bluuebunny/crossref_metadata_2025_split huggingface dataset:
560-P: Thermal Indicators of Previously Undiagnosed Diabetic Peripheral Neuropathy
Authors: BURGE MARK R. , CALDER CHRISTOPHER STEWART , WIGDAHL JEFFREY , JOSHI VINAYAK , GUO XIAOSHAN , CARMICHAEL JUSTIN C. , SOLIZ PETER 
Published: June 2019

Purpose: Neurological clinical exams, quantitative sensory tests (QST), and nerve conduction studies (NCS) have been reported to have low accuracy in diagnosing diabetic peripheral neuropathy (DPN). This study explores the use of infrared (thermal) video imaging to detect small and large fiber DPN.
Methods: 48 subjects with and 148 subjects without DPN were studied and compared to age-matched control subjects (n=84). All subjects’ feet were examined for sores, deformities, and other signs of disease, and patients with recent foot surgeries were excluded. Monofilament and vibration threshold testing ware performed on all subjects. Thermal videos were collected for all subjects, and NCS exams were performed on a subset of subjects. Thermal imaging followed a standard procedure: Imaging pre- and post-cooling to 2°C. A thermal classification model using thermal features extracted from the videos was developed with NCS as the reference standard to assess the performance of thermoregulation models.
Results: Monofilament and vibration test results were compared with clinical diagnoses and had sensitivities of 52% and 57%, respectively. Sensitivity and specificity increase to 74% and 85% when the two tests were combined in an “either/or” decision. NCS was performed on 39 subjects: 11 control subjects, 12 subjects with clinical DPN, and 16 subjects with DM but without DPN. QST demonstrated a best sensitivity of 59% for the vibration test and a best individual specificity of 100% for the monofilament test when compared to NCS. When combined, QST demonstrated best overall sensitivity and specificity of 63% and 87%. The thermal model returned a sensitivity/specificity of 82%/94% and 91%/75% for different cut-points.
Conclusions: Thermal recovery modeling from a cold stimulus yielded superior agreement with clinical and NCS diagnoses as compared to QST in the detection of DPN. A thermal imaging device can be made that is feasible for use in clinics at a lower cost than NCS devices.

Disclosure
M.R. Burge: None. C.S. Calder: None. J. Wigdahl: None. V. Joshi: None. X. Guo: None. J.C. Carmichael: None. P. Soliz: Stock/Shareholder; Self; VisionQuest Biomedical LLC.

Funding
National Institutes of Health
561-P: Serum C-Peptide Concentrations Are Inversely Associated with Cardiovascular Autonomic Neuropathy in Type 2 Diabetic Individuals With and Without Renal Impairment Independently of Estimated Glomerular Filtration Rate
Authors: CHUNG JIN OOK , PARK SEON-YOUNG , CHO DONG HYEOK , CHUNG DONG JIN , CHUNG MIN YOUNG 
Published: June 2019

Cardiovascular autonomic neuropathy (CAN) is a significant cause of cardiovascular morbidity and mortality in patients with type 2 DM. C-peptide is suggested as a bioactive peptide with protective roles on microangiopathy. However, due to renal metabolism of C-peptide, previous studies have been limited to diabetic patients without renal impairment. Serum C-peptide levels might be increased despite reduced beta cell function in patients with renal impairment. Therefore, we tested the hypothesis that C peptide would relate to the risk of CAN in patients with type 2 DM independently of renal function. A total of 1070 type 2 diabetic patients were investigated in this cross-sectional study. Prior dialysis or renal transplantation was excluded. CAN was diagnosed by a cardiovascular reflex test. Fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide levels were measured. The estimated glomerular filtration rate (eGFR) was calculated from CKD-EPI equation. In individuals with and without renal impairment, patients with CAN showed lower levels of fasting C-peptide, postprandial C-peptide and ΔC-peptide. In multivariate analysis, serum C-peptide levels were significantly associated with CAN (OR, 0.80; 95% CI, 0.67-0.96 for fasting C-peptide, p=0.014; OR, 0.78; 95% CI, 0.64-0.95 for postprandial C-peptide, p=0.013; OR, 0.80; 95% CI, 0.66-0.97 for ΔC-peptide, p=0.023) after adjustment for age, gender and other confounders including eGFR. Our results show that serum C-peptide levels are inversely associated with CAN in type 2 diabetic patients with and without renal impairment independently of eGFR. These findings might suggest the beneficial effects of serum C-peptide levels on CAN independently of eGFR.

