease, and peripheral vascular disease that are all mainly driven by atherosclerosis, as well as microvascular complications, such as diabetic retinopathy, nephropathy, and neuropathy. We summarize conducted genetic deletion studies of different isoforms as well as pharmacological intervention studies using NOX inhibitors in the context of preclinical as well as clinical research on diabetic complications. We outline the isoforms that are most promising for future clinical trials in the context of micro- and macrovascular complications of diabetes.
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http://dx.doi.org/10.1089/ars.2020.8047DOI Listing
August 2020

Expansion and Impaired Mitochondrial Efficiency of Deep Subcutaneous Adipose Tissue in Recent-Onset Type 2 Diabetes.

J Clin Endocrinol Metab 2020 04;105(4)

Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Context/objective: Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D.

Design/patients: Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging.

Results: T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P < 0.01) and AT IS (P < 0.05), 73% and 31% higher HCL (P < 0.05), and DSAT-thickness (P < 0.001), but similar hepatic IS compared with CON. Mitochondrial efficiency was ~22% lower in SSAT and DSAT of T2D patients (P < 0.001) and ~8% lower in SSAT vs DSAT (P < 0.05). In both fat depots, mitochondrial coupling correlated positively with muscle IS and metabolic flexibility (r ≥ 0.40; P < 0.05), proton leak correlated positively (r ≥ 0.51; P < 0.01) and oxidative capacity negatively (r ≤ -0.47; P < 0.05) with fasting free fatty acids (FFA). Metabolic flexibility correlated positively with SAT-oxidative capacity (r ≥ 0.48; P < 0.05) and negatively with DSAT-thickness (r = -0.48; P < 0.05). DSAT-thickness correlated negatively with mitochondrial coupling in both depots (r ≤ -0.50; P < 0.01) and muscle IS (r = -0.59; P < 0.01), positively with FFA during clamp (r = 0.63; P < 0.001) and HCL (r = 0.49; P < 0.01).

Conclusions: Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.
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http://dx.doi.org/10.1210/clinem/dgz267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060761PMC
April 2020

Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy.

BMJ Open Diabetes Res Care 2019 27;7(1):e000752. Epub 2019 Nov 27.

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

Introduction: The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities.

Methods: In a cross-sectional study using multimarker proximity extension assay technology we assessed 71 serum biomarkers including cytokines, chemokines, growth factors, receptors, and others in patients with type 2 diabetes with DSPN (DSPN+) (n=304) or without DSPN (DSPN-) (n=158) and persons with normal glucose tolerance (NGT) without polyneuropathy (n=354).

Results: After adjustment for multiple testing and sex, age, body mass index, HbA1c, and smoking, the serum levels of 17 biomarkers (four cytokines, five chemokines, four growth factors, two receptors, two miscellaneous) were lower in DSPN+ than in DSPN- and NGT. In DSPN+, six of these biomarkers were associated with peripheral nerve function. The concentrations of 15 other biomarkers differed between NGT and both DSPN+ and DSPN-, but not between DSPN+ and DSPN-. No differences in biomarker levels were found between patients with painful (n=164) and painless DSPN (n=140).

Conclusions: Deficits in systemic cytokines, chemokines, and growth factors promoting nerve regeneration in patients with type 2 diabetes are linked to polyneuropathy in general but not specifically to the painful or painless entity.

Trial Registration Number: NCT02243475.
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http://dx.doi.org/10.1136/bmjdrc-2019-000752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887496PMC
August 2020

Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy.

J Clin Endocrinol Metab 2019 12;104(12):6220-6228

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

Context: The factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.

Objective: We hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.

Design And Methods: In this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.

Results: After adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.

Conclusion: Despite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.
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http://dx.doi.org/10.1210/jc.2019-01072DOI Listing
December 2019

Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study.

