bluuebunny/crossref_metadata_2025_split huggingface dataset:
525-P: Integrated Mirnome and Proteomic Analyses in Plasma and Progression to ESRD in Diabetes
Authors: SATAKE EIICHIRO , SKUPIEN JAN , MD DOM ZAIPUL I. , KOBAYASHI HIROKI , IHARA KATSUHITO , PEZZOLESI MARCUS G. , NIEWCZAS MONIKA , KROLEWSKI ANDRZEJ 
Published: June 2019

Background: MicroRNAs (miRNAs) are involved in gene regulation and play important roles in the etiology of various diseases including diabetic kidney disease. The objective of this study was to determine miRNAs profile and their target proteins associated with risk of progression to end-stage renal disease (ESRD) in diabetes.
Methods: Using HTG edge sequence platform, 2,083 miRNAs were measured in baseline plasma specimens of patients with renal impairment (CKD stage 3 and 4). We also measured 1,029 protein levels using SomaScan proteomics platform to assess the target proteins of candidate miRNAs. We studied 375 patients with diabetes: 239 patients with type 1 diabetes as our exploratory panel and 136 patients with type 2 diabetes as our replication panel.
Results: We identified 19 circulating miRNAs that were strongly associated with progression to ESRD in both T1D and T2D. Among them, 4 representative miRNAs were selected. In pathway analysis, Axon guidance (AG) was the most significant pathway enriched by genes targeted by the representative miRNAs. Our proteomics platform included 41 AG proteins and 6 of them were identified to be associated with ESRD in T1D and T2D. Mediation analysis revealed that 10-83% of the miRNAs effect on ESRD is mediated through axon guidance proteins, namely 2 Ephrin ligands and 4 Ephrin receptors.
Conclusions: Our results suggest that certain miRNAs play a significant etiological role in progression of diabetic kidney disease to ESRD mediated by axon guidance proteins. These miRNAs and AG proteins have the potential to be used as novel therapeutic targets and prognostic biomarkers.

Disclosure
E. Satake: None. J. Skupien: None. Z.I. Md Dom: None. H. Kobayashi: None. K. Ihara: None. M.G. Pezzolesi: None. M. Niewczas: None. A. Krolewski: None.

Funding
National Institutes of Health; Novo Nordisk Foundation; Sunstar Foundation
53-LB: Availability of Diabetes Self-Management Education and Support Programs in United States Counties
Authors: JAYAPAUL-PHILIP BINA , DAI SHIFAN , WOGHIREN EFOMO , RUTLEDGE GIA E. 
Published: June 2019

Authors developed an interactive map visualizing county level availability of Diabetes Self-Management Education and Support (DSMES) site or program locations. Location data were overlaid with diabetes prevalence data and socio-economic status data. Over 4200 locations were geocoded including 3471 sites (American Diabetes Association recognized) and 802 program locations (American Association of Diabetes Educators accredited). Counties were characterized as having or not having DSMES class locations. Counties were additionally characterized based on tertiles of diabetes prevalence and socio-economic disadvantage (using the Area Deprivation Index (ADI) score). This analysis showed that 48 percent of U.S. counties (1515/3142 counties and county equivalents) had a DSMES program with at least one site or program location. Approximately 39% of counties in the highest diabetes prevalence tertile (greatest diabetes burden) had DSMES programs compared to 53% in the middle tertile of diabetes prevalence and 54% in the lowest tertile of diabetes prevalence. Approximately 26% of counties in the tertile with highest ADI scores (representing greatest socio-economic disadvantage) had DSMES programs compared to 48% in the middle tertile and 69% percent in the tertile with the lowest ADI scores (least socio-economic disadvantage). This interactive map is a tool that can be used at a national level and by state and local health departments and others to prioritize establishment and expansion of programs in underserved counties with higher rates of diabetes prevalence and greater socio-economic disadvantage.

