Publications by authors named "Eva L Feldman"

316 Publications

The determinants of complication trajectories in American Indians with type 2 diabetes.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

BACKGROUNDWe aimed to determine whether metabolic syndrome (MetS) affects longitudinal trajectories of diabetic complications, including neuropathy, cardiovascular autonomic neuropathy (CAN), and kidney disease in American Indians with type 2 diabetes.METHODSWe performed a prospective study where participants underwent annual metabolic phenotyping and outcome measurements. The updated National Cholesterol Education Program criteria were used to define MetS and its individual components, using BMI instead of waist circumference. Neuropathy was defined using the Michigan Neuropathy Screening Instrument index, CAN with the expiration/inspiration ratio, and kidney disease with glomerular filtration rate. Mixed-effects models were used to evaluate associations between MetS and these outcomes.RESULTSWe enrolled 141 participants: 73.1% female, a mean (±SD) age of 49.8 (12.3), and a diabetes duration of 19.6 years (9.7 years) who were followed for a mean of 3.1 years (1.7 years). MetS components were stable during follow-up except for declining obesity and cholesterol. Neuropathy (point estimate [PE]: 0.30, 95% CI: 0.24, 0.35) and kidney disease (PE: -14.2, 95% CI: -16.8, -11.4) worsened over time, but CAN did not (PE: -0.002, 95% CI: -0.006, 0.002). We found a significant interaction between the number of MetS components and time for neuropathy (PE: 0.05, 95% CI: 0.01-0.10) but not CAN (PE: -0.003, 95% CI: -0.007, 0.001) or kidney disease (PE: -0.69, 95% CI: -3.16, 1.76). Systolic blood pressure (SBP, unit = 10 mmHg) was associated with each complication: neuropathy (PE: 0.23, 95% CI: 0.07, 0.39), CAN (PE: -0.02, 95% CI: -0.03, -0.02), and kidney disease (PE: -10.2, 95% CI: -15.4, -5.1).CONCLUSIONIn participants with longstanding diabetes, neuropathy and kidney disease worsened during follow-up, despite stable to improving MetS components, suggesting that early metabolic intervention is necessary to prevent complications in such patients. Additionally, the number of MetS components was associated with an increased rate of neuropathy progression, and SBP was associated with each complication.FUNDINGThe following are funding sources: NIH T32NS0007222, NIH R24DK082841, NIH R21NS102924, NIH R01DK115687, the Intramural Program of the NIDDK, the NeuroNetwork for Emerging Therapies, the Robert and Katherine Jacobs Environmental Health Initiative, the Robert E. Nederlander Sr. Program for Alzheimer's Research, and the Sinai Medical Staff Foundation.TRIAL REGISTRATIONClinicalTrials.gov, NCT00340678.
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http://dx.doi.org/10.1172/jci.insight.146849DOI Listing
May 2021

NK cells associate with ALS in a sex- and age-dependent manner.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Department of Neurology and.

NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.
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http://dx.doi.org/10.1172/jci.insight.147129DOI Listing
June 2021

Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes.

Ann Clin Transl Neurol 2021 Jun 6;8(6):1292-1307. Epub 2021 May 6.

Department of Neurology, University of Michigan, Ann Arbor, Michigan.

Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown.

Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants.

Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids.

Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.
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http://dx.doi.org/10.1002/acn3.51367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164865PMC
June 2021

Differential effects of minocycline on microvascular complications in murine models of type 1 and type 2 diabetes.

J Transl Sci 2021 Feb 16;7(1). Epub 2020 Jun 16.

Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.

Diabetes is a global healthcare problem associated with enormous healthcare and personal costs. Despite glucose lowering agents that control glycaemia, both type 1 (T1D) and type (T2D) diabetes patients often develop microvascular complications that increase morbidity and mortality. Current interventions rely on careful glycemic control and healthy lifestyle choices, but these are ineffective at reversing or completely preventing the major microvascular complications, diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). Minocycline, a tetracycline antibiotic with anti-inflammatory and anti-apoptotic properties, has been proposed as a protective agent in diabetes. However, there are no reported studies evaluating the therapeutic efficacy of minocycline in T1D and T2D models for all microvascular complications (DPN, DR, and DKD). Therefore, we performed metabolic profiling in streptozotocin-induced T1D and db/db T2D models and compared the efficacy of minocycline in preventing complications to that of insulin and pioglitazone in both models. Minocycline partially ameliorated DR and DKD in T1D and T2D animals, but was less effective than insulin or pioglitazone, and failed to improve DPN in either model. These results suggest that minocycline is unlikely to improve outcomes beyond that achieved with current available therapies in patients with T1D or T2D associated microvascular complications.
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http://dx.doi.org/10.15761/jts.1000431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048053PMC
February 2021

Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects.