Lancet Diabetes Endocrinol 2019 09 22;7(9):684-694. Epub 2019 Jul 22.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research, Munich, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. Electronic address:

Background: Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether comprehensive phenotyping validates and further characterises these clusters at diagnosis and whether relevant diabetes-related complications differ among these clusters, during 5-years of follow-up.

Methods: Patients with newly diagnosed type 1 or type 2 diabetes in the German Diabetes Study underwent comprehensive phenotyping and assessment of laboratory variables. Insulin sensitivity was assessed using hyperinsulinaemic-euglycaemic clamps, hepatocellular lipid content using magnetic resonance spectroscopy, hepatic fibrosis using non-invasive scores, and peripheral and autonomic neuropathy using functional and clinical criteria. Patients were reassessed after 5 years. The German Diabetes Study is registered with ClinicalTrials.gov, number NCT01055093, and is ongoing.

Findings: 1105 patients were classified at baseline into five clusters, with 386 (35%) assigned to mild age-related diabetes (MARD), 323 (29%) to mild obesity-related diabetes (MOD), 247 (22%) to severe autoimmune diabetes (SAID), 121 (11%) to severe insulin-resistant diabetes (SIRD), and 28 (3%) to severe insulin-deficient diabetes (SIDD). At 5-year follow-up, 367 patients were reassessed, 128 (35%) with MARD, 106 (29%) with MOD, 88 (24%) with SAID, 35 (10%) with SIRD, and ten (3%) with SIDD. Whole-body insulin sensitivity was lowest in patients with SIRD at baseline (mean 4·3 mg/kg per min [SD 2·0]) compared with those with SAID (8·4 mg/kg per min [3·2]; p<0·0001), MARD (7·5 mg/kg per min [2·5]; p<0·0001), MOD (6·6 mg/kg per min [2·6]; p=0·0011), and SIDD (5·5 mg/kg per min [2·4]; p=0·0035). The fasting adipose-tissue insulin resistance index at baseline was highest in patients with SIRD (median 15·6 [IQR 9·3-20·9]) and MOD (11·6 [7·4-17·9]) compared with those with MARD (6·0 [3·9-10·3]; both p<0·0001) and SAID (6·0 [3·0-9·5]; both p<0·0001). In patients with newly diagnosed diabetes, hepatocellular lipid content was highest at baseline in patients assigned to the SIRD cluster (median 19% [IQR 11-22]) compared with all other clusters (7% [2-15] for MOD, p=0·00052; 5% [2-11] for MARD, p<0·0001; 2% [0-13] for SIDD, p=0·0083; and 1% [0-3] for SAID, p<0·0001), even after adjustments for baseline medication. Accordingly, hepatic fibrosis at 5-year follow-up was more prevalent in patients with SIRD (n=7 [26%]) than in patients with SAID (n=5 [7%], p=0·0011), MARD (n=12 [12%], p=0·012), MOD (n=13 [15%], p=0·050), and SIDD (n=0 [0%], p value not available). Confirmed diabetic sensorimotor polyneuropathy was more prevalent at baseline in patients with SIDD (n=9 [36%]) compared with patients with SAID (n=10 [5%], p<0·0001), MARD (n=39 [15%], p=0·00066), MOD (n=26 [11%], p<0·0001), and SIRD (n=10 [17%], p<0·0001).

Interpretation: Cluster analysis can characterise cohorts with different degrees of whole-body and adipose-tissue insulin resistance. Specific diabetes clusters show different prevalence of diabetes complications at early stages of non-alcoholic fatty liver disease and diabetic neuropathy. These findings could help improve targeted prevention and treatment and enable precision medicine for diabetes and its comorbidities.

Funding: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Research Network SFB 1116 of the German Research Foundation, and Schmutzler Stiftung.
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http://dx.doi.org/10.1016/S2213-8587(19)30187-1DOI Listing
September 2019

A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy.

Mol Pain 2019 Jan-Dec;15:1744806919849802

1 Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.

Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in α-subunits of voltage-gated sodium channels (Nas) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Nas could expand the spectrum of patients with Na-related peripheral neuropathies. The auxiliary sodium channel β-subunits (β1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na. Mutations in β-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in β-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel α-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the β2-subunit. Functional analysis using current-clamp revealed that the β2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the β2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Na1.7 fast inactivation and reduced use-dependent inhibition of the Na1.7 channel.
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http://dx.doi.org/10.1177/1744806919849802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510061PMC
May 2020

Novel Insights into Sensorimotor and Cardiovascular Autonomic Neuropathy from Recent-Onset Diabetes and Population-Based Cohorts.

Trends Endocrinol Metab 2019 05 30;30(5):286-298. Epub 2019 Mar 30.

Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, Düsseldorf, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; These authors contributed equally. Electronic address:

The most prevalent chronic complications of diabetes are diabetic neuropathies, among which distal sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) are the best studied. Their major clinical sequelae such as foot ulcers, neuropathic pain, and orthostatic hypotension are associated with lower quality of life and increased risk of mortality. Here we discuss the recent insights into DSPN and CAN focusing on two prospective cohorts; that is, the German Diabetes Study (GDS) including recent-onset diabetes patients and the population-based Cooperative Health Research in the Region of Augsburg, Germany (KORA) surveys. The insights from these studies investigating novel tools for early detection and prediction of (pre)diabetic neuropathy as well as biomarkers of oxidative stress and inflammation should ultimately culminate in improving the health care of patients affected by this serious condition.
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http://dx.doi.org/10.1016/j.tem.2019.02.007DOI Listing
May 2019

General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort.

Diabetes Care 2019 02 6;42(2):240-247. Epub 2018 Dec 6.

German Center for Diabetes Research, München-Neuherberg, Germany.

Objective: To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator.

Research Design And Methods: This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations.

Results: After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor-related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker.

Conclusions: General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association.
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http://dx.doi.org/10.2337/dc18-1842DOI Listing
February 2019

Emerging Biomarkers, Tools, and Treatments for Diabetic Polyneuropathy.

Endocr Rev 2019 02;40(1):153-192

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

Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. In this review, we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy. Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.
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http://dx.doi.org/10.1210/er.2018-00107DOI Listing
February 2019

German Diabetes Study - Baseline data of retinal layer thickness measured by SD-OCT in early diabetes mellitus.

Acta Ophthalmol 2019 Mar 21;97(2):e303-e307. Epub 2018 Sep 21.

Department of Ophthalmology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Purpose: Recent studies highlighted that early diabetic neurodegeneration is present before microvascular changes are visible. Retinal neurodegeneration can decrease retinal layer thickness. We aimed to determine whether decreased retinal layer thickness is present already in the early time course of disease.

Methods: A cross-sectional analysis of patients and healthy adults from the German Diabetes Study (GDS, ClinicalTrials.gov Identifier number: CT01055093, https://clinicaltrials.gov/ct2/show/NCT01055093). Inclusion criteria were a diagnosis of diabetes mellitus (DM) within the last 12 months. Retinal layers thickness in the nasal pericentral segment was measured by spectral domain ocular coherence tomography (SD-OCT). For statistical analysis proc mixed (sas-version 9.4) was used.

Results: One hundred and seventy-eight eyes of 89 patients with type 1 DM (58 males, age 36 ± 11 years, BMI 25.5 ± 4.2 kg/m²) and 242 eyes of 121 patients with type 2 DM (84 males, age 53 ± 10 years, BMI 31.9 ± 6.3 kg/m²) with a disease duration of less than 1 year were compared to 76 eyes of 38 controls (27 males, age 41 ± 16 years, BMI 27.3 ± 6.4 kg/m²). Analysis of retinal layer thickness and visual function did not reveal a significant difference between patients and controls.

Conclusion: In the early course of DM potential, neurodegeneration does not relate to measureable changes of retinal layer thickness.
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http://dx.doi.org/10.1111/aos.13851DOI Listing
March 2019

A Systemic Inflammatory Signature Reflecting Cross Talk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study.