Disclosure
J. Chung: None. S. Park: None. D. Cho: None. D. Chung: None. M. Chung: None.
562-P: The Effect of Vitamin D Supplementation on the Cytokines Levels in Patients with Type 2 Diabetes Mellitus and Diabetic Neuropathy
Authors: STEPANOVA ANNA P. , KARONOVA TATYANA L. , GALAGOUDZA MICHAEL , VASILEVA ELENA YU , JUDE EDWARD B. 
Published: June 2019

Background: Inflammation plays an important role in the pathogenesis of diabetic neuropathy (DN) in patients with type 2 diabetes (DM2). It seems that vitamin D ((VitD) could be involved in this process, however, the relationship between VitD status and inflammatory markers has not been wildly studied.
Hypothesis: The aim was to study the association between VitD status and inflammatory markers in patients with DM2 and DN.
Methods: The single-centre randomized study included 62 subjects with DM2 and DN (more than 4 points according to NDS), HbA1c up to 9%. Antihyperglycemic treatment was stable during the study. Patients were randomized in two groups: 5000 IU (group I) and 40000 IU (group II) of cholecalciferol supplementation per week. Body mass index (BMI), glycated hemoglobin (HbA1c), serum 25(OH)D level, Interleukins 6, 10 (IL-6, IL-10) were determined at baseline and after 24 weeks of treatment. The correlation analysis was evaluated by Pearson test.
Results: Group I (n = 31, F16) and Group II (n = 31, F15) were matched for age, gender, BMI and baseline HbA1c levels. VitD insufficient/deficiency was revealed in 78% of diabetic patients with DN. After 6 months of VitD supplementation, the BMI, HbA1c and IL-6 levels significantly decreased, and 25(OH)D and IL-10 concentration increased only in Group II. We found associations between serum 25(OH)D and IL-6 (r = -0.912, p = 0.017) as well as IL-10 (r = 0.903, p = 0.014), and between HbA1c and IL-6 (r = 0.825, p = 0.031) and IL-10 (r = -0.897, p = 0.025) exclusively in Group II after treatment.
Conclusions: VitD supplementation in 40000 IU of cholecalciferol per week during 6 months was associated with improved vitamin D status, pro-inflammatory markers and better glycemic control in patients with DM2 and DN. Vitamin D supplementation in 5000 IU per week did not change vitamin D status and inflammatory markers in this population.

Disclosure
A.P. Stepanova: None. T.L. Karonova: None. M. Galagoudza: None. E.Y. Vasileva: None. E.B. Jude: None.
565-P: Serum 25-Hydroxy Vitamin D Levels in Relation to Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes
Authors: ZHANG LEI , GU YAN , YANG YUXIU , ZHU YAMEI , YIN XIAOYAN , DONG YANHU 
Published: June 2019