FASEB J 2021 May;35(5):e21467

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS-/- mice receiving renin-angiotensin-aldosterone system (RAS)-blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data analysis method, SOM, or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatic analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers.
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http://dx.doi.org/10.1096/fj.202002387RDOI Listing
May 2021

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function .

J Neurosci 2021 May 30;41(19):4321-4334. Epub 2021 Mar 30.

Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca levels and impairs impulse conduction within the saphenous nerve in prediabetic PN. Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia .
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http://dx.doi.org/10.1523/JNEUROSCI.1852-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143198PMC
May 2021

Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing.

PLoS Genet 2021 Mar 29;17(3):e1009445. Epub 2021 Mar 29.

The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Jerusalem, Israel.

Expansion of the hexanucleotide repeat (HR) in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasians. All C9orf72-ALS/FTD patients share a common risk (R) haplotype. To study C9orf72 expression and splicing from the mutant R allele compared to the complementary normal allele in ALS/FTD patients, we initially created a detailed molecular map of the single nucleotide polymorphism (SNP) signature and the HR length of the various C9orf72 haplotypes in Caucasians. We leveraged this map to determine the allelic origin of transcripts per patient, and decipher the effects of pathological and normal HR lengths on C9orf72 expression and splicing. In C9orf72 ALS patients' cells, the HR expanded allele, compared to non-R allele, was associated with decreased levels of a downstream initiated transcript variant and increased levels of transcripts initiated upstream of the HR. HR expanded R alleles correlated with high levels of unspliced intron 1 and activation of cryptic donor splice sites along intron 1. Retention of intron 1 was associated with sequential intron 2 retention. The SNP signature of C9orf72 haplotypes described here enables allele-specific analysis of transcriptional products and may pave the way to allele-specific therapeutic strategies.
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http://dx.doi.org/10.1371/journal.pgen.1009445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031855PMC
March 2021

Lessons for clinical trial design in Friedreich's ataxia.

Lancet Neurol 2021 05 23;20(5):330-332. Epub 2021 Mar 23.

NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(21)00064-8DOI Listing
May 2021

Immune-mediated vincristine-induced neuropathy: Unlocking therapies.

J Exp Med 2021 May;218(5)

NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI.

Vincristine-induced peripheral neuropathy (VIPN) is a prevalent and painful complication in cancer patients that lacks effective treatments. In this issue of JEM, Starobova et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201452) report that VIPN is driven by innate immune system activation, a discovery that unlocks immunotherapies as potential treatments.
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http://dx.doi.org/10.1084/jem.20210286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992412PMC
May 2021

Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.

Brain 2021 Mar 12. Epub 2021 Mar 12.

Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in to 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one third of painful DN patients derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc, which leads to the best therapeutic outcomes.
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http://dx.doi.org/10.1093/brain/awab079DOI Listing
March 2021

Sex differences in insulin resistance, but not peripheral neuropathy, in a diet-induced prediabetes mouse model.

Dis Model Mech 2021 Apr 15;14(4). Epub 2021 Apr 15.