Diabetes 2018 11 16;67(11):2434-2442. Epub 2018 Aug 16.

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

Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 ( = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease.
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http://dx.doi.org/10.2337/db18-0060DOI Listing
November 2018

Neuropathic pain is not adequately treated in the older general population: Results from the KORA F4 survey.

Pharmacoepidemiol Drug Saf 2018 07 24;27(7):806-814. Epub 2018 May 24.

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

Purpose: We evaluated the pharmacological treatment of distal sensorimotor polyneuropathy (DSPN) among older subjects from the general population.

Methods: The study included subjects aged 61 to 82 years from the KORA F4 survey (2006-2008). DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. Pain intensity was assessed with the painDETECT questionnaire.

Results: From the included 1076 older persons, 172 (16%) persons reported pain in the lower extremities and DSPN was present in 150 (14%) subjects. Forty-eight people with pain in the lower extremities reported DSPN. Only 38% of the subjects with DSPN reporting an average pain level of ≥4 during the past 4 weeks received medical treatment, predominantly nonsteroidal anti-inflammatory drugs (NSAIDs 20% and opioids 12%). The medication of choice for neuropathic pain, antidepressants, anticonvulsants, and opioids was relatively being underused. However, opioids and neuropathy preparations were prescribed preferably for subjects with painful DSPN.

Conclusions: In the older general population, only a small proportion of subjects with painful DSPN receive analgesic pharmacotherapy. Although not recommended by guidelines for the treatment of neuropathic pain, NSAIDs were the most frequently used class of analgesic drugs.
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http://dx.doi.org/10.1002/pds.4559DOI Listing
July 2018

Sympathetic and Parasympathetic Coactivation Induces Perturbed Heart Rate Dynamics in Patients with Paroxysmal Atrial Fibrillation.

Med Sci Monit 2018 Apr 11;24:2164-2172. Epub 2018 Apr 11.

Department of Electrophysiology, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

BACKGROUND Recent evidence indicates that sympathetic/parasympathetic coactivation (CoA) is causally linked to changes in heart rate (HR) dynamics. Whether this is relevant for patients with atrial fibrillation (AF) is unknown. MATERIAL AND METHODS In patients with paroxysmal AF (n=26) and age-matched controls, (n=10) we investigated basal autonomic outflow and HR dynamics during separate sympathetic (cold hand immersion) and parasympathetic activation (O2-inhalation), as well as during CoA (cold face test). In an additional cohort (n=7), HR response was assessed before and after catheter-based pulmonary vein isolation (PVI). Ultra-high-density endocardial mapping was performed in patients (n=6) before and after CoA. RESULTS Sympathetic activation increased (control: 74±3 vs. 77±3 bpm, p=0.0098; AF: 60±2 vs. 64±2 bpm, p=0.0076) and parasympathetic activation decreased HR (control: 71±3 vs. 69±3 bpm, p=0.0547; AF: 60±1 vs. 58±2 bpm, p<0.0009), while CoA induced a paradoxical HR increase in patients with AF (control: 73±3 vs. 71±3 bpm, p=0.084; AF: 59±2 vs. 61±2 bpm, p=0.0006), which was abolished after PVI. Non-linear parameters of HR variability (SD1) were impaired during coactivation in patients with AF (control: 61±7 vs. 69±6 ms, p=0.042, AF: 44±32 vs. 32±5 ms, p=0.3929). CoA was associated with a shift of the earliest activation site (18±4 mm) of the sinoatrial nodal region, as documented by ultra-high-density mapping (3442±343 points per map). CONCLUSIONS CoA perturbs HR dynamics and shifts the site of earliest endocardial activation in patients with paroxysmal AF. This effect is abolished by PVI, supporting the value of emerging methods targeting the intrinsic cardiac autonomic nervous system to treat AF. CoA might be a valuable tool to assess cardiac autonomic function in a clinical setting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910663PMC
http://dx.doi.org/10.12659/msm.905209DOI Listing
April 2018

Myeloperoxidase, superoxide dismutase-3, cardiometabolic risk factors, and distal sensorimotor polyneuropathy: The KORA F4/FF4 study.

