bluuebunny/crossref_metadata_2025_split huggingface dataset:
Palmitoylethanolamide in Add-On to Alpha Lipoic Acid for Control of Symptoms of Diabetic Peripheral Neuropathy
Authors: MADDALONI ERNESTO , MAURIZI ANNA RITA , MINUTOLO ALESSANDRA , FIORITI ELVIRA , TORO ROSSELLA DEL , NACIU ANDA MIHAELA , PIERALICE SILVIA , ROSATI MILENA M. , MANFRINI SILVIA , POZZILLI PAOLO 
Published: June 2018

Background: Palmitoylethanolamide (PEA) is an amide with “autacoid local inflammation antagonism” effects, protecting nerve degeneration due to mast cell degranulation. PEA add-on to alpha-lipoic acid (ALA) is successfully used as treatment of neuropathic pain, but there are no data in diabetic peripheral neuropathy (DPN) specifically.
Aim: To evaluate whether PEA in add-on to ALA has potentials in controlling DPN symptoms.
Methods: In this pilot longitudinal observational study, clinical and biochemical data from ninety-eight consecutive subjects with type 1 diabetes (T1D) evaluated for DPN symptoms between January and July 2017 in our outpatient clinic were retrospectively retrieved. DPN symptoms were assessed by Neuropathy Symptoms Score (NSS). Follow-up data were retrieved for patients with NSS ≥3 and receiving treatment with ALA 600mg/daily ± PEA 600mg/daily or receiving no treatment.
Results: NSS was ≥3 in 34 (34.7%) subjects. Of these, 17 were treated with ALA ± PEA (9 with ALA in monotherapy and 8 with PEA in add-on to ALA), and 17 were not treated. After a mean follow-up of 8.1±3.4 months, NSS was ≥3 in 76.5% of non-treated subjects vs. 29.4% of treated subjects (p&lt;0.01). The percentage of subjects with NSS≥3 did not differ between subjects treated with ALA vs. those treated with ALA+PEA (p=0.62). The mean time for symptoms resolution (NSS&lt;3) was lower in subject treated with ALA+PEA than in those treated with ALA in monotherapy (14.0±8.6 vs. 25.0±9.1 days, p&lt;0.05). Among treated subjects, baseline HDL-cholesterol was inversely related to the time to symptoms resolution (p=0.026)
Conclusions: PEA add-on to ALA accelerates the resolution of neuropathic symptoms in T1D subjects with DPN. This study also suggests HDL-cholesterol may be a biomarker for the response to treatment with ALA ± PEA.

Disclosure
E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; European Foundation for the Study of Diabetes. A. Maurizi: None. A. Minutolo: None. E. Fioriti: None. R. Del Toro: None. A. Naciu: None. S. Pieralice: None. M.M. Rosati: None. S. Manfrini: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp..
Amelioration of Peripheral Neuropathy in Mouse Models of Diabetes by Dietary Reversal
Authors: O'BRIEN PHILLIPE D. , GUO KAI , HINDER LUCY M. , HAYES JOHN M. , MENDELSON FAYE , TABBEY MAEGAN A. , HUR JUNGUK , FELDMAN EVA L. 
Published: June 2018

Peripheral neuropathy (PN) is a common complication of prediabetes and type 2 diabetes (T2D). Lifestyle changes, including dietary reversal (DR), can reverse PN, although the mechanisms involved remain unclear. The goal of this study was to identify the mechanisms that underlie PN development in prediabetes and T2D and understand which of these are corrected upon DR. To achieve this, we used two models of PN and looked at the effects of DR on global gene expression and lipid profiles in peripheral nerves.
C57BL/6J mice were fed a standard diet (10% kcal fat; SD) or high fat diet (60% kcal fat; HF) from 5 week. A subset of HF mice were injected with STZ at 12 week to induce hyperglycemia, reflecting a more diabetic-like phenotype. At 16 week, subsets of HF and HF-STZ mice were placed on the standard diet for 8 week (HF-DR and HF-STZ-DR, respectively) until 24 week when terminal phenotyping was performed. At baseline and at study completion, sciatic nerve tissue was processed for gene expression by RNAseq or for lipid species profiling by untargeted shotgun lipidomics.
HF and HF-STZ mice display PN compared to controls. In contrast, peripheral nerve function of HF-DR and HF-STZ-DR mice was corrected upon DR. Neural gene expression analysis revealed numerous differentially expressed genes (DEG) when comparing SD to HF or HF-STZ mice. Interestingly, a proportion of the genes dysregulated in HF and HF-STZ, were similarly reversed by DR. KEGG enrichment of these genes revealed that lipid metabolism pathways were enriched. Lipidomic analysis revealed a similar pattern of differentially altered lipids that were reversed by DR in HF and HF-STZ mouse models. Lipids reversed by DR include diacylglycerol, a known mediator of insulin resistance.
We demonstrate that DR of HF and HF-STZ mice can restore peripheral nerve function. We also show that genes related to lipid function are dysregulated in diseased states and are reversed by DR. This study supports the idea that DR improves peripheral nerve function by restoring lipid homeostasis.