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

Peripheral neuropathy (PN) is a common complication of prediabetes and diabetes and is an increasing problem worldwide. Existing PN treatments rely solely on glycemic control, which is effective in type 1 but not type 2 diabetes. Sex differences in response to anti-diabetic drugs further complicate the identification of effective PN therapies. Preclinical research has been primarily carried out in males, highlighting the need for increased sex consideration in PN models. We previously reported PN sex dimorphism in obese leptin-deficient ob/ob mice. This genetic model is inherently limited, however, owing to leptin's role in metabolism. Therefore, the current study goal was to examine PN and insulin resistance in male and female C57BL6/J mice fed a high-fat diet (HFD), an established murine model of human prediabetes lacking genetic mutations. HFD mice of both sexes underwent longitudinal phenotyping and exhibited expected metabolic and PN dysfunction compared to standard diet (SD)-fed animals. Hindpaw thermal latencies to heat were shorter in HFD females versus HFD males, as well as SD females versus males. Compared to HFD males, female HFD mice exhibited delayed insulin resistance, yet still developed the same trajectory of nerve conduction deficits and intraepidermal nerve fiber density loss. Subtle differences in adipokine levels were also noted by sex and obesity status. Collectively, our results indicate that although females retain early insulin sensitivity upon HFD challenge, this does not protect them from developing the same degree of PN as their male counterparts. This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.048909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077554PMC
April 2021

Amyotrophic Lateral Sclerosis Survival Associates With Neutrophils in a Sex-specific Manner.

Neurol Neuroimmunol Neuroinflamm 2021 03 2;8(2). Epub 2021 Feb 2.

From the Department of Neurology (B.J.M., S.A.G., E.L.F.), and Department of Biostatistics (J.B., S.K.), School of Public Health, University of Michigan, Ann Arbor.

Objective: To determine whether neutrophils contribute to amyotrophic lateral sclerosis (ALS) progression, we tested the association of baseline neutrophil count on ALS survival, whether the effect was sex specific, and whether neutrophils accumulate in the spinal cord.

Methods: A prospective cohort study was conducted between June 22, 2011, and October 30, 2019. Blood leukocytes were isolated from ALS participants and neutrophil levels assessed by flow cytometry. Participant survival outcomes were analyzed by groups (<2 × 10, 2-4 × 10, and >4 × 10 neutrophils/mL) with adjustments for relevant ALS covariates and by sex. Neutrophil levels were assessed from CNS tissue from a subset of participants.

Results: A total of 269 participants with ALS within 2 years of an ALS diagnosis were included. Participants with baseline neutrophil counts over 4 × 10/mL had a 2.1 times higher mortality rate than those with a neutrophil count lower than 2 × 10/mL (95% CI: 1.3-3.5, = 0.004) when adjusting for age, sex, and other covariates. This effect was more pronounced in females, with a hazard ratio of 3.8 (95% CI: 1.8-8.2, = 0.001) in the >4 × 10/mL vs <2 × 10/mL group. Furthermore, ALS participants (n = 8) had increased neutrophils in cervical ( = 0.049) and thoracic ( = 0.022) spinal cord segments compared with control participants (n = 8).

Conclusions: Higher neutrophil counts early in ALS associate with a shorter survival in female participants. Furthermore, neutrophils accumulate in ALS spinal cord supporting a pathophysiologic correlate. These data justify the consideration of immunity and sex for personalized therapeutic development in ALS.

Classification Of Evidence: This study provides Class III evidence that in female participants with ALS, higher baseline neutrophil counts are associated with shorter survival.
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http://dx.doi.org/10.1212/NXI.0000000000000953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057067PMC
March 2021

Traumatic Brain Injury: A Success Stemming from Stem Cells.

Neurology 2021 Jan 6. Epub 2021 Jan 6.

NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI

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http://dx.doi.org/10.1212/WNL.0000000000011455DOI Listing
January 2021

Energizing the Conversation: How to Identify and Overcome Gender Inequalities in Academic Medicine.

J Contin Educ Health Prof 2020 ;40(4):274-278

Dr. Sakowski: Managing Director, NeuroNetwork for Emerging Therapies, Department of Neurology, University of Michigan, Ann Arbor, MI. Ms. Feldman: Russell N. DeJong Professor of Neurology, Director, NeuroNetwork for Emerging Therapies, Department of Neurology, University of Michigan, Ann Arbor, MI. Ms. Jagsi: Newman Family Professor, Deputy Chair, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, and Center for Bioethics and Social Sciences in Medicine, University of Michigan, Ann Arbor, MI. Dr. Singer: Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, University of Michigan, Ann Arbor, MI.