Diabetes Metab Res Rev 2018 07 6;34(5):e3000. Epub 2018 Apr 6.

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

Background: Oxidative stress has been proposed as important pathomechanism of cardiometabolic diseases and distal sensorimotor polyneuropathy (DSPN). However, the relevance of biomarkers of oxidative stress has not been investigated in this context. Therefore, this study aimed to assess the association of the prooxidant myeloperoxidase (MPO) and the antioxidant extracellular superoxide dismutase (SOD3) with cardiometabolic risk factors and with prevalence and incidence of DSPN.

Methods: Cross-sectional analyses comprised 1069 participants (40.3% with prediabetes and 20.5% with type 2 diabetes) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006-2008), 181 of whom had DSPN at baseline. Prospective analyses included 524 individuals without DSPN at baseline who also participated in the KORA FF4 study (2013-2014), 132 of whom developed DSPN during the 6.5-year follow-up. Serum MPO and SOD3 were measured by ELISA, and their association with cardiometabolic risk factors and DSPN were estimated by using linear and logistic regression analyses.

Results: Higher MPO and SOD levels showed multiple positive associations with cardiometabolic risk factors including age, indices of obesity, insulin resistance, serum lipids, renal dysfunction, and biomarkers of inflammation. Higher MPO levels were associated with prevalent DSPN (fully adjusted OR 1.38 [95% CI 1.10; 1.72] per doubling of MPO). Higher baseline SOD3 levels were related to incident DSPN (age and sex-adjusted OR 2.14 [1.02; 4.48] per doubling of SOD3), which was partially explained by cardiometabolic risk factors.

Conclusions: Systemic levels of both pro- and antioxidant enzymes appear involved in cardiometabolic risk and development of DSPN.
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http://dx.doi.org/10.1002/dmrr.3000DOI Listing
July 2018

Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study).

Diabetes Res Clin Pract 2018 May 6;139:147-154. Epub 2018 Mar 6.

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

Aims: We conducted a nationwide educational initiative to determine the prevalence and risk factors of diagnosed and undiagnosed painful and painless distal sensory polyneuropathy (DSPN).

Methods: Among 1850 participants, 781 had no history of diabetes (ND), 126 had type 1 diabetes (T1D), and 943 had type 2 diabetes (T2D). Painful DSPN was defined as polyneuropathy detected by bedside tests with pain and/or burning in the feet, while painless DSPN was defined as polyneuropathy with paresthesias, numbness, or absence of symptoms.

Results: DSPN was detected in 48.2% of ND, 44.3% of T1D, and 55.3% of T2D subjects. DSPN was painful, painless, or atypical in 62.1, 24.8, and 13.1% of the participants. Painful DSPN was more severe than painless DSPN. Painful and painless DSPN were previously undiagnosed in 61.5 and 81.1% of the participants, respectively. In T2D subjects, painful and painless DSPN were associated with a higher and lower BMI, respectively. Among ND participants 39.2% had HbA1c levels indicating prediabetes/diabetes.

Conclusions: Around half of participants in an educational initiative had DSPN, 62% of whom had the painful entity that correlated with BMI in T2D. Since many cases of neuropathy and diabetes remain undiagnosed, effective strategies to timely detect both conditions should be implemented.
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http://dx.doi.org/10.1016/j.diabres.2018.02.043DOI Listing
May 2018

Neuropathy in Diabetes: "One Cannot Begin It Too Soon".

Angiology 2018 10 15;69(9):752-754. Epub 2018 Jan 15.

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

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http://dx.doi.org/10.1177/0003319717751759DOI Listing
October 2018