bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Association of Microaneurysm Wall Characteristics with Perfusion and Local Neuroretinal Pathology
Authors: SUN JENNIFER K. , ABU-QAMAR OMAR , SAMPANI KONSTANTINA , FICKWEILER WARD , AIELLO LLOYD P. 
Published: June 2018

Although microaneurysms (MAs) are a hallmark lesion of diabetic retinopathy, it is unclear why some MAs result in local neural retinal pathology while others are benign. To address this issue, longitudinal follow-up of MAs with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SDOCT) was performed. AOSLO MA images were graded for wall hyperreflectivity (WH), wall deformability (WD), cross-sectional area and perfusion percentage. SDOCT images were graded within a 500μm zone centered on each MA for disorganization of the retinal inner layers (DRIL). Fluorescein angiography evaluated leakage in a subset. A total of 457 MAs of 102 eyes (57 subjects: mean±SD age 44±12 years, DM duration 23#x00B1;10 years, 61% male, 73% type 1 DM) were assessed over 843 visits (154 MAs with ≥1 visit and mean follow-up of 0.52#x00B1;0.35 years). At baseline, MAs with WH were larger (p≤0.0001), less perfused (p≤0.0001), and associated with DRIL (p=0.002). There was a borderline trend for such MAs to leak fluorescein (p=0.05). Over time, MAs with resolved WH had greater likelihood of DRIL improvement. Conversely, MAs that developed WH had more DRIL worsening (p=0.005). WH change vs. stability was associated with decreased perfusion over time (p≤0.0001). At baseline, WD was associated with smaller MAs (p≤0.0001) and increased perfusion (p≤0.0001), but was not related to fluorescein leakage or DRIL. WD resolution and development were associated with decreased and increased perfusion, respectively (p≤0.0001), but not with change in DRIL. These data suggest that whereas WH is a feature of more mature, larger and less perfused MAs associated with local neural pathology, WD may be present in earlier-stage MAs that are smaller and more fully perfused. Future studies will determine whether these parameters can be used to predict changes in MA size, perfusion, leakage or local neural retinal pathology over time.

Disclosure
J.K. Sun: Other Relationship; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Genentech, Inc., Optovue, Incorporated, Boston Micromachines Corporation, Adaptive Sensory Technology, Kalvista Pharmaceuticals, Inc.. Other Relationship; Self; Novo Nordisk Inc.. O. Abu-Qamar: None. K. Sampani: None. W. Fickweiler: None. L.P. Aiello: Consultant; Self; Novo Nordisk Inc., Sanofi Genzyme. Stock/Shareholder; Self; Kalvista Pharmaceuticals, Inc.. Consultant; Self; Kalvista Pharmaceuticals, Inc..
Intracellular Calcium Levels in Patients with Type 2 Diabetes, First-Degree Relatives of Patients with Type 2 Diabetes, and Age-Matched Controls
Authors: STERGIOU IOANNIS F. , DIDANGELOS TRIANTAFYLLOS , TZIOMALOS KONSTANTINOS , KONTONINAS ZISIS , RAIKOS NIKOLAOS , VYZANTIADIS TIMOLEON-ACHILLEAS , HATZITOLIOS APOSTOLOS I. 
Published: June 2018

Purpose: Measurement of Intracellular Calcium (iCa) levels in red blood cells in patients with predisposition to type 2 diabetes (T2D), such as the first-degree relatives of patients with T2D, in comparison with healthy individuals and patients with T2D.
Materials and Methods: Our study comprised of three groups of 25 age-matched, 38-65 years-old persons (58% males): 1.) non-insulin treated T2D patient (body mass index (βμΙ) 28.3±3.4 kg/m2, HbA1c 7.5±1.6%) 2.) first-degree relatives of T2D patients (βμΙ 25.3±3.6 kg/m2, HbA1c 5.3±0.4%) 3.) healthy controls (βμΙ 24.3±3.4 kg/m2, HbA1c 4.9±0.5%). Measurement of iCa was conducted by the method of atomic resonance with the use of a spectrophotometer.
Results: Lower levels of iCa were observed in the relatives of patients with T2D vs. the control group (0.39±0.16 vs. 0.48±0.3 mg/L, p=0.049) and in patients with T2D vs. the control group (0.33±0.21 vs. 0.48±0.3 mg/L, p=0.041). In contrast, iCa levels did not differ between patients with T2D and the first-degree relatives of patients with T2D (p=0.38).
Conclusion: The comparison of iCa levels in the three groups shows a gradual decrease from control group to T2D patients. It is impressive that statistical analysis revealed significant differences between the first-degree relatives of patients with T2D and the control group, and between patients with T2D and the control group, but not between patients with T2D and the first-degree relatives of patients with T2D. It could be reasonably hypothesized that individuals with known predisposition for T2D have a defective genotype that negatively affects intracellular molecular signaling in which calcium is implicated.