Gender inequality exists in advanced faculty and leadership positions at academic medical centers; however, despite growing awareness, how to best approach and rectify the issue is unknown. To energize the conversation on gender inequality at one academic medical center, chairs and women faculty were surveyed to identify barriers faced by women navigating their careers. A symposium with short talks to increase awareness, a panel with University leaders to discuss issues and successful strategies to overcome gaps, and focus groups to delve further into key areas that underlie inequity through an active café style format were planned and implemented. This multifaceted approach resulted in a wealth of knowledge. The symposium and panel highlighted important relevant issues and offered personal strategies for successful career advancement, while the focus group discussions further identified barriers and inspired ongoing efforts across departments and novel approaches to overcome three key issues (work-life integration, deliberate promotion of mentor/sponsor relationships, and overcoming unconscious bias) identified through the initial surveys. Compiled data were then disseminated to participants and University leaders to enhance awareness of available programs and prompt action in critical areas lacking support. Overall, the approach indicated that securing support from leaders and the academic community alike are pertinent to emphasize actions needed to overcome issues affecting women in academic medicine. Moreover, bringing leaders and faculty together for an informational session and brainstorming appears to energize the conversation. Such efforts can ultimately instill change and establish an inclusive environment where all members of the academic medicine community can thrive.
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http://dx.doi.org/10.1097/CEH.0000000000000296DOI Listing
January 2020

Diabetic neuropathy in children and youth: New and emerging risk factors.

Pediatr Diabetes 2021 Mar 24;22(2):132-147. Epub 2020 Nov 24.

Department of Neurology, University of Michigan Medicine, Ann Arbor, Michigan, USA.

Pediatric neuropathy attributed to metabolic dysfunction is a well-known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth.
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http://dx.doi.org/10.1111/pedi.13153DOI Listing
March 2021

Differential Effects of Empagliflozin on Microvascular Complications in Murine Models of Type 1 and Type 2 Diabetes.

Biology (Basel) 2020 Oct 22;9(11). Epub 2020 Oct 22.

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

Microvascular complications account for the significant morbidity associated with diabetes. Despite tight glycemic control, disease risk remains especially in type 2 diabetes (T2D) patients and no therapy fully prevents nerve, retinal, or renal damage in type 1 diabetes (T1D) or T2D. Therefore, new antidiabetic drug classes are being evaluated for the treatment of microvascular complications. We investigated the effect of empagliflozin (EMPA), an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), on diabetic neuropathy (DPN), retinopathy (DR), and kidney disease (DKD) in streptozotocin-induced T1D and / T2D mouse models. EMPA lowered blood glycemia in T1D and T2D models. However, it did not ameliorate any microvascular complications in the T2D model, which was unexpected, given the protective effect of SGLT2 inhibitors on DKD progression in T2D subjects. Although EMPA did not improve DKD in the T1D model, it had a potential modest effect on DR measures and favorably impacted DPN as well as systemic oxidative stress. These results support the concept that glucose-centric treatments are more effective for DPN in T1D versus T2D. This is the first study that provides an evaluation of EMPA treatment on all microvascular complications in a side-by-side comparison in T1D and T2D models.
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http://dx.doi.org/10.3390/biology9110347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690408PMC
October 2020

Statin Therapy and Risk of Polyneuropathy in Type 2 Diabetes: A Danish Cohort Study.

Diabetes Care 2020 12 30;43(12):2945-2952. Epub 2020 Sep 30.

Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Objective: Statins may reduce the risk of diabetic polyneuropathy (DPN) as a result of lipid-lowering and anti-inflammatory effects, but statins have also been associated with neurotoxicity. We examined whether statin therapy affects the risk of DPN.

Research Design And Methods: We identified all Danish patients with incident type 2 diabetes during 2002-2016. New users initiated statins between 180 days before and 180 days after their first diabetes record, while prevalent users had initiated statins before that period. Patients were followed for incident DPN using validated hospital diagnosis codes, starting 180 days after their first diabetes record. Cox proportional hazard analysis was used to compute adjusted hazard ratios (aHRs) for DPN.