Disclosure
P.D. O'Brien: None. K. Guo: None. L.M. Hinder: None. J.M. Hayes: None. F. Mendelson: None. M.A. Tabbey: None. J. Hur: None. E.L. Feldman: None.
The Association between Urinary N-Acetyl-ß-D-Glucosaminidase and Cardiovascular Autonomic Neuropathy in Patients with Diabetes
Authors: CHOI MIN SUN , JUN JI EUN , KIM GYURI , JIN SANG-MAN , HUR KYU YEON , LEE MOON-KYU , KIM JAE HYEON 
Published: June 2018

Background: Cardiovascular autonomic neuropathy (CAN) is a microvascular complication of diabetes, which involves autonomic nerve fibers innervating the heart and vessels, resulting in increased cardiovascular morbidity and mortality. Previous studies reported that diabetic CAN is related to microalbuminuria. However, it is unclear whether CAN is related with urinary N-acetyl-β-D-glucosaminidase (uNAG), which was suggested as an early marker of renal tubular injury in diabetic nephropathy recently.
Methods: Cross-sectional data of 1052 patients with diabetes were analyzed who had tests for uNAG and autonomic function test at outpatient clinic. The presence and severity of CAN were assessed by the five autonomic function tests.
Results: The association between uNAG and the presence of CAN in patients with type 1 diabetes (T1D) (n=161) was significant in multivariate analysis (OR 1.20, 95% CI 1.03-39; p = 0.018) after correction of variables including age, duration of diabetes, glycemic index and albuminuria, but it was insignificant in patients with type 2 diabetes (T2D) (n=891). Among quartile groups divided by uNAG levels, prevalence of CAN was significantly increased across with higher quartiles of uNAG level only in patients with T1D (p = 0.013). The association between uNAG and the total CAN score, assessed as the severity of CAN, was significant in both patients with T1D (p = 0.033) and T2D (p = 0.006) in multivariate analyses.
Conclusion: Elevated uNAG is associated with the prevalence of CAN only in patients with T1D, and it is also related to the severity of CAN in both patients with T1D and T2D. It suggests that elevated uNAG might be a potential marker for the development and progression of CAN in patients with diabetes.

Disclosure
M. Choi: None. J. Jun: None. G. Kim: None. S. Jin: None. K. Hur: None. M. Lee: None. J. Kim: None.
Analysis of Different Methods for the Diagnosis of Subclinical and Clinical Stages Polyneuropathy in Patients with Type 2 Diabetes Mellitus
Authors: FOKINA ANASTASIIA , ZILOV ALEXEY , STROKOV IGOR , SURNINA ZOYA 
Published: June 2018

Many patients with T2DM have a late complication at the time of diagnosis,most commonly diabetic peripheral neuropathy (DPN).We explored whether clinical indiced of polyneuropathy correlate with large and small nerve fiber pathology.
The goal of this study is to analyzed various diagnostic techniques for the detection of lesions of nerve fibers in patients with T2DM and subclinical and clinical stages of DNP by electrophysiology study and nerve conduction velocity (NCV),skin biopsy and corneal confocal microscopy (CCM) with use of the author's algorithm for calculating the tortuosity and orientation of the nerve fibers of the cornea.
Materials and methods: Electrophysiological study of large nerve fibers and microscopic examination of small nerve fibers in patients with T2DM with subclinical (n=50) and clinical stages of DPN (n=50) were performed.
Results: The changes in the S-response and in NCV were received the most frequently in patients with subclinical and clinical stages of DPN in the study of the sensory gastrocnemius nerve.At stimulation of the motor nerves,the changes were related to the M-response and NCV of the peroneal and tibial nerves.At skin biopsy,we saw that the intraepidermal nerve fibers density (IENFD) in patients with T2DM was significantly reduced in subclinical and clinical stages of DPN.In the subclinical form of DPN,some values of CCM significant correlate with IENFD and with NCV along the gastrocnemius nerve in the entire studied population,but this correlation was not strong.At symptomatic DPN,a strong correlation was found between IENFD and parameters of NCV (p&lt;0.05),as well as with data of electroneyromyograpry (p&lt;0.05).
Conclusion: The results of the study showed that the changes in large fiber function accompany the loss of small nerve fibers and occurs in patients with T2DM already in the preclinical stage of DPN. CCM can be a powerful tool for non-invasive early diagnosis of neuropathy in subclinical stage DPN.