Disclosure
I.F. Stergiou: None. T. Didangelos: None. K. Tziomalos: None. Z. Kontoninas: None. N. Raikos: None. T. Vyzantiadis: None. A.I. Hatzitolios: None.
Serum Uric Acid Reduction Is Associated with Gender Differences and Body Fat Distribution after Laparoscopic Sleeve Gastrectomy
Authors: ZHANG XUANE , MEI FANGYUN , GAO JINGYANG , CHENG XIAOYUN , BU LE , ZHU CUILING , QU SHEN 
Published: June 2018

Background: Uric acid is believed be an important modulator in glucose and lipid metabolism. This study is aimed to estimate the efficacy of laparoscopic sleeve gastrectomy (LSG) on obese patients and find out the relationship of serum uric acid (SUA) to body fat distribution in both male and female of Chinese patients.
Methods: A total of 65 obese patients (32 females and 33 males) who underwent LSG were enrolled for this study. Their body composition was measured by dual-energy X-ray absorptiometry (DEXA). The data of anthropometric measurements, glucolipid metabolism and SUA was collected before and 6 months after LSG separately.
Results: More significant reduction of SUA was observed in the female group than the male group after LSG (female (17.98±12.72)% vs. male(3.22±15.66)%, p&lt;0.001). Furthermore, changes in SUA showed significantly positive correlation with visceral adipose tissue (VAT) in female patients (r=0.542,p=0.011). And it was also positively correlated with changes of the area under the curve(AUC) for glucose during 75g oral glucose tolerance test(r=0.567,p=0.002), fasting insulin(r=0.505,p=0.006) and natural logarithm of HOMA-IR (r=0.427,p=0.023). Post-surgery high-density lipoprotein (HDL) levels significantly increased from 0.89±0.19 to 1.18±0.23 mmol/L (p&lt;0.001) in males. The reduction of SUA in male patients were positively associated with changes in neck circumference(r=0.617,p=0.000)and hip circumference(r=0.381,p=0.042), and negatively correlated with changes in HDL levels (r = -0.422, P = 0.018). It was also positively correlated with changes of fat content in upper arm, legs and gynoid area (r=0.450, r=0.650, r=0.432, respectively; all p&lt;0.05), while unrelated to visceral fat in the male group.
Conclusions: The efficacy of LSG on glycolipid metabolism may be associated with gender-related differences in body fat distribution. Uric acid may be a gendered modulator of glucose and lipid metabolism.

Disclosure
X. Zhang: None. F. Mei: None. J. Gao: None. X. Cheng: None. L. Bu: None. C. Zhu: None. S. Qu: None.
Presessions to the National Diabetes Prevention Program Are a Promising Strategy to Improve Attendance and Weight Loss Outcomes
Authors: RITCHIE NATALIE , KAUFMANN PETER G. , GRITZ MARK , HOLTROP JODI S. 
Published: June 2018