Results: The study cohort comprised 59,255 (23%) new users, 75,528 (29%) prevalent users, and 124,842 (48%) nonusers; median follow-up time was 6.2 years (interquartile range 3.4-9.6). The incidence rate of DPN events per 1,000 person-years was similar in new users (4.0 [95% CI 3.8-4.2]), prevalent users (3.8 [3.6-3.9]), and nonusers (3.8 [3.7-4.0]). The aHR for DPN was 1.05 (0.98-1.11) in new users and 0.97 (0.91-1.04) in prevalent users compared with statin nonusers. New users had a slightly increased DPN risk during the first year (1.31 [1.12-1.53]), which vanished after >2 years of follow-up. Findings were similar in on-treatment and propensity score-matched analyses and with additional adjustment for pretreatment blood lipid levels.

Conclusions: Statin therapy is unlikely to increase or mitigate DPN risk in patients with type 2 diabetes, although a small acute risk of harm cannot be excluded.
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http://dx.doi.org/10.2337/dc20-1004DOI Listing
December 2020

COVID-19 and Diabetes: A Collision and Collusion of Two Diseases.

Diabetes 2020 12 16;69(12):2549-2565. Epub 2020 Sep 16.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

The coronavirus disease 2019 (COVID-19) pandemic has infected >22.7 million and led to the deaths of 795,000 people worldwide. Patients with diabetes are highly susceptible to COVID-19-induced adverse outcomes and complications. The COVID-19 pandemic is superimposing on the preexisting diabetes pandemic to create large and significantly vulnerable populations of patients with COVID-19 and diabetes. This article provides an overview of the clinical evidence on the poorer clinical outcomes of COVID-19 infection in patients with diabetes versus patients without diabetes, including in specific patient populations, such as children, pregnant women, and racial and ethnic minorities. It also draws parallels between COVID-19 and diabetes pathology and suggests that preexisting complications or pathologies in patients with diabetes might aggravate infection course. Finally, this article outlines the prospects for long-term sequelae after COVID-19 for vulnerable populations of patients with diabetes.
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http://dx.doi.org/10.2337/dbi20-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679769PMC
December 2020

Untargeted metabolomics yields insight into ALS disease mechanisms.

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1329-1338. Epub 2020 Sep 14.

Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA

Objective: To identify dysregulated metabolic pathways in amyotrophic lateral sclerosis (ALS) versus control participants through untargeted metabolomics.

Methods: Untargeted metabolomics was performed on plasma from ALS participants (n=125) around 6.8 months after diagnosis and healthy controls (n=71). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon rank-sum tests, adjusted logistic regression and partial least squares-discriminant analysis (PLS-DA), while group lasso explored sub-pathway-level differences. Adjustment parameters included sex, age and body mass index (BMI). Metabolomics pathway enrichment analysis was performed on metabolites selected by the above methods. Finally, machine learning classification algorithms applied to group lasso-selected metabolites were evaluated for classifying case status.

Results: There were no group differences in sex, age and BMI. Significant metabolites selected were 303 by Wilcoxon, 300 by logistic regression, 295 by PLS-DA and 259 by group lasso, corresponding to 11, 13, 12 and 22 enriched sub-pathways, respectively. 'Benzoate metabolism', 'ceramides', 'creatine metabolism', 'fatty acid metabolism (acyl carnitine, polyunsaturated)' and 'hexosylceramides' sub-pathways were enriched by all methods, and 'sphingomyelins' by all but Wilcoxon, indicating these pathways significantly associate with ALS. Finally, machine learning prediction of ALS cases using group lasso-selected metabolites achieved the best performance by regularised logistic regression with elastic net regularisation, with an area under the curve of 0.98 and specificity of 83%.

Conclusion: In our analysis, ALS led to significant metabolic pathway alterations, which had correlations to known ALS pathomechanisms in the basic and clinical literature, and may represent important targets for future ALS therapeutics.
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http://dx.doi.org/10.1136/jnnp-2020-323611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677469PMC
December 2020

Correction to: Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy.

Clin Epigenetics 2020 Aug 27;12(1):130. Epub 2020 Aug 27.

Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 North Columbia Rd. Stop 9037, Grand Forks, ND, 58202-9037, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13148-020-00922-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453542PMC
August 2020

Magnetic resonance imaging of human neural stem cells in rodent and primate brain.

Stem Cells Transl Med 2021 Jan 25;10(1):83-97. Epub 2020 Aug 25.

Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

Stem cell transplantation therapies are currently under investigation for central nervous system disorders. Although preclinical models show benefit, clinical translation is somewhat limited by the absence of reliable noninvasive methods to confirm targeting and monitor transplanted cells in vivo. Here, we assess a novel magnetic resonance imaging (MRI) contrast agent derived from magnetotactic bacteria, magneto-endosymbionts (MEs), as a translatable methodology for in vivo tracking of stem cells after intracranial transplantation. We show that ME labeling provides robust MRI contrast without impairment of cell viability or other important therapeutic features. Labeled cells were visualized immediately post-transplantation and over time by serial MRI in nonhuman primate and mouse brain. Postmortem tissue analysis confirmed on-target grft location, and linear correlations were observed between MRI signal, cell engraftment, and tissue ME levels, suggesting that MEs may be useful for determining graft survival or rejection. Overall, these findings indicate that MEs are an effective tool for in vivo tracking and monitoring of cell transplantation therapies with potential relevance to many cellular therapy applications.
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http://dx.doi.org/10.1002/sctm.20-0126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780819PMC
January 2021

Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy.

Clin Epigenetics 2020 08 12;12(1):123. Epub 2020 Aug 12.

Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 North Columbia Rd. Stop 9037, Grand Forks, ND, 58202-9037, USA.

Background: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN.

Results: Unbiased clustering of transcriptomics data separated samples into groups, which correlated with HbA1c levels. Accordingly, we found 998 differentially expressed genes (DEGs) and 929 differentially methylated genes (DMGs) between the groups with the highest and lowest HbA1c levels. Functional enrichment analysis revealed that DEGs and DMGs were enriched for pathways known to play a role in DPN, including those related to the immune system, extracellular matrix (ECM), and axon guidance. To understand the interaction between the transcriptome and methylome in DPN, we performed an integrated analysis of the overlapping genes between DEGs and DMGs. Integrated functional and network analysis identified genes and pathways modulating functions such as immune response, ECM regulation, and PI3K-Akt signaling.

Conclusion: These results suggest for the first time that DNA methylation is a mechanism regulating gene expression in DPN. Overall, DPN patients with high HbA1c have distinct alterations in sural nerve DNA methylome and transcriptome, suggesting that optimal glycemic control in DPN patients is an important factor in maintaining epigenetic homeostasis and nerve function.
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http://dx.doi.org/10.1186/s13148-020-00913-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425575PMC
August 2020

Diabetic neuropathy: the future is promising. Reply to Uusitupa M, Niskanen L, Laitinen T [letter] and Coppini DV [letter].

Diabetologia 2020 09 17;63(9):1951-1952. Epub 2020 Jul 17.

Department of Neurology, University of Michigan, 109 Zina Pitcher Place, 4021 BSRB, Ann Arbor, MI, 48104, USA.

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http://dx.doi.org/10.1007/s00125-020-05233-1DOI Listing
September 2020

Distal Symmetric Polyneuropathy in 2020.

JAMA 2020 07;324(1):90-91

Department of Neurology, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1001/jama.2020.0700DOI Listing
July 2020

The metabolic drivers of neuropathy in India.

J Diabetes Complications 2020 10 11;34(10):107653. Epub 2020 Jun 11.

M.V. Hospital for Diabetes and Prof M Viswanathan Diabetes Research Centre, Royapuram, Chennai, India.

Aims: To determine the association between the metabolic syndrome (MetS) and neuropathy in Chennai, India.

Methods: We recruited participants attending the M.V. Hospital for Diabetes. Neuropathy was defined using the Michigan Neuropathy Screening Instrument combined index and MetS was defined using the updated National Cholesterol Education Program criteria. Multivariable logistic regression models were used to assess the associations between individual metabolic components and neuropathy.

Results: Of the 652 participants (42% female and mean (SD) age of 45.5 (9.7)) included in the study, the prevalence of neuropathy was 9.8%. Neuropathy prevalence increased with worsening glycemic status (p < 0.01), but not as the number of MetS components increased (p = 0.12). Among normoglycemic participants, an increasing neuropathy trend was observed as the number of MetS components increased (p = 0.04). Multivariable logistic regression found that diabetes (OR:3.41,1.28-9.11) was associated with neuropathy, but waist circumference was not (OR:1.002,0.88-1.14).