Vitamin D deficiency is not only related to bone-related diseases but also associated with cardiovascular disease, diabetes, cancer and autoimmune diseases. Previous studies show that vitamin D deficiency increases risk of diabetic peripheral neuropathy (DPN). Data is limited among Chinese patients with type 2 diabetes. In this cross-sectional study, we enrolled 5362 patients (2359 men and 3003 women aged 30 to 89 years) with type 2 diabetes from Jan 1, 2016 to Oct 31, 2018. Serum 25-hydroxyvitamin D (25(OH)D) level was measured by electrochemiluminescence assay. Vitamin D deficiency was defined as Serum 25(OH)D level &lt; 20 ng/mL according to the Endocrine Society Clinical Practice Guideline 2011. Diabetic peripheral neuropathy was diagnosed by motor/sensory nerve conduction velocity. Patients with diabetic peripheral neuropathy had lower serum 25(OH)D concentration (16.81±3.83 ng/mL vs. 18.05±4.11 ng/mL, P&lt;0.05) compared with those without neuropathy. The prevalence of vitamin D deficiency was higher in patient with neuropathy than those without the complication (83.2% vs. 71.4%, P&lt;0.05). We did not find gender difference on the prevalence of vitamin D deficiency. In the logistical regression model, Vitamin D deficiency was associated with increased risk of diabetic neuropathy, after adjustment of age, gender, duration of diabetes, smoking, body mass index, systolic blood pressure, fasting glucose, HbA1c, fasting C-peptide, total cholesterol, and microalbuminuria, the corresponding odds ratio was 1.76 (95% CI 1.05-3.37) (P&lt;0.05). Vitamin D deficiency, a common hypovitaminosis in Chinese patients with type 2 diabetes, is independently associated with increased risk for diabetic peripheral neuropathy. Whether vitamin D supplementation improves diabetic peripheral neuropathy deserves further study.

Disclosure
L. Zhang: None. Y. Gu: None. Y. Yang: None. Y. Zhu: None. X. Yin: None. Y. Dong: None.
576-P: Prevalence of Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes Mellitus Patients
Authors: KOTHIWALE VEERAPPA , CHAFEKAR NAHUSH D. , BABALICHE PRAKASH , CHOUGULE NIKHIL A. 
Published: June 2019

Background and Objectives: Metformin is a cornerstone in the treatment of type 2 DM (type 2 diabetes mellitus) and is used as 1st line therapy. Studies showed that an average of 10-30% of patients on metformin for longer duration and at higher dosage had Vit. B12 deficiency. Sr.(Serum) Vit. B12 levels were studied and correlated with presence of peripheral neuropathy in type 2 DM patients on long term Metformin, attending OPD of our hospital.
Methods: 100 consecutive type 2 DM patients on Metformin for &gt;3 years, aged &gt;18 years attending OPD of the Dept. of Medicine from 1st January - 31st December 2017, were included in our study after the informed consent. Estimation of Sr. Vit. B12 levels was done and correlated with monofilament testing in all the study participants and metformin doses of 1 gm/day and &gt;1 gm/day were classified.
Results: In our study, 35% of Diabetic patients on Metformin had Vit. B12 deficiency with mean 168.2 ± 17.9 pg/ml which also correlated with the abnormalities in the monofilament testing, graded on a scale of 1-10, 1 being severe peripheral neuropathy and 10 being normal. The mean monofilament score was found to be 6 out of 10. The remaining 65% had a mean Vit. B12 level of 502.3 ± 16.8 and a mean monofilament score of 8 out of 10. Total mean Vit. B12 level was found to be 619.2. By applying Chi square test as test of significance, odds of positive outcome for monofilament test in Vit. B12 deficient person is 25.5 and p value is significant (P&lt;0.001). Degree of dosage of metformin did not have any significant correlation with Sr. Vit. B12 levels and monofilament score. We also found evidence of Megaloblastic anemia in study participants, with 29% of patients having high MCV with a mean of 98.4 ± 2.1 fl, and dimorphic (23%) and macrocytic (6%) picture on peripheral smear. The mean Hb range was 11.1 to 14.0 g/dL.
Conclusion: There is higher prevalence of Vit. B12 deficiency and linear correlation with peripheral neuropathy with long term Metformin use in type 2 DM patients which needs to be diagnosed and treated.