Disclosure
A. Fokina: None. A. Zilov: None. I. Strokov: None. Z. Surnina: None.
The Reference Distribution of Annual Change in Corneal Nerve Fibre Length in Diabetes Mellitus
Authors: LEWIS EVAN J.H. , TAVAKOLI MITRA , LOVBLOM LEIF ERIK , HALPERN ELISE M. , JEZIORSKA MARIA , PACAUD DANIÈLE , PRITCHARD NICOLA , SHTEIN RONI M. , EFRON NATHAN , BRIL VERA , MALIK RAYAZ A. , PERKINS BRUCE A. 
Published: June 2018

The measurement of corneal nerve fibre length (CNFL) by in vivo corneal confocal microscopy is a biomarker for the presence of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, its prevalence in T1D and T2D, and its clinical predictors. We examined longitudinal data from 94 nondiabetic controls and 297 diabetes participants (224 T1D and 73 T2D) from an ongoing multi-centre NIH-funded study of IVCCM in diabetes. Participants were included if they had at least 1-year of follow-up data and were classified as progressors with “rapid corneal nerve fibre loss” (RCNFL) if the loss of CNFL was beyond the 5th percentile (-14%/y) of the nondiabetic controls. Nondiabetic controls were 43.0±15.8 y, had a median of 2 follow-up visits over a median of 2 y, baseline CNFL of 15.4±4.2 mm/mm2, and the median annual change in CNFL was -1.7%[90% CI, -14.3 to 30.9%]. Diabetes participants were 49.6±15.5 y, had a median of 3 visits over a median of 2 y, baseline CNFL of 14.3±4.4 mm/mm2 and the median annual change in CNFL was 1.8%[90% CI, -26.1 to 25.0%]. There were 33(11.1%) cases of RCNFL in the diabetes sub-cohort, which was comparable between T1D (26(11.6%)) and T2D (7(9.6%)). Progressors did not differ from non-progressors for baseline levels of age, sex, BMI, HbA1c or CNFL levels. However, progressors were more likely to have baseline DSP (16(50%) vs. 83(32%), p=0.048), lower cooling detection threshold (21.3 C±8.5 vs. 25.3 C±7.2, p=0.048) and lower heart rate variability (26.3±13.1 vs. 38.2±25.4, p=0.036). A more rapid loss of CNFL (RCNFL) exceeding 14%/y occurs in ∼11% of diabetes patients. This more rapid of corneal nerves may identify patients at highest risk for the development or progression of DSP.

Disclosure
E.J.H. Lewis: Employee; Self; Nutarniq Corp. M. Tavakoli: None. L. Lovblom: None. E.M. Halpern: None. M. Jeziorska: None. D. Pacaud: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Versartis, Inc. N. Pritchard: Other Relationship; Self; JDRF, NHMRC. R.M. Shtein: None. N. Efron: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc.. R.A. Malik: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc..
Dapagliflozin Doesn't Increase Dietary Intake in Japanese
Authors: KITAOKA MASAFUMI , FUJII HITOMI , IMAI KENTA , ECHIDA YOSHIHISA , KANNO KAZUO , MIYAKAWA TAKAICHI , SHIGETA MASAYUKI 
Published: June 2018