Disclosure
B. Jayapaul-Philip: None. S. Dai: None. E. Woghiren: None. G.E. Rutledge: None.
541-P: The Il-8-CXCR1/2 Axis and Its Targeting in Diabetic Kidney Disease
Authors: ROCCHIO FRANCESCA , NASR MOUFIDA BEN , D'ADDIO FRANCESCA , LORETELLI CRISTIAN , USUELLI VERA , ASSI EMMA , NIEWCZAS MONIKA , ESSAWY BASSET EL , PEZZOLESI MARCUS G. , CORRADI DOMENICO , ZUCCOTTI GIANVINCENZO , FIORINA PAOLO 
Published: June 2019

Introduction: Recent studies suggested a major involvement of the inflammation process in the onset and maintenance of diabetic kidney disease (DKD). We aimed to evaluate the role of the IL-8-CXCR1/2 pathway in DKD.
Material and Methods: Human studies: We measured the urinary IL-8 levels from a cohort of 1182 patients affected by type 2 diabetes (T2D) using Luminex and quantified IL-8 protein/mRNA expression in kidney samples by immunohistochemistry, immunofluorescence and RT-PCR. Murine in vivo studies: The expression of KC (a murine homologue of IL-8) was quantified during the progression of DKD while the effect of CXCR1/2 blockade was analyzed in diabetic Lepdb/db mice. In vitro studies: We mechanistically determined the impact of the IL-8-CXCR1/2 pathway in vitro in an immortalized cell line of human podocytes.
Results: (i) Human studies: IL-8 urinary levels are increased in T2D patients with DKD. In addition, we found that those with microalbuminuria showed high urinary IL-8 levels which are associated with a higher Glomerular Filtration Rate (GFR) decline, a significant increase of the Albumin/Creatine Ratio (ACR) and development of worst renal outcomes. Patients affected by T2D and DKD have higher IL-8 glomerular expression compared to controls. CXCR1/2 are mainly localized at glomerular level and expressed by podocytes while IL-8 is localized in CD31+ endothelial cells. (ii) Murine studies: KC blockade reduces albuminuria and renal damage in Lepdb/db mice. (iii) In vitro studies: Podocytes express high levels of CXCR1/2. Treatments with the recombinant IL-8 induce DNA damage in podocytes while CXCR1/2 blockade prevent it.
Conclusion: IL-8-CXCR1/2 pathway may have a role in DKD onset by inducing a podocyte-mediated damage and its blockade may represent an add-on therapy to current therapeutic strategies.

Disclosure
F. Rocchio: None. M. Ben Nasr: None. F. D'Addio: None. C. Loretelli: None. V. Usuelli: None. E. Assi: None. M. Niewczas: None. B. El Essawy: None. M.G. Pezzolesi: None. D. Corradi: None. G. Zuccotti: None. P. Fiorina: None.
545-P: The Difference in the Effects on Microalbuminuria Depending on the Order of GLP-1RA and SGLT2i Therapy in Type 2 Diabetes
Authors: OHARA MASAYA , MOTOYAMA KOKA , TAMAI ANNA , SAKURA TAKESHI , YAKUSHIJI YOSUKE , HOSOI MASAYUKI 
Published: June 2019

Background: It has been reported that the combination therapy of Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i) decrease micro-albuminuria in type 2 diabetes (T2DM) with nephropathy. There is the possibility that protective effects on estimate glomerular filtration rate (eGFR) and micro-albuminuria are different between (1) GLP-1RA add-on therapy to SGLT2i and (2) SGLT2i to GLP-1RA.
Objective: In this study, we aimed to clarify whether there are differences in the changes of eGFR and micro-albuminuria depending on the order of combination therapy between (1) and (2) in T2DM.
Method: We studied 69 patients with T2DM who took GLP-1RA together with SGLT2i in Our Hospital, retrospectively. We investigated urine albumin to creatinine ratio (ACR), eGFR, body mass index (BMI), systolic blood pressure (SBP), HbA1c, UA, Na, Cl, hematocrit (Ht) and platelet (Plt) before and after six months of the therapy. Six months changes (delta:Δ) of clinical parameters were compared between each combination therapy.
Result: In all subjects, HbA1c, BMI and logACR were significantly decreased with the therapies, respectively. As the comparison of Δ in each clinical factors between (1) and (2) groups, ΔHbA1c of (1) significantly showed lower levels than (2). Whereas ΔNa and ΔCl of (1) significantly showed higher levels. Multiple regression analysis including ΔPlt, ΔHt, ΔUA, ΔBMI, ΔHbA1c, and the type of combination therapy as an independent factor for eGFR, ΔUA, ΔHt and ΔHbA1c were the significant contributing factors. Multiple regression analysis including ΔBMI, ΔHDL-C, ΔHbA1c, age, sex and the type of combination therapy as an independent factor for ΔlogACR, ΔHDL-C was the significant contributing factor. The type of combination therapy was not shown as a significant associated factor for ΔlogACR.
Conclusions: Both GLP-1RA add-on therapy to SGLT2i and SGLT2i to GLP-1RA equally reduce albuminuria in T2DM with nephropathy.