Disclosure
V. Kothiwale: None. N.D. Chafekar: None. P. Babaliche: None. N.A. Chougule: None.
578-P: Evaluation of Autonomic Function and Its Relation to Glucose Variability, Insulin Resistance, and Oxidative Stress in Prediabetes
Authors: DIMOVA RUMYANA , CHAKAROVA NEVENA , KIRILOV GEORGI , GROZEVA GRETA , TANKOVA TSVETALINA 
Published: June 2019

Aim: The present study assesses the relation between cardiovascular autonomic function and some indexes of glycose variability, insulin resistance and oxidative stress in prediabetes.
Material and Methods: A total of 50 subjects - 12 males, mean age 55.6±9.7 years, mean BMI 28.4±6.4 kg/m2, divided into 2 groups according to glucose tolerance: 32 subjects with prediabetes and 18 subjects with normal glucose tolerance (NG) were included. Glucose tolerance was assessed by OGTT in accordance with WHO 2006 criteria. Plasma glucose was measured by hexokinase method and immunoreactive insulin - by immuno-chemiluminescence method at fasting, 120-minute and 180-minute during the test; and also oxLDL and 5-Nitrotyrosine - by ELISA method at fasting and 120-minute during the test. Indirect indexes of insulin resistance - HOMA-IR and insulin sensitivity - OGIS were calculated. HbA1c was assessed by immuno-turbidimetric, NGSP certified method. Continuous glucose monitoring was performed with blind sensor for professional use - FreeStyle Libre Pro - for a mean period of 13.6 ± 2.3 days.
Results: There was a significantly decreased parasympathetic tone during deep breathing test (p=0.009) and sympathetic tone at rest (p=0.021) and during Valsalva maneuver test (p=0.026) in prediabetes. Sympathetic activity was related to the standard deviation of glycemic excursions in prediabetes (F [1,31]=7.91, p=0.018); whilst parasympathetic activity was related to J-index and % time spent in glycemic range &gt;7.8 mmol/l in prediabetes (F [1,31]=7.20, p=0.004) and with CONGA index in NGT (F [1,18]=6.75, p=0.025). No significant correlation between autonomic tone and the assessed markers of insulin resistance and oxidative stress was established.
Conclusions: The autonomic tone has been found to be declined in prediabetes. Glucose variability is probably an additional risk factor for autonomic dysfunction at these early stages of glucose intolerance.

Disclosure
R. Dimova: None. N. Chakarova: None. G. Kirilov: None. G. Grozeva: None. T. Tankova: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Novo Nordisk A/S, Servier.
579-P: Prevalence of and Risk Factors for Peripheral Neuropathy in Chinese Patients with Diabetes: A Multicenter Cross-Sectional Study
Authors: PAN QI 
Published: June 2019

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, and its progression significantly worsens the patient’s quality of life. This study investigated the prevalence and risk factors associated with DPN in a large sample of Beijing individuals with type 1 and 2 diabetes, as well as compared the diagnostic methods for DPN. A total of 2,048 diabetic patients from 13 centers in Beijing were assessed for DPN through questionnaires and examination. Patients were divided into DPN group and suspected DPN/non-DPN group. The demographic, clinical and biological characteristics between the two groups were compared. Binary logistic regression analysis was performed to identify potential variables associated with DPN in diabetic patients. The diagnostic methods for DPN were also compared. Among the 2,048 diabetic patients, 73 cases of type 1 diabetes mellitus, 1,975 cases of type 2 diabetes were included in this study. Among them, 714 (34.86%) were identified with DPN, 537 (26.22%) were suspected of having DPN, and 797 (38.92%) were identified without DPN. Patient’s age, duration of diabetes, and diabetic retinopathy were the significant independent risk factor for DPN among patients with type 2 diabetes. The odds ratio (OR) was 1.439 (95% confidence interval (CI): 1.282-1.616, P &lt; 0.001), 1.297 (95% CI: 1.151-1.462, P &lt; 0.001), and 0.637 (95% CI: 0.506-0.802, P &lt; 0.001), respectively. Ankle reflex, temperature sensation plus vibration sensation are the best screening test for patients with type 1 and 2 diabetes. The Youden indexes were 62.2 and 69.8%, respectively. The prevalence rates of DPN in the Chinese patients with type 1 and type 2 diabetes in Beijing were 21.92 and 35.34%, respectively. Patient’s age, duration of diabetes, and diabetic retinopathy are the independent risk factors for DPN.