Purpose: We randomly allocate to dapagliflozin (DAPA) administered group (group A) and the group continuing current treatment (group B) for type 2 diabetic patients with stable glycemic control and investigate whether changes in eating behavior are observed or not.
Method: group A orally administer 5 mg of DAPA once daily for 12 weeks in addition to current diet therapy · exercise therapy and diabetes drugs. In the group B, the current diet therapy/exercise therapy and diabetes drugs are continued for 12 weeks. Blood test and urinalysis were conducted 0 weeks, 4 weeks, 12 weeks after. The main endpoint was the comparison between the two groups of total calorie intake change using brief-type self-administered diet history questionnaire (BDHQ) at 12 weeks. And the secondary endpoints were comparison between two groups of the following items before and after treatment. 1.) nutritional status based on BDHQ, 2.) body weight, abdominal girth, blood pressure, grip strength, 3.) blood glucose profile, 4.) lipid profile.
Subject: There were 76 cases of consent to participation in this study, but since there were three dropout cases, the analysis subjects were 35 patients in group A, 38 patients in group B.
Result: In the group A, HbA1c (7.47±0.67 vs. 7.09±0.56 p&lt;0.0001) and body weight (70.20±11.79 vs. 69.15±12.13 p&lt;0.0002) decreased significantly, but no change in total caloric intake by BDHQ (1675.23±580.67 vs. 1636.92±625.32) was observed. On the other hand, in the group B, no changes in total calorie intake by BDHQ, HbA1c, body weight, were observed.
Discussion: This study indicated that no increase in dietary intake was observed upon weight loss by DAPA. It has already been reported that weight loss due to DAPA improves patients’ QoL. Improvement of this QoL may be expected to have a positive influence on improvement of treatment motivation and diet therapy/exercise therapy which is the basis of diabetes treatment. This study suggests that in humans, unlike animal experiments, calorie loss by DAPA may have a positive effect on dietary behavior.

Disclosure
M. Kitaoka: Research Support; Self; AbbVie Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd.. H. Fujii: None. K. Imai: None. Y. Echida: None. K. Kanno: Research Support; Self; Astellas Pharma Inc.. Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi K.K., MSD K.K.. Research Support; Self; Taisho Toyama Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, Takeda Phamaceutical Company Ltd. T. Miyakawa: Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, MSD K.K.. M. Shigeta: None.
Screening for Diabetic Retinopathy in African Immigrants—The Africans in America Study
Authors: CHRISTAKIS PANOS G. , KABAKAMBIRA JEAN DAMASCENE , BRIKER SARA M. , DUBOSE CHRISTOPHER , SUMNER ANNE E. , CHEW EMILY 
Published: June 2018

The degree to which retinopathy occurs in Africans with abnormal glucose tolerance is unknown. Therefore, the objective of this study was to screen for diabetic retinopathy in self-identified healthy African immigrants. A total of 167 Africans now living in the Washington DC area underwent a medical workup and eye exam at the NIH. Visual acuity, intraocular pressure, slit lamp biomicroscopy and dilated fundus biomicroscopy were performed. Diagnostic testing included color fundus photography, fundus autofluorescence, and optical coherence tomography of the macula and optic nerve. The participants were 41 ± 10 years old (mean ±SD) and duration of stay in the U.S.A was 12 ± 10y. BMI was 28 ± 4 kg/m2, and 17 (10%) participants were being treated for hypertension. OGTT revealed diabetes in 15 (9%) participants, and prediabetes in 58 (35%) participants. Retinopathy was detected in 7 (4.2%) participants, 5 of whom had findings consistent with mild non-proliferative diabetic retinopathy in the setting of diabetes (n=3) or prediabetes (n=2) on OGTT. One participant had a flame shaped hemorrhage due to untreated Stage 2 hypertension, and one participant without vascular risk factors had peripheral dot-blot hemorrhages. Participants with retinopathy were older (49 ± 10 vs. 40 ± 10 years old, p=0.02), had higher systolic BP (140 ± 25 vs. 119 ± 14 mmHg, p&lt;0.001) and higher A1C (6.4 ± 2.2% vs. 5.4 ± 0.6%, p&lt;0.001) than participants without retinopathy. There was no difference in retinopathy rates based on sex, African region, BMI, education level, income, drinking/smoking status, physical activity, or sickle cell/HbC trait status. In short, OGTT testing reveals that African immigrants who self-identify as healthy have high rates of undetected diabetes and prediabetes. Some (4.2%) already have retinopathy, and require annual follow-up to monitor for progression. Vascular risk factors including hypertension and prediabetes were associated with retinopathy, and we would recommend screening at-risk individuals.

Disclosure
P.G. Christakis: None. J. Kabakambira: None. S.M. Briker: None. C. DuBose: None. A.E. Sumner: None. E. Chew: None.
Male Type 2 Diabetic Patients Have Higher Diabetic Retinopathy Prevalence
Authors: CHERCHI SARA , GIGANTE ALFONSO , CONTINI PIERPAOLO , PISTIS DANILA , PILOSU ROSANGELA M. , SPANU MARIA A. , FOIS MARIA A. , LAI ALESSIO , MELONI GISELLA , TONOLO GIANCARLO 
Published: June 2018