Disclosure
M. Ohara: None. K. Motoyama: None. A. Tamai: None. T. Sakura: None. Y. Yakushiji: None. M. Hosoi: Speaker's Bureau; Self; Eli Lilly and Company.
546-P: Deep Learning Predictions of Diabetic Retinopathy Associated with Progression of Renal Disease in Type 1 Diabetes
Authors: MELLOR JOSEPH C. , STORKEY AMOS J. , COLHOUN HELEN , MCKEIGUE PAUL M. ,   ON BEHALF OF THE SDRNT1BIO INVESTIGATORS
Published: June 2019

Background and Aims: We considered if deep learning (DL) models trained to predict diabetic retinopathy (DR) are also useful for prediction of renal disease in people with type 1 diabetes.
Materials and Methods: We used 35000 retinal images and associated ground truth DR grades from the online Kaggle dataset. These were used to train a Resnet convolutional neural network (CNN) to predict the ground truth DR grades. The CNN was then applied to retinal images for each patient in the SDRNT1BIO available from the national screening program generating 10 DL outputs corresponding to DR gradings for both eyes. Longitudinal eGFR readings and risk factor data were available for the SDRNT1BIO through linkage to clinical records. Univariate associations of DL outputs with final eGFR at follow-up was tested via linear regression models. A penalised Bayesian approach using 10-fold cross-validation was used to select the most predictive DL features and assess prediction performance.
Results: We found 7 DL outputs had a significant univariate association with follow-up eGFR adjusting for age, sex, duration of diabetes, baseline eGFR, and length of follow-up at p&lt;10-4. 4 DL outputs remained significant on adjusting for the screening program manual DR grading of the image (p ranging from 1.62x10-8 to 9.9x10-5). For predicting achieved eGFR we found that DL outputs improved test log-likelihood by 22.2 natural log units (equivalent to a p-value of &lt; 10-9) increasing the R2, from 0.64 to 0.65.
Conclusion: This small study demonstrates that retinal images contain information for predicting eGFR decline and that deep learning can extract this information. Future work on a larger dataset using DL to predict renal disease progression directly is therefore warranted.

Disclosure
J.C. Mellor: None. A.J. Storkey: None. H. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. P.M. McKeigue: Advisory Panel; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Stock/Shareholder; Spouse/Partner; Bayer AG, Roche Pharma.
55-LB: Mobile Phone Text Message Intervention on Self-Care Activities and Food Choices among Patients with Type 2 Diabetes
Authors: NEPPER MARTHA J. 
Published: June 2019

This study examined the effects of educational text messages on diabetes self-care, cardiovascular disease (CVD) risk awareness and food choices (home food availability) among patients with type 2 diabetes. Quasi-experimental design was used with 40 patients (58.0±10.6 years) in the intervention and 39 (55.7±12.2 years) in the control group. In addition to the usual care provided for all participants, the intervention group received three educational text messages weekly for 12 weeks (total of 36 text messages). Pre- and post-intervention measures were collected for both groups. Analysis of covariance was used to assess the intervention effects. Ninety-four percent (94%) of the participants receiving text messages indicated the usefulness of this program and would highly recommend this program to others with type 2 diabetes. The intervention group either maintained the same level at baseline or demonstrated a trend of improvement in self-care activities (healthy eating, exercise, blood glucose testing, medication adherence and foot care) after intervention. Non-statistical significant improvements in weekly MET (Metabolic Equivalent Test) minutes for total minutes of exercise (absolute change=768 minutes; p=0.62) and moderate/vigorous physical activities (absolute change=1688 minutes, p=0.62) were observed for the intervention group. There was no significant differences in nutrients intake (carbohydrate, sugar, added sugar, total fat, and saturated fat) between the intervention and control group at baseline and at 12-week follow-up and no significant changes were observed for dietary nutrients after intervention. However, significant increases in scores of CVD awareness (P=0.04) and availability of fresh fruits (P=0.01) and fresh vegetables (P=0.02) in the home were observed for intervention relative to control group. The pilot results suggest the feasibility and usefulness of the text message program for diabetes education.