Introduction: The National Diabetes Prevention Program (NDPP) is a widely-disseminated lifestyle intervention. Retention in the NDPP is problematic and leads to suboptimal weight loss, especially among racial/ethnic minority participants. We report results of implementing a novel “pre-session” protocol to support engagement among a diverse sample of NDPP participants.
Methods: The NDPP was delivered in a safety net healthcare system. As of September 2016, pre-sessions were offered prior to NDPP attendance and focused on (1) education on diabetes risks, (2) motivational interviewing to participate in the NDPP, and (3) problem-solving barriers to engagement. We compared NDPP attendance and weight loss outcomes between 75 pre-session participants and a historical control group of 42 individuals who were not offered a pre-session prior to their beginning the NDPP in July 2016. This comparator group was selected to reduce potentially confounding effects of other prior modifications to NDPP dissemination over time.
Results: The majority of participants in this analysis were female (78.3%), low-income (51.1%), and Hispanic (57.6%). Mean age was 46.6 (SD=12.7) with a mean baseline BMI of 35.9 (SD=5.7). There were no significant baseline differences in characteristics between NDPP participants who received a pre-session and historical controls. Pre-session participants attended 5.3 (SD=1.4) more NDPP sessions (p&lt;.001) and stayed in the program 96.4 (SD=24.6) days longer (p&lt;.001) than historical controls. Pre-session participants achieved 1.8% (SD=0.8) greater weight loss (p=.039) and were 2.4 times more likely to achieve ≥5% weight loss in the NDPP as historical controls; p=.044, 95% CI [1.0-5.8].
Conclusions: By improving engagement and weight loss, findings suggest pre-sessions may be a promising strategy to improve NDPP effectiveness and mitigate health disparities in program outcomes.

Disclosure
N. Ritchie: None. P.G. Kaufmann: None. M. Gritz: None. J.S. Holtrop: None.
Cornus Officinalis Increases Proliferation, Inhibits Cytokine-Induced Apoptosis, and Promotes the Oxidative Capacity of the Human 1.1B4 Pancreatic Cell Line
Authors: SHARP ARIELLE , BURKHARDT BRANT R. 
Published: June 2018

Type 1 diabetes (T1D) affects 1.25 million Americans with about 40,000 individuals newly diagnosed each year. T1D is caused by an autoimmune-induced loss of pancreatic β cells and subsequent deterioration of insulin production. Although exogenous insulin is an efficient treatment, there is a strong need to develop therapies that can inhibit the loss of β cells and promote their function. For this purpose, we have been analyzing the antidiabetic capability of Cornus officinalis (CF), which has been utilized in traditional Chinese medicine for over 2,000 years primarily for treatment of T2D. We hypothesize that CF may inhibit β cell destruction and promote β cell function. Using the human 1.1B4 pancreatic β cell line, we have examined the proliferative effect of CF treatment on 1.1B4 cells in a time- and dose-dependent manner via cell viability assays. Within two hours, CF rapidly and significantly induced 1.1B4 proliferation by over 300% as compared to controls. Activation of Th1 cytokines plays a detrimental role in the pathogenesis of T1D. Therefore, we determined whether CF can inhibit cytokine induced β cell death and promote β cell proliferation following treatment with Th1 cytokines of IL-1β, TNF-α, and IFN-γ. CF induced a 200% increase in 1.1B4 proliferation following Th1 cytokine treatment compared to controls. In addition, a metabolic analysis of CF induced 1.1B4 cells was examined using the Agilent Seahorse XF analyzer. At a two-hour time point, there was a remarkable increase in maximal respiratory and glycolytic capacity following CF treatment. Therefore, CF is a strong inducer of metabolism. Ongoing experiments will provide greater detail into the mechanism and metabolic role in which CF is promoting proliferation and metabolism and inhibiting cytokine-induced β-cell death.

Disclosure
A. Sharp: None. B.R. Burkhardt: None.
Enabling Data-Driven Decision Making for Personalized Care in Type 2 Diabetes with Clinical and Lifestyle Journey Data Using a Digital Therapeutic
Authors: CHAWLA RAJEEV , SHAIKH MAAZ , SHAH ABHISHEK , SABOO BANSHI D. , MAKKAR BRIJ M. , KESAVADEV JOTHYDEV , JOSHI SHILPA , DESHPANDE NEETA , AGARWAL SANJAY , MAHESHWARI ANUJ , SOSALE ARAVIND R. , MADHU SV 
Published: June 2018