Conclusions: Similar to previous studies, diabetes was the most important metabolic risk factor for neuropathy in a population from Chennai, India. In contrast to other population-based studies, waist circumference was not associated with neuropathy. Whether the distribution of obesity affects nerves differently in Indian populations requires future studies with more precise anthropometric measures.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502489PMC
October 2020

Central Obesity is Associated With Neuropathy in the Severely Obese.

Mayo Clin Proc 2020 07;95(7):1342-1353

University of Michigan, Ann Arbor, MI.

Objective: To determine the prevalence of neuropathy stratified by glycemic status and the association between extensive anthropometric measurements and neuropathy.

Patients And Methods: We performed a cross-sectional, observational study in obese individuals, before surgery, with body mass index (BMI) greater than 35 kg/m. Lean controls were recruited from a research website. Neuropathy was defined by the Toronto consensus definition of probable neuropathy. We compared nine anthropometric measurements between obese participants with and without neuropathy. We used multivariable logistic regression to explore associations between these measures, and other metabolic risk factors, and neuropathy.

Results: We recruited 138 obese individuals and 46 lean controls. The mean age (SD) was 45.1 (11.3) years in the obese population (76.1% female, n=105) and 43.8 (12.1) years in the lean controls (82.2% female, n=37). The prevalence of neuropathy was 2.2% (n=1) in lean controls, 12.1% (n=4) in obese participants with normoglycemia, 7.1% (n=4) in obese participants with pre-diabetes, and 40.8% (n=20) in obese participants with diabetes (p≤.01). Waist circumference was the only anthropometric measure that was larger in those with neuropathy (139.3 cm vs 129.1 cm, p=.01). Hip-thigh (71.1 cm vs 76.6 cm, p<.01) and mid-thigh (62.2 cm vs 66.3 cm, p=.03) circumferences were smaller in those with neuropathy. The body mass index was comparable between patients who were obese with and without neuropathy (p=.86). Waist circumference (odds ratio [OR], 1.39; 95% CI, 1.10 to 1.75), systolic blood pressure (OR, 2.89; 95% CI, 1.49 to 5.61), and triglycerides (OR, 1.31; 95% CI, 1.00 to 1.70) were significantly associated with neuropathy.

Conclusion: Normoglycemic obese patients have a high prevalence of neuropathy indicating that obesity alone may be sufficient to cause neuropathy. Waist circumference, but not general obesity, is significantly associated with neuropathy.
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http://dx.doi.org/10.1016/j.mayocp.2020.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340115PMC
July 2020

Cytoplasmic TDP43 Binds microRNAs: New Disease Targets in Amyotrophic Lateral Sclerosis.

Front Cell Neurosci 2020 12;14:117. Epub 2020 May 12.

Department of Neurology, University of Michigan, Ann Arbor, MI, United States.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and incurable neurodegenerative disease. Recent studies suggest that dysregulation of gene expression by microRNAs (miRNAs) may play an important role in ALS pathogenesis. The reversible nature of this dysregulation makes miRNAs attractive pharmacological targets and a potential therapeutic avenue. Under physiological conditions, miRNA biogenesis, which begins in the nucleus and includes further maturation in the cytoplasm, involves trans-activation response element DNA/RNA-binding protein of 43 kDa (TDP43). However, TDP43 mutations or stress trigger TDP43 mislocalization and inclusion formation, a hallmark of most ALS cases, that may lead to aberrant protein/miRNA interactions in the cytoplasm. Herein, we demonstrated that TDP43 exhibits differential binding affinity for select miRNAs, which prompted us to profile miRNAs that preferentially bind cytoplasmic TDP43. Using cellular models expressing TDP43 variants and miRNA profiling analyses, we identified differential levels of 65 cytoplasmic TDP43-associated miRNAs. Of these, approximately 30% exhibited levels that differed by more than 3-fold in the cytoplasmic TDP43 models relative to our control model. The hits included both novel miRNAs and miRNAs previously associated with ALS that potentially regulate several predicted genes and pathways that may be important for pathogenesis. Accordingly, these findings highlight specific miRNAs that may shed light on relevant disease pathways and could represent potential biomarkers and reversible treatment targets for ALS.
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http://dx.doi.org/10.3389/fncel.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235295PMC
May 2020

Facial Nerve Surgery in the Rat Model to Study Axonal Inhibition and Regeneration.