Disclosure
Q. Pan: None.
58-OR: The Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide Transiently Delays Gastric Emptying Similarly to a Selective Long-Acting GLP-1 Receptor Agonist
Authors: URVA SHWETA , NAUCK MICHAEL A. , COSKUN TAMER , CUI XUEWEI , HAUPT AXEL , BENSON CHARLES , LOGHIN CORINA 
Published: June 2019

A long-acting GLP-1 receptor agonist (RA) transiently delays gastric emptying (GE). We investigated the GE effect of a novel dual GIP and GLP-1 RA, tirzepatide (TZP), compared to that of a selective GLP-1 RA in nonclinical and clinical studies. No effect on GE was seen with GIP RA alone in mice. Combination of GIP RA with GLP-1 RA or a dual agonist, TZP, did not delay GE more than GLP-1 RA alone. The effect of TZP on GE was evaluated in a Phase 1 study, comprising 4 week multiple ascending dose (MAD; N=35) QW in healthy subjects and 4-week proof of concept (PoC) (N=53) in patients with T2DM. In MAD, TZP was administered QW at fixed doses of 0.5, 1.5, 4.5 mg, and a titration dose of 5-5-8-10 mg. A selective GLP-1 RA, dulaglutide (dula), 1.5 mg QW was also included. In PoC, TZP was administered QW at fixed doses of 0.5 mg and 5 mg, and at titration doses of 5-5-10-10 mg and 5-5-10-15 mg. Acetaminophen (APAP) was administered on Day -1 (prior to TZP or dula), at 24 hours after the first (Day 2) and fourth (Day 23) doses to coincide with peak TZP or dula exposure. Impact of TZP on GE was evaluated using APAP Cmax, AUC, and tmax, compared to placebo (PL). Baseline adjusted Cmax of APAP (ratio to Day -1) was used to compare the GE effect of TZP with that of dula. APAP Cmax decreased by approximately 50% and tmax was delayed by an hour after the first TZP dose (doses &gt;1.5 mg), suggesting a delay in GE while AUC was not notably altered. Evaluation of APAP PK after the first and fourth doses of the fixed dose regimen of TZP showed that impact of TZP on GE was maximized after first dose (Day 2 vs. PL), and showed complete tachyphylaxis after repeated dosing (Day 23 vs. PL). Similarly, in the titration cohort, impact of TZP on GE was significant after the first dose. However, incomplete tachyphylaxis was observed after 4 weeks of TZP administration due to the titration regimen. Impact of the fixed doses of TZP on GE was comparable to that of a selective GLP 1 RA (dula).

Disclosure
S. Urva: None. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. T. Coskun: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.
593-P: Diabetes Enhances Translation of the mRNA Encoding CD40 in Müller Glia to Promote Retinal Inflammation
Authors: DIERSCHKE SADIE K. , TORO ALLYSON , MILLER WILLIAM P. , DENNIS MICHAEL D. 
Published: June 2019

