bluuebunny/crossref_metadata_2025_split huggingface dataset:
533-P: Predicting Treatment Response in Painful Diabetic Neuropathy Using Magnetic Resonance Brain Imaging
Authors: TEH KEVIN , WILKINSON IAIN D. , SLOAN GORDON P. , TESFAYE SOLOMON , SELVARAJAH DINESH 
Published: June 2020

Background: Painful diabetic polyneuropathy (DPN) is difficult to manage as treatment response is often varied. The aim of this study was to explore the central mechanisms to explain the variance in treatment response.
Methods: Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. All subjects completed a treatment efficacy questionnaire. Twenty-nine patients (responders n=14 and non-responders n=15) along with 26 healthy controls subsequently underwent multimodal brain magnetic resonance (MR) imaging to acquire anatomical and resting state functional data (3T, Achieva, Phillips Healthcare).
Results: There was no significant difference in age (p=0.53), pain duration (p=0.89), diabetes duration (p=0.19) and clinical parameters of neuropathy (TCNS, p=0.16 and NTSS-6, p=0.61) between responders and non-responders to lidocaine treatment. Neither was there a difference in the use of concurrent neuropathic pain treatments. Non-responders to lidocaine had significantly lower mean S1 cortical volumes and mean number of vertices compared to responders and healthy controls (ANOVA p=0.02 and 0.02 respectively). There was no significant difference in S1 cortical volumes or vertices between responders and healthy controls. There was significantly greater resting state functional connectivity in lidocaine responders between the insula cortex [F(4)(13)=10.33; p-FDR=0.01] and the orbital frontal cortex [T(20)=3.88; p-FDR=0.02], amygdala [T(20)=3.65; p-FDR=0.02] and anterior cingulate gyrus [T(20)=4.04; p-FDR=0.01].
Conclusion: To the best of our knowledge, this is the first assessment of CNS mechanisms of treatment response in painful DPN. Key nociceptive processing areas showed decreased grey matter density (S1 cortex) and reduced functional connectivity (insula) relating to treatment response. MR neuroimaging may serve as a Central Pain Signature which could be used to predict treatment response.

Disclosure
K. Teh: None. I.D. Wilkinson: None. G.P. Sloan: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, Wörwag Pharma. Speaker’s Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, Napp Pharmaceuticals, Novo Nordisk Inc., Pfizer Inc. D. Selvarajah: None.

Funding
European Foundation for the Study of Diabetes; University of Sheffield
538-P: Inter-Rater Agreement of Vibration and Pressure Sensation in the Assessment of Sensorimotor Dysfunction in Diabetes
Authors: JUDE EDWARD B. , TENTOLOURIS ANASTASIOS , ELEFTHERIADOU IOANNA , TENTOLOURIS NIKOLAOS 
Published: June 2020

Assessment of large fibre dysfunction is based on tuning fork (TF) for vibration perception and on monofilament (MF) for pressure sensation. Herein we examined the inter-rater variability of the MF and TF alongside with the VibraTip™ (VT), a new measure of vibration perception. We recruited 100 subjects with diabetes. Patients with active ulcers or peripheral vascular disease were excluded. A consultant diabetologist (CD) initially performed a general physical and foot examination at each foot which included MF, TF and VT. The tests were then performed by a podiatrist (P) and a diabetes specialist nurse (DSN) and the results were compared among the healthcare professionals (HCP); each examiner was blinded to the results of the other examiners. Inter-rater agreement was determined by weighted kappa (k) statistics. k values 0.41-0.60 represent moderate agreement, 0.61-0.8 good and &gt;0.81 very good agreement. Diagnosis of insensation (%) by the CD, P and DSN were as follows: MF insensation 37.5%, 34.5% and 34.0%, respectively; TF insensation, 48.0%, 31.5% and 45.0%, respectively; VT insensation 39.0%, 35.0% and 35.5%, respectively. The inter-rater agreement (k, 95% confidence intervals) between the CD and the P, the P and the DSN as well as the CD and the DSN were as follows: TF 0.62 (0.52-0.73), 0.62 (0.51-0.72), 0.68 (0.57-0.78), respectively; MF 0.67 (0.57-0.78), 0.70 (0.59-0.80), 0.73 (0.63-0.83), respectively; VT 0.72 (0.62-0.82), 0.70 (0.60-0.81), 0.67 (0.56-0.78), respectively. The k statistics suggested good level (&gt;0.6) of agreement of the three neurological modalities between the HCP. Despite the differences observed in the ability of various tests to diagnose reduced sensation, there is good overall agreement in the results of neurological examination by MF, TF and VT between HCP. Further research is required to examine the performance of these tests in the diagnosis of neuropathy.