Background: Lack of data on patient lifestyle between consultation visits is a major limitation in practice of data-driven clinical decision making in type 2 diabetes (T2DM). We showcase Wellthy Diabetes (WD), a digital therapeutic, as an effective tool for the amplification of patient's clinical and lifestyle journey data between visits to aid doctors in practice of data-driven decision-making.
Methods: Wellthy Diabetes (WD) smartphone app is a digital therapeutic that delivers an artificial intelligence (AI) augmented lifestyle modification program for people with T2DM, developed in scientific collaboration with the Research Society for Study of Diabetes India (RSSDI). The WD app uses an AI-based digital persuasion model to encourage users through personalized reminders and nudges to self-report data on blood glucose, weight, meals, and physical activity. The app also tracks the duration of physical activity through inbuilt sensors on the phone. This study presents data from a cohort (N=102) of completers of a 16-week program.
Results: During the study 121,675 diabetes-related clinical and lifestyle data points (including 112,960 mins of sensor-tracked physical activity) were reported by 102 participants over 17,052 person days. The mean duration of a participant on WD was 167 days during which, on average, 452 clinical and lifestyle data points were tracked per participant at a mean velocity of 5.6 data points per day. On average each participant reported 68.8, 11.4, 5.1, and 1107.7 instances of meals, blood sugar, weight, and activity respectively.
Conclusion: The results confirm WD amplifies self-reporting of clinically relevant lifestyle data by users during the journey between doctor consultations. First-hand data on clinical trends and lifestyle between consultations provide personalized insight into patient behavior enabling doctors to make data-driven decisions for personalizing evidence-based care for T2DM.

Disclosure
R. Chawla: None. M. Shaikh: Employee; Self; Wellthy Therapeutics Pvt Ltd. A. Shah: Stock/Shareholder; Self; Wellthy Therapeutics. B.D. Saboo: None. B.M. Makkar: None. J. Kesavadev: Advisory Panel; Self; Novo Nordisk India Private Limited. Speaker's Bureau; Self; Novo Nordisk India Private Limited. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; MSD. Speaker's Bureau; Self; MSD. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. S. Joshi: None. N. Deshpande: None. S. Agarwal: None. A. Maheshwari: None. A.R. Sosale: None. S. Madhu: None.
Newly Designed Alginate-Based Microcapsules (AgMc) for the Molecular Therapy of Type 1 Diabetes
Authors: CALAFIORE RICCARDO , MONTANUCCI PIA , BASTA GIUSEPPE P. , NOCENTINI GIUSEPPE , PESCARA TERESA , RICCARDI CARLO 
Published: June 2018

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) plays a crucial role in either thymic t-Treg differentiation and expansion, or peripheral p-Treg expansion, thus representing a potential tool to contrast the autoimmune process. AgMc are usually intended to constitute an immunobarrier to prevent rejection of the embodied islet/insulin producing cell grafts in T1D. We aimed to reverse this principle, and engineered the AgMc membranes, in order to make them permeable to outflowing rat anti-mouse GITR IgM MAb, derived from microencapsulated rat G3C hybridoma cells. To this end, we changed our AgMc original formulation to obtain thicker and looser membranes. We observed intra-AgMc IgM retention and their progressive release into the culture medium in vitro. Prediabetic NOD mice were divided into two groups: (1) n=20, received graft (TX) of G3C containing microcapsules; (2) n=10 received TX of empty microcapsules. Both (1) and (2) were monitored for the onset of DM. BG in basal and after IPGTT, morphological, immuno-molecular, and cell immuno-phenotyping testing, as well as G3C plasma levels assay in (1) were performed. In (2): 5/10 animals developed DM within 70d; in (1) no animals developed DM at 180 of TX. In the spleen of G3C-AgMc-treated mice either CD4+FoxP3+GITRbright, or CD4+CD25-GITR(sp), or CD8+CD25+GITRlowFoxP3+, or CD8+CD25-GITRintFoxP3+ Tregs significantly increased from 4 week of TX as compared to controls. Pancreatic histology at 26 week of TX was associated with either completely destroyed islets (1) or intact islets with minor insulitis (2). Significant diabetes-free time of (1) vs. (2) may relate to increase of islet B-cell specific Tregs, expanded by G3C-released MAb, and antigenic stimulation, at early stage of the autoimmune disease process.
In conclusion, the newly engineered AgMc, by permitting GITR triggering by anti-GITR IgM, may represent a new approach to expand Tregs and inhibit Teff, and to avert the onset of autoimmune DM in NOD mice.