This study investigated the hypothesis that diabetes-induced hyperglycemia promotes retinal inflammation by augmenting translation of the immune costimulatory molecule CD40. In response to diabetes, Müller glia initiate retinal inflammation via activation of CD40. CD40 activation in Müller glia leads to ATP release, stimulation of P2X7 purinergic receptors on microglia/macrophages, and their subsequent release of inflammatory cytokines. Increased CD40 expression is a common feature of inflammatory diseases driven by CD40. Indeed, CD40 protein expression is elevated in Müller glia of diabetic mice, yet the mechanisms responsible for this increase have not been fully explored. In microglia/macrophages, inflammatory cytokines enhance CD40 gene transcription via cis-elements in the CD40 promoter. However, cytokine-mediated CD40 transcriptional upregulation is not sufficient to explain a model wherein retinal inflammation is initiated by CD40 expression in Müller glia. A recent genome-wide functional screening revealed that the untranslated region of the mRNA encoding CD40 was capable of promoting translation independent of the mRNA m7GTP cap. Our laboratory has previously demonstrated that diabetes-induced hyperglycemia promotes O-GlcNAcylation of the translational repressor 4E-BP1, leading to enhanced cap-independent mRNA translation. In the present study, in vivo translation of the CD40 mRNA was enhanced in Müller glia of STZ-diabetic RiboTag mice concomitant with increased protein O-GlcNAcylation. Enhanced O-GlcNAcylation was sufficient to promote CD40 mRNA translation in both retina and cells in culture, and O-GlcNAcylation-induced CD40 mRNA translation was ablated by 4E-BP deletion. In the retina of diabetic 4E-BP-deficient mice, CD40 translation and retinal pathology were normalized. Thus, therapeutic approaches targeting diabetes-induced defects in mRNA translation may be beneficial for preventing diabetic retinopathy progression.

Disclosure
S.K. Dierschke: None. A. Toro: None. W.P. Miller: None. M.D. Dennis: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.)
598-P: Lower Hematocrit Is Predictive of Treatment-Required Eye Diseases in Japanese Patients with Diabetes Mellitus
Authors: YAMAMOTO MASAHIKO , FUJIHARA KAZUYA , OSAWA TAEKO , HARADA MAYUKO , ISHIZAWA MASAHIRO , SUZUKI HIROSHI , ISHIGURO HAJIME , SEIDA HIROYASU , YAMANAKA NAUTA , MATSUBAYASHI YASUHIRO , SONE HIROHITO 
Published: June 2019

Hematological markers such as hematocrit (Hct), hemoglobin (Hb) or red blood cell (RBC) count were reported to be associated with the development of diabetic retinopathy with conflicting results. Moreover, which of these markers is the best to predict incident retinopathy remains unknown. To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that included 7,182 participants (1,490 women, mean age 50.8 y, HbA1c 6.9%, mean follow-up period 5.5y) classified as having diabetes mellitus or vision-threatening treatment-required diabetic eye diseases (TRDED). Multivariate Cox regression model was used to identify predictors of TRDED. During the study period, 177 patients developed TRDED (4.5/1000 person-years). Cox analysis demonstrated that the lower Hcts were significant predictors TRDED and lower Hcts were more predictive than lower RBC counts. The Hb level was not significantly associated with TRDED. Hazard ratios (HRs) per 1 standard deviation (SD) increase in Hct, RBC count and Hb for incident TRDED were 0.792 (95% confidence interval [CI], 0.666-0.942), 0.874(0.765-0.998), and 0.861 (0.725-1.023) as continuous variables, respectively. The interaction between Hct and RBC count was not statistically significant. Multivariate tertile analysis also revealed that a lower Hct was more predictive of TRDED (HR 2.03 [95% CI, 1.33-3.08] for the bottom [≤43.4%] vs. the top [≥46.7%] tertile [P value = 0.001]) than lower RBC counts (HR 1.54 [95% CI, 0.99-2.38] for the bottom [≤468×104/m3] vs. the top [≥507×104/m3] [P value = 0.054]). These findings demonstrated that lower Hcts were significant predictor of vision-threatening retinopathy for people with diabetes and more useful than the RBC count or Hb. Association of the influence of these three markers on severe retinopathy awaits further investigation.

Disclosure
M. Yamamoto: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Ishizawa: None. H. Suzuki: None. H. Ishiguro: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.