Disclosure
E.B. Jude: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk Inc., Sanofi. Other Relationship; Self; Lilly Diabetes, Menarini Group. A. Tentolouris: None. I. Eleftheriadou: None. N. Tentolouris: None.
555-P: Current Status of Diabetic Peripheral Neuropathy in Type 2 Diabetes: Results from a National Health Insurance Service National Sample Cohort, 2006-2015
Authors: KIM CHONG HWA , PARK TAE SUN , MOON SEONG-SU , KIM SUNG RAE , LEE KIYOUNG 
Published: June 2020

Objectives: To determine the prevalence and clinical characteristics of diabetic peripheral neuropathy in patients with type 2 diabetes in Korea.
Methods: From the National Health Information database maintained by the Korean National Health Insurance Service (NHIS) a representative sample cohort of 1,201,208 participants was randomly selected, comprising 2.2% of the total eligible Korean population in 2006, and followed until 2015. Data source: NHIS-NSC: National Health Insurance Service-National Sample Cohort.
Results: The annual prevalence of DPN increased from 24.5% in 2006 to 26.3% in 2007 and thereafter it tended to gradually decrease to 21.2% in 2015. DPN medication was administered in 68% to 69% of DPN patients. Drug therapy was prescribed for up to 90% mono therapy, dual combination treatment for up to 10%, and triple combination treatment for up to 1%. Prescribed medications for DPN from 2006 to 2015 were α-lipoic acid (54.7% to 43.2%), anticonvulsant drugs (21.7% to 36.8%), tricyclic antidepressants (21.3% to 12.6%), serotonin-norepinephrine reuptake inhibitors (0.3% to 5.5%), γ-linoleic acid (2.3% to 1.9%). Persistency for pharmacological treatment of DPN was 30.0%- 48.5%, and the rate of persistency was increasing over time. The incidence of lower-extremity amputation was greater in patients with DPN compared with those without and the incidence has been gradually increasing through the follow-up period.
Conclusion: The prevalence of DPN patients is about a quarter of those with diabetes, and medication is about 70 percent, and most medications are administered with mono therapy.

Disclosure
C. Kim: None. T. Park: None. S. Moon: None. S. Kim: None. K. Lee: None.
556-P: 20-Hydroxyeicosatetraenoic Acid: A Prospective Therapeutic Target for Diabetes-Induced Neuropathy
Authors: HADDAD MARY , EID STEPHANIE , EID ASSAAD A. 
Published: June 2020