Diabetic retinopathy (DR) is one of the main causes of visual loss in individuals aged 20-64 years old. Some evidence indicate clear sex gender differences in diabetes complications, but studies focused on sex-gender differences in DR do not give clear data. The aim of this study was to investigate sex gender difference in DR type 2 diabetic patients (T2DM).
Methods: During 2015-2017 in seven diabetic out- patient clinics in Sardinia we examined under midriatic funduscopy 19.951 (11.409 males, 8.542 females) T2DM with known diabetes duration more than 5 years. Patients were classified as having: a) No DR (NRD),b) Mild non proliferative DR (RDNP), c) pre-proliferative and proliferative DR (RDPP), maculopathy (MAC). Each patient had full clinical and laboratory data available. In the same period in three diabetic outpatient clinics we performed also non midriatic retinography in other 1916 T2DM during the outpatient visit using a semi automated digital fundus camera and each imagine was evaluated by an experienced diabetologist/oculist.
Results: Diabetic retinopathy was more frequent under midriatic fundoscopy in males than females: (RDNP 15.9% vs. 14.3%,p&lt;0.01 and RDPP 5,0% vs. 4.0%, p&lt;0.001). Semi automated non midriatic retinography allowed to exclude DR in 68% of patients.
Conclusions: Our preliminary results indicate that: a) In this large sample of T2DM with known diabetes duration more than 5 years, DR is present in 24.1% of the subjects, with unit 3 having the highest prevalence (27.6%) and unit 6 the lowest (16.5%), P&lt;0.00001 b) females have significantly less DR than males (p&lt;0.00001), this effect is evident also excluding Unit 3 p=0.0002. c) retinography may allows to exclude DR in almost 68% of outpatient T2DM patients avoiding the more expensive classical oculist assessment. Further analysis is under way in order to identify possible markers of sex gender difference in DR.

Disclosure
S. Cherchi: None. A. Gigante: None. P. Contini: None. D. Pistis: None. R.M. Pilosu: None. M.A. Spanu: None. M.A. Fois: None. A. Lai: None. G. Meloni: None. G. Tonolo: None.
High Prevalence of Distress among Patients with Type 2 Diabetes (T2DM)—A Hospital-Based Cross-Sectional Study from South India
Authors: SANKAR PRASANTH , SASIKUMAR PRIYANKA , MEDAYIL RITUNA , JACOB RITTIN , SASIDHARAN SARANYA 
Published: June 2018

Background: Diabetes distress (DD) refers to unique, often hidden emotional burdens and worries, distinct from clinical depression, that are part of the spectrum of patient experience when managing diabetes.
Aim: To assess DD and its association with various parameters in patients with T2DM.
Methodology: A cross sectional study was done on 262 out-patients with T2DM in a multispecialty hospital in South India. DD was measured by DDS-17, a 17-item self-reported DD scale used with subscales in 4 domains - Emotional burden (EB), Physician, Regimen and Interpersonal distress. Overall score &lt;2.0 was little or no distress, 2.0-2.9 moderate, ≥3.0 was high distress. Data was analysed using SPSS version 11.5.
Results: Mean age of participants was 59.7 ± 9.1 years. Females constituted 71.8%. BMI was ≤ 25kg/m2 in 32.8%. Duration of diabetes was &lt;10 years in 42%. Insulin was used by 45%. Mean HbA1c was 8.7±1.7%. Prevalence of DD was 27.9%, with moderate distress in 22.1% and high distress in 5.7%. Mean total DD score was 1.67± 0.59. Mean for EB, physician-related, regimen-related and interpersonal distress were (2.1 ± 1.02), (1.09 ± 0.33), (1.92 ± 0.89), (1.30± 0.76) respectively. Total DD had significant association with BMI (p=0.04), duration of T2DM (p=0.04), HbA1c (p=0.01), neuropathy (p=0.002) and nephropathy (p=0.008). EB, considered most important domain, was associated with duration of T2DM (p=0.02), insulin use (p=0.002), neuropathy (p&lt;0.001), nephropathy (p=0.008), high HbA1c levels (p=0.001), ASCVD in females (p&lt;0.001). Regimen related distress was more in those with high HbA1c (p=0.001) and smokers (p=0.04).
Discussion: The study, first of its kind from South India, identifies high prevalence of DD in this population. Assessment of DD should be integrated into patients’ self-care plan. Patients become more involved in managing diabetes if their specific emotional distress are taken care of, and have a better sense of social care, health control and self-efficacy.

Disclosure
P. Sankar: None. P. Sasikumar: None. R. Medayil: None. R. Jacob: None. S. Sasidharan: None.