J Vis Exp 2020 05 5(159). Epub 2020 May 5.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine;

This protocol describes consistent and reproducible methods to study axonal regeneration and inhibition in a rat facial nerve injury model. The facial nerve can be manipulated along its entire length, from its intracranial segment to its extratemporal course. There are three primary types of nerve injury used for the experimental study of regenerative properties: nerve crush, transection, and nerve gap. The range of possible interventions is vast, including surgical manipulation of the nerve, delivery of neuroactive reagents or cells, and either central or end-organ manipulations. Advantages of this model for studying nerve regeneration include simplicity, reproducibility, interspecies consistency, reliable survival rates of the rat, and an increased anatomic size relative to murine models. Its limitations involve a more limited genetic manipulation versus the mouse model and the superlative regenerative capability of the rat, such that the facial nerve scientist must carefully assess time points for recovery and whether to translate results to higher animals and human studies. The rat model for facial nerve injury allows for functional, electrophysiological, and histomorphometric parameters for the interpretation and comparison of nerve regeneration. It thereby boasts tremendous potential toward furthering the understanding and treatment of the devastating consequences of facial nerve injury in human patients.
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http://dx.doi.org/10.3791/59224DOI Listing
May 2020

Early life metal dysregulation in amyotrophic lateral sclerosis.

Ann Clin Transl Neurol 2020 06 21;7(6):872-882. Epub 2020 May 21.

Department of Environmental Medicine and Public Health, and Senator Frank Lautenberg Laboratory for Environmental Health Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Objective: Deficiencies and excess of essential elements and toxic metals are implicated in amyotrophic lateral sclerosis (ALS), but the age when metal dysregulation appears remains unknown. This study aims to determine whether metal uptake is dysregulated during childhood in individuals eventually diagnosed with ALS.

Methods: Laser ablation-inductively coupled plasma-mass spectrometry was used to obtain time series data of metal uptake using biomarkers in teeth from autopsies or dental extractions of ALS (n = 36) and control (n = 31) participants. Covariate data included sex, smoking, occupational exposures, and ALS family history. Case-control differences were identified in temporal profiles of metal uptake for individual metals using distributed lag models. Weighted quantile sum (WQS) regression was used for metals mixture analyses. Similar analyses were performed on an ALS mouse model to further verify the relevance of dysregulation of metals in ALS.

Results: Metal levels were higher in cases than in controls: 1.49 times for chromium (1.11-1.82; at 15 years), 1.82 times for manganese (1.34-2.46; at birth), 1.65 times for nickel (1.22-2.01; at 8 years), 2.46 times for tin (1.65-3.30; at 2 years), and 2.46 times for zinc (1.49-3.67; at 6 years). Co-exposure to 11 elements indicated that childhood metal dysregulation was associated with ALS. The mixture contribution of metals to disease outcome was likewise apparent in tooth biomarkers of an ALS mouse model, and differences in metal distribution were evident in ALS mouse brains compared to brains from littermate controls.

Interpretation: Overall, our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult-onset ALS.
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http://dx.doi.org/10.1002/acn3.51006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318091PMC
June 2020

Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy.

J Peripher Nerv Syst 2020 06;25(2):76-84

Department of Neurology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

Diabetic peripheral neuropathy (DPN) is one of the most widespread and disabling neurological conditions, accounting for half of all neuropathy cases worldwide. Despite its high prevalence, no approved disease modifying therapies exist. There is now a growing body of evidence that DPN secondary to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) represents different disease processes, with T2DM DPN best understood within the context of metabolic syndrome rather than hyperglycemia. In this review, we highlight currently understood mechanisms of DPN, along with their corresponding potential therapeutic targets. We frame this discussion within a practical overview of how the field evolved from initial human observations to murine pathomechanistic and therapeutic models into ongoing and human clinical trials, with particular emphasis on T2DM DPN and metabolic syndrome.
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http://dx.doi.org/10.1111/jns.12387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375363PMC
June 2020