Background: Diabetic Neuropathy is one of the most prevalent complications of diabetes. Clinically, Diabetic Peripheral Neuropathy (DPN) is characterized by reduced electrophysiological recordings and sensorimotor deficits which have been correlated with myelin defects in nerve fibers and limited regenerative potential. Oxidative stress emerged as the final key mediator of diabetic complications. Cytochrome P450 (CYPs) enzymes are major contributors which have been shown to mediate diabetes-induced organ injuries. Yet, no studies have investigated their role in DPN.
Methods: We assessed peripheral nerve functionality in a murine model of type 2 diabetes mellitus (T2D) treated with either a potent and selective inhibitor of 20-HETE synthesizing enzyme, HET0016, or with metformin, an AMPK activator. Behavioral, histological, biochemical and molecular assessments were performed.
Results: Hyperglycemia resulted in CYP4A protein upregulation and 20-HETE overproduction in sciatic nerves of diabetic animals which correlated with alterations in myelin protein levels culminating in sensorimotor deficits. Elevated 20-HETE levels were concurrent with increased ROS production. This was paralleled by AMPK inactivation in addition to alterations in Beclin-1 and LC3B levels. Interestingly, 20-HETE synthesizing enzyme inhibition via HET0016 was shown to normalize myelin protein profiles, p-AMPK levels, ROS production and autophagic defenses, restoring sensorimotor function in diabetic animals. Of interest, mice treated with metformin exhibited a decrease in CYP4A protein expression as well as in 20-HETE levels. Similarly, metformin treatment withdrew the injurious effect of diabetes on Schwann cells and attenuated peripheral neuropathy.
Conclusion: Our study suggest that hyperglycemia leads to oxidative injury via CYP4A alteration and AMPK inactivation, altering autophagy which compromises myelin integrity and peripheral nerve functionality.

Disclosure
M. Haddad: None. S. Eid: None. A.A. Eid: None.

Funding
American University of Beirut
565-P: Diabetic Retinopathy in African-Born Blacks Living In America: Prevalence, Risk Factors, and Diagnostic Tests
Authors: HWANG CHRISTOPHER K. , AGRON ELVIRA , CHEN MICHELLE A. , DUBOSE CHRISTOPHER , SUMNER ANNE E. , CHEW EMILY 
Published: June 2020

The prevalence of diabetic retinopathy (DR), risk factors for DR and the best diagnostic tests for prediction of DR in Africans with prediabetes (preDM) and diabetes (DM) are unknown. Evaluation for atrophy of the retinal inner layers may be helpful but has not been studied in Africans. Therefore, African-born blacks (n=249, male 63%, age 40±10y (mean±SD), BMI 27.8±4.5 kg/m2) living in the United States had OGTT and eye exams with spectral-domain optical coherence tomography (OCT) and fundus photos. A validated automated algorithm was applied to OCT images to measure thickness of retinal layers. Both A1C and glucose criteria during the OGTT was used to diagnose glucose tolerance status. Newly diagnosed DM occurred in 9.6% (24/249), preDM in 40.6% (101/249), normal glucose tolerance (NGT) in 49.8% (124/249). Retinopathy was present in 4% (10/249) overall, 20.8% (5/24) in those with DM, 1.9% (2/101) with preDM, and 2.4% (3/124) with NGT. The NGT cases with retinopathy had hypertension, anemia and/or thrombocytopenia and were excluded from DR analysis. Fasting plasma glucose had the highest correlation with DR (P&lt;0.001), followed by 2h glucose from the OGTT (P=0.001). Higher total abdominal adipose tissue (TAT) was associated with DR (P=0.043). Higher waist circumference and age trended towards significance (P=0.054 and 0.075, resp). However, BP, BMI, years in the U.S., GFR, urine microalbumin:creatinine, CHOL, TG, HDL, LDL, hip circumference, % body fat and refractive error were not correlated. No correlations were found with A1C, fructosamine or glycated albumin. Neither DM nor preDM were associated with atrophy of the various retinal layers evaluated. The overall prevalence of DM and preDM combined was high (50.2%), and DR was present in 21% with DM. Higher FPG and 2-hr OGTT could be predictive of DR, and higher TAT was significantly associated with DR, but atrophy at different retinal layers was not. As the study is on-going, analyses will be repeated with a larger sample.