Disclosure
M.J. Nepper: None.

Funding
University of Nebraska-Lincoln
552-P: Baroreflex Function and Postprandial Hypotension in Older Adults With and Without Type 2 Diabetes
Authors: MADDEN KENNETH M. , FELDMAN BORIS , MENEILLY GRAYDON S. 
Published: June 2019

Background: Type 2 diabetes (T2DM) is a common etiology of postprandial hypotension (PPH), possibly as a result of autonomic neuropathy resulting in baroreflex dysfunction. We examined baroreflex function in older adults with PPH (with and without T2DM) during a standardized meal test.
Methods: 57 adults with PPH (age &gt;= 65; 30 without T2DM, 27 with T2DM) were recruited sequentially from a geriatric medicine clinic (mean age 77.9±0.9 years, 54% female) and had meal tests performed. A Finometer (Finapres Medical Systems) was used to monitor blood pressure. The baroreflex effectiveness index (BEI, percent) was calculated using the sequence method.
Results: Baseline BEI showed no association with the average PPH response (p=0.521), the maximal PPH response (p=0.282), or the number of hypotensive episodes (p=0.859). As shown in Figure 1, baseline BEI was lower in subjects with T2DM than in those without T2DM (p&lt;0.001), but this impairment in baroreflex function was not observed postprandially. There was no significant difference in the average PPH response between those with and without T2DM (p=0.358).
Conclusions: Although older subjects with PPH secondary to T2DM have lower baseline baroreflex function than older subjects with PPH without T2DM, this baroreflex impairment was not associated with the size of the PPH response. This suggests that PPH in the T2DM is not due to impairments in the arterial baroreflex.

Disclosure
K.M. Madden: None. B. Feldman: None. G.S. Meneilly: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc.

Funding
Allan M. McGavin Foundation; Canadian Diabetes Association
553-P: Differential Effects of High-Intensity Interval Training on Somatosensory and Autonomic Nerve Function in Patients with Type 2 Diabetes
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , APOSTOLOPOULOU MARIA , PESTA DOMINIK , RODEN MICHAEL , ZIEGLER DAN 
Published: June 2019

It remains unclear, whether exercise training as part of lifestyle intervention has favorable effects on the development or progression of diabetic neuropathy in patients with type 2 diabetes (T2D). Therefore, we assessed peripheral and autonomic nerve fiber function and morphology in patients with T2D as well as in individuals with normal glucose tolerance (CON) before and after a high intensity interval training (HIIT) intervention program over 12 weeks. The T2D group included 20 male individuals ([median (1st; 3rd quartile)] age: 56 (53; 63) years; diabetes duration: 5 (2; 9) years; BMI: 31.2 (28.6; 32.8) kg/m²; HbA1c: 6.9 (6.4; 8.0)%). The CON group was matched for age, sex, and BMI (n=23; age: 57 (53; 60) years; BMI: 30.3 (28.4; 32.2) kg/m²; HbA1c: 5.4 (5.2; 5.7)). Somatosensory and autonomic nerve tests included nerve conduction velocity, quantitative sensory testing, skin biopsy, corneal confocal microscopy, cardiovascular autonomic function tests (CAFT), and spontaneous baroreflex sensitivity (BRS). After 12 weeks of HIIT, no improvement in somatosensory nerve tests was detected in T2D or CON. In both groups, resting heart rate decreased ([mean±SEM] baseline vs. follow-up: T2D: 68.8±2.3 vs. 63.4±1.8 bpm; CON: 65.1±1.8 vs. 60.2±1.9 bpm; both P&lt;0.05). The change in systolic blood pressure after standing up (-13.9±2.6 vs. -9.4±2.2 mmHg) and three BRS sequence analysis indices (e.g., BRS-slope: 7.9±1.9 vs. 12.6±5.1 ms/mmHg) improved in T2D (P&lt;0.05), while the standard deviation of normal RR intervals (SDNN; 36.1±2.6 vs. 55.3±8.8 ms; P&lt;0.05) and coefficient of variation (CV; 3.8±0.3 vs. 5.2±0.7%; P&lt;0.05) improved in CON.
In conclusion, while cardiovascular autonomic function improved moderately after 12 weeks of HIIT in male T2D patients, a longer training period may be required to achieve favorable effects on somatosensory nerve function or morphology.