Disclosure
C.K. Hwang: None. E. Agron: None. M.A. Chen: None. C. DuBose: None. A.E. Sumner: None. E. Chew: None.
573-P: Construction and Validation of a Hierarchical-Driven Network for Decoding the Potential Molecular Mechanisms in Diabetic Microvascular Complications
Authors: LI HAICHENG , FU XIANAN , HE XUEMIN , PENG RONGDONG , NIE YUANPENG , LI TING , CHEN YANMING 
Published: June 2020

Aim: Diabetic microvascular complications, including diabetic nephropathy (DN) and diabetic retinopathy (DR), lead to poor life quality and increased mortality. Accumulating evidence indicates that the complexity of pathophysiology is controlled by hierarchical molecular factors at the epigenetic, transcriptional and post-transcriptional levels. Yet most studies focus on one of the driven factors, it still lacks a systematic classification model that links hierarchical molecular factors to the precise diagnosis of diabetic microangiopathy. This study aimed to construct driven networks that reveal the potential molecular mechanisms for the precise diagnosis of diabetic microangiopathy.
Methods: By combining multi-regulators, transcriptional kinetics, gene expression, DNA-protein binding signals and lncRNA targets, we based on the hierarchical Bayesian Model, DrivenRN, to construct driven networks for detecting the signature of key function genes. Then we tested this model using public datasets, followed by real-time PCR validation of the identified genes’ expression in the peripheral blood mononuclear cells (PBMCs) from patients.
Results: Through DrivenRN analysis, we identified four genes that are specifically involved in driving DN, including TIMP3, CNDP1, MYH9 and ENPP1. We also identified three genes that are specifically involved in driving DR-, including EDN1, CD34 and CYR61. Furthermore, we validated CNDP1, MYH9 and ENPP1 in DN PBMCs, and CD34 in DR PBMCs.
Conclusion: This study has constructed a novel model, DrivenRN, which effectively maps the driven networks for the prediction of potential pathological factors in diabetic microvascular complications.

Disclosure
H. Li: None. X. Fu: None. X. He: None. R. Peng: None. Y. Nie: None. T. Li: None. Y. Chen: None.
577-P: Choroidal Thickness Is Dependent on BMI and Acute Changes in Blood Glucose
Authors: MEYHOEFER SVENJA , WILMS BRITTA , CHAMORRO RODRIGO , PAGELS ANNA-JOSEPHIN , GREIN HANS-JÜRGEN , SCHMID SEBASTIAN M. 
Published: June 2020

Background: Diabetic retinopathy (DR) is a serious complication of diabetes that can lead to blindness. As diagnosis is often made when cell and vision loss are already existing, detecting retinal changes at early stages is crucial. Due to its high vascularization, changes in the choroid play an important role in the pathogenesis of retinal impairment and therefore might be an early diagnostic target.
Aim: The aim of this pilot study was to evaluate BMI- and glucose-dependent changes in choroidal thickness (ChT) of healthy volunteers under standardized conditions.
Methods: 18 healthy volunteers aged 19 to 42 years (mean±SEM: 26.2±1.7 years) with a body mass index (BMI) between 20 to 34 kg/m2 (24.9±0.8 kg/m2) were included. During an intravenous glucose tolerance test (ivGTT), blood glucose profiles were measured by a gold-standard laboratory system. Simultaneously, a second researcher assessed ChT by optical coherence tomography (OCT, company Heidelberg Engineering GmbH). Researchers were blinded to measurements done by the other one.
Results: In general, ChT was positively correlated with BMI (r=0.229; P=0.045). Moreover, the steeper increase of blood glucose up to minute 6 of the ivGTT was significantly associated with greater ChT (r=0.254; P=0.039).
Conclusion: ChT is modulated by BMI and short-term fluctuations in blood glucose in healthy subjects without any history of diabetes. It is tempting to speculate that increased ChT and/or reduced susceptibility to glucose dynamics could be a novel marker for early impairment of posterior eye structures. Ongoing studies evaluate ChT and its glucose-dependent variability in patients with diabetes.

Disclosure
S. Meyhoefer: None. B. Wilms: None. R. Chamorro: None. A. Pagels: None. H. Grein: None. S.M. Schmid: None.

Funding
German Center for Diabetes Research
580-P: Role of Bile Acids in Hepatic Lipid Metabolism: Characterization of the Fasting Lipid and Lipoprotein Profile of Tgr5-/- Hamsters
Authors: ALVARES DANIELLE C.L. , HOFFMAN SIMON S. , ADELI KHOSROW 
Published: June 2020

Introduction: A major complication of insulin resistant states is fasting dyslipidemia, a lipid profile characterized by elevated triglycerides, increased small dense LDL and low HDL-cholesterol. Recently, bile acid signaling has been suggested to improve hepatic insulin sensitivity and lipid accumulation through activation of the Takeda G protein-coupled receptor 5 (TGR5). Using CRISPR/CAS9 gene editing, and in collaboration with the Wang laboratory at Utah State University, we have developed a novel Tgr5-/- hamster model. As the role of TGR5 in regulating hepatic lipid and lipoprotein metabolism has not been explored, the present study was performed to characterize the fasting lipid profile of this model in normal and mild insulin resistant states and further examine bile acid signaling within these hamsters.
Methods/Results: Eight-week-old Tgr5+/+ and Tgr5-/- hamsters were fed a high fat, high fructose and low cholesterol (FFLC) diet for 6 weeks. Glucose tolerance and fasting plasma lipids were examined at baseline, and following 6-weeks of FFLC consumption. Unlike the Tgr5+/+ hamsters, who exhibited impaired glucose tolerance following 6-weeks of FFLC-feeding, Tgr5-/- hamsters did not. This alteration in glucose tolerance was not associated with any significant differences in body weight or food consumption, or hepatic triglyceride or cholesterol between genotypes. Lipoprotein profiling was performed via FPLC analysis. Preliminary results suggest that Tgr5-/- hamsters exhibit reduced VLDL-triglyceride and -cholesterol, and HDL-cholesterol. Finally, chow fed hamsters received intraduodenal injections of deoxycholic acid (DCA), a bile acid with a strong affinity for TGR5. DCA administration was associated with reduced VLDL-triglyceride secretion in Tgr5+/+ hamsters, an effect that was blunted in Tgr5-/- hamsters. The present research will set a framework to expand our knowledge of the role of TGR5 signaling in hepatic lipogenesis.

Disclosure
D.C.L. Alvares: None. S.S. Hoffman: None. K. Adeli: None.

Funding
Heart and Stroke Foundation of Canada
587-P: The Relationship between Metabolic Index, Liver Enzyme Index, and the Incidence of Diabetes: The Jinchang Cohort Study
Authors: HUANG PEIYAO , YANG JINGLI , HUANG WENYA , LIU NIAN , WANG RUONAN , ZHANG RUI , BAI ZHAO , BAI YANA , CHENG NING , WANG MINZHEN , ZHENG SHAN 
Published: June 2020

Objectives: To explore the incidence of diabetes under different indicator and interaction between metabolic index and liver enzyme index for diabetes mellitus.
Methods: This study based on the Jinchang cohort, which is a prospective cohort included 48,001 subjects at baseline. To compare the incidence of diabetes under different metabolic indexes and liver enzyme indexes; Cox proportional hazard model was used to analysis the risk of diabetes with different metabolic indexes and liver enzymes indexes; The multiplicative model was used to analyze the interaction between different metabolic indexes and liver enzymes indexes for diabetes.
Results: With the increase of TC, TG, ALT and AST, the incidence of diabetes gradually increased(p&lt;0.05), with the increase of HDL-C level, the incidence of diabetes gradually decreased(p&lt;0.05).With the increase of TC, TG, LDL-C, ALT, AST and GGT, the risk of diabetes were rising(p&lt;0.05), and the increase of HDL-C reduced the risk of diabetes. In men, the interaction between TC and TG, TC and ALT, TG and ALT, ALT and GGT are positively and multiply; which HR(95%CI) was 6.71 (1.66∼27.04),20.62(9.50∼44.76),10.23(6.42∼16.29) and 6.63(4.38∼10.04), respectively. In women, TC and TG, ALT and GGT are positively and multiply, they also play a synergistic role in the risk of diabetes, and the HR(95%CI) was 6.75(2.12∼21.50) and 15.93(4.95∼51.25), respectively.
Conclusion: TC, TG, LDL-C,ALT, AST and GGT were risk factors for the incidence of diabetes, and HDL-C was a protective factor for the incidence of diabetes. In the male population, the interaction of TC and TG, TC and ALT, TG and ALT, ALT and GGT were all positively multiplied. In the female population, TC and TG, ALT and GGT were positively multiplied by the interaction.