Disclosure
G.J. Bönhof: None. A. Strom: None. M. Apostolopoulou: None. D. Pesta: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D. Ziegler: Advisory Panel; Self; Allergan, TrigoCare. Consultant; Self; Mitsubishi Tanabe Pharma Corporation, Mylan, Novartis Pharmaceuticals Corporation, Wörwag. Speaker's Bureau; Self; Berlin-Chemie AG.

Funding
German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research
554-P: Glycemic Variation Predicts Microvascular Risk in both ACCORD and VADT
Authors: ZHOU JIN , REAVEN PETER 
Published: June 2019

The relationship of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) is controversial. Using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veteran Affairs Diabetes Trial (VADT), we investigated this relationship. In ACCORD, fasting glucose was measured every 4 months during the first year then annually for up to 84 months in 10251 individuals. In the VADT, fasting glucose were measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV). In Cox proportional hazard models, log CV in both ACCORD and the VADT were associated with development of future microvascular outcomes (composite of nephropathy and retinopathy) even after adjusting for other risk factors, including average glycemic control (Figure 1). Additional adjustment for severe hypoglycemic episodes did not account for the effect of glucose variability. This analysis indicates that variability of fasting glucose may play a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.

Disclosure
J. Zhou: None. P. Reaven: Advisory Panel; Self; Boston Heart Diagnostics. Research Support; Self; AstraZeneca, Novo Nordisk Inc.

Funding
National Institutes of Health
558-P: Rate of Progression of Utah Early Neuropathy Symptom Score in Diabetic Neuropathy
Authors: SINGLETON J. ROBINSON , HAUER PETER E. , REVERE CATHY , FOSTER-PALMER STORMY C. , APERGHIS ADRIENNE B. , SMITH A. GORDON 
Published: June 2019

The Utah Early Neuropathy Scale (UENS) is a brief, validated exam scale focused on injury to small diameter nociceptive fibers. Twenty-four of 42 possible points are related to measurement of length dependent loss of pin sensation in legs and feet. While the UENS has been accepted as a standard clinical measure for diagnosis of small fiber neuropathy, its utility as a primary outcome measure in clinical trials has not been evaluated. Here we report natural history progression of the UENS. In an NIDDK DP3 single center study, 190 patients with diabetes were screened for neuropathy using Toronto criteria, then 83 found to have neuropathy were followed longitudinally at 9-month intervals for up to 27 months using a variety of clinical and ancillary measures, including the UENS. Among those with neuropathy, baseline UENS score significantly correlated with scores of symptom questionnaires including the Norfolk Quality of Life-Diabetes Neuropathy (NQoL-DN) and the NTSS-6; with nerve conduction study measures including sural sensory amplitude, peroneal amplitude and proximal conduction velocity; with intraepidermal nerve fiber density (IENFD) from distal thigh and distal leg 3m punch skin biopsies; but not with confocal corneal microscopy measures of nerve fiber length and density. Overall, 75 participants were followed for 9 months, and 56 for at least 18 months for a total of 149 9-month segments. UENS worsened (increased) 1.08 (+/- StDev 3.51) points per 9-month segment overall. For those followed at least 18 months, there was a 2.2 (+/-4.1) point increase over this period. Change in UENS significantly correlated with change in NQoL-DN and IENFD, among other measures. The UENS is an objective, responsive, validated clinical instrument for which a linear natural progression slope can be measured, and would be an appropriate primary endpoint in small fiber neuropathy clinical trials.

Disclosure
J. Singleton: None. P.E. Hauer: None. C. Revere: None. S.C. Foster-Palmer: None. A.B. Aperghis: None. A. Smith: Consultant; Self; Alexion Pharmaceuticals, Inc., Disarm, Regenesis.

Funding
National Institutes of Health (DP3DK104394)