Disclosure
P. Huang: None. J. Yang: None. W. Huang: None. N. Liu: None. R. Wang: None. R. Zhang: None. Z. Bai: None. Y. Bai: None. N. Cheng: None. M. Wang: None. S. Zheng: None.

Funding
National Institutes of Health (1R01ES02908201A1); Lanzhou University (2018LDBRZD008)
591-P: Macrophage IL-1beta–Dependent VEGF-A Expression Is Required for Inflammatory Arteriogenesis and Wound Healing in Type 2 Diabetes
Authors: MANTSOUNGA CHRIS S. 
Published: June 2020

Impaired wound healing in patients with diabetes mellitus (DM) is a major source of morbidity and mortality. Current treatments for diabetic wounds are modestly effective at promoting healing. Recently, we identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/arteriogenesis required for adequate wound healing. We sought to understand the impact of diabetes on inflammatory angiogenesis and consequent healing. We hypothesized that diabetes mellitus (DM) results in reduced inflammatory macrophage VEGF-A expression with consequent impairments in angiogenesis-dependent wound healing. Mice with experimental diabetes demonstrated profound delays both in wound healing using a dermal punch biopsy model and in perfusion recovery using the femoral artery ligation model of hind limb ischemia. VEGF-A expression is highly upregulated in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing macrophages. This is supported by a strong association between IL-1β and VEGF-A expression. In order to understand whether this relationship between IL-1β and VEGF-A was causal, we generated a novel mouse with a LoxP flanked IL-1β allele to create an inducible macrophage deletion of IL-1β. Myeloid IL-β deletion resulted in severely impaired macrophage VEGF-A expression and consequent decreases in angiogenesis and wound healing, consistent with the experimental model of DM. Moreover, macrophages from diabetic mice demonstrated reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A expression. Defining inflammatory macrophages as key, early drivers of angiogenesis supports a paradigm shift away from inflammation-suppression for adequate wound healing, allowing for macrophage reprograming strategies that promote appropriate inflammation-dependent healing responses.

Disclosure
C.S. Mantsounga: None.

Funding
National Institutes Health (1R01HL139795)
599-P: Magnetic Field vs. Calcium Channel Blockade Effect on Microcirculation: Potential Implementation in Diabetic Foot Microvascular Dysfunction
Authors: GMITROV JURAJ 
Published: June 2020

The goal was to compare static magnetic field (SMF) vasodilator capacity with verapamil (VER) a potent Ca2+ channel blocking agent infusion, aimed to asses SMF potential implementation in conditions with vascular ischemia. Mean femoral artery blood pressure, heart rate and ear lobe skin microcirculatory blood flow measured by microphotoelectric plethysmogram (MPPG) were simultaneously recorded in conscious rabbits after 40-min carotid baroreceptor exposure to 0.35 T SMF (SMF-Car, n = 14) or 0.25 T SMF, generated by Nd-Fe-B magnets, exposed directly to ear microvascular net (SMF-Ves, n = 20), Fig. 1a, and compared with that after 30 min VER i.v. infusion (20 mg kg-1 min-1, n = 20), Fig. 1b. The principal finding is that SMF-Car, SMF-Ves and VER significantly increased microcirculation by: 22.6 ± 11.11%, 17.9 ± 9.58% and 30.5 ± 14.06% (mean ± SEM) resp. and that was no significant difference between all of three treatments (p = 0.986). Microvascular dilation was accompanied by significant decrease of baroreflex sensitivity in VER and its increase in SMF-Car coupled with enhanced vessel sensitivity to nitric oxide dilatory effect. This suggests SMF strong, comparable with VER vasodilator property tailored to address neural and myogenic component of microvascular dysfunction in diabetic foot and nephropathy especially employing both SMFs vasodilation synergy.

Disclosure
J. Gmitrov: None.