Disclosure
R. Calafiore: None. P. Montanucci: None. G.P. Basta: None. G. Nocentini: None. T. Pescara: None. C. Riccardi: None.
Liver-Specific Deletion of the Mitochondrial Stress UBL-5 Gene Leads to Fatty Liver That Is Rescued by Pioglitazone Administration or ACE2 Overexpression
Authors: NTOUMA VIKTORIA , HARALAMBOUS CHRISTIAN 
Published: June 2018

Fatty liver disease is associated with metabolic syndrome, increased risk of type 2 diabetes (T2D), and other metabolic complications. There has been little progress in treatments for fat-induced liver failure and further studies are required for clarification of mechanisms. Mitochondrial dysfunction has been implicated in insulin resistance and is associated with hepatic fat accumulation and T2D. Studies in C. Elegans have shown that UBL-5 is involved in the activation of the mitochondrial unfolded protein response (UPRmt). This pathway upregulates mitochondrial proteases and chaperone proteins to alleviate proteostatic stress. To further explore the role of UBL-5 in the mammalian UPRmt, we generated a tamoxifen-inducible, liver-specific UBL-5 knockout mouse. Liver-specific deletion of UBL-5 in adult mice caused increased plasma hepatic enzymes, gross steatosis and death within 12 days following tamoxifen-induction. Histological examination of the liver revealed severe and diffuse multifocal hepatocellular necrosis, vacuolation, inflammation, lipid accumulation, and apoptosis. Most UPRmt genes (CHOP, ClpP, ClpX, Lonp1, HSP10, HSP70, ATF-5) were downregulated while mtHSP70 was upregulated. PGC1a mitochondrial biogenesis gene was downregulated. Interestingly, angiotensin-converting enzyme 2 (ACE2) expression was also reduced in KO livers. Mice were then treated with pioglitazone, or an ACE2-containing virus to determine if such treatments provide benefit. ACE2 expression was increased with both ACE2 virus and pioglitazone treatment. Liver enzymes showed significant improvement after treatment with both pioglitazone and ACE2.
In conclusion, we have generated a model that develops severe fatty liver disease and have shown that both genetic and pharmacological therapies may diminish this disease process. This study provides the first evidence for a critical role for UBL-5 in hepatic function.

Disclosure
V. Ntouma: None. C. Haralambous: None.
SGLT2 Inhibitor Ipragliflozin Induces Breast Cancer Apoptosis via Membrane Hyperpolarization and Mitochondria Dysfunction
Authors: KOMATSU SHIHO , NOMIYAMA TAKASHI , NUMATA TOMOHIRO , KAWANAMI TAKAKO , HAMAGUCHI YURIKO , TANAKA TOMOKO , INOUE RYUJI , YANASE TOSHIHIKO 
Published: June 2018

Currently, cancer is one of major cause of death in patients with type 2 diabetes. We have previously reported the anti-prostate and anti-breast cancer effect of GLP-1R agonist Exendin-4 (Diabetes 2014, Endocrinology 2017). In the present study, we examined the anti-cancer effect of SGLT2 inhibitor ipragliflozin (Ipra) using a breast cancer model. In human breast cancer cell line, MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. 1-50nM Ipra significantly and dose-dependently suppressed the growth curve of MCF-7 cells. BrdU assay revealed that Ipra attenuates the proliferation rate of MCF-7 in a dose dependent manner. Further, apoptosis was also induced by Ipra in Tunel assay. Because the anti-breast cancer effect of Ipra was completely canceled by knocking down of SGLT2, this effect could be induced by SGLT2 inhibition by Ipra. We next measured membrane potential and whole cell current using the patch clamp technique. When we treated MCF-7 cell with Ipra or glucose free medium, membrane hyperpolarization was observed. In addition, the replacement of sodium with NMDG and knock-down of SGLT2 by siRNA suppressed glucose induced whole cell current of MCF-7 cell, suggesting that Ipra inhibits sodium and glucose incorporation through SGLT2. Further, mitochondrial membrane protein Bcl-2 was decreased and Bax was increased in western blotting, and JC-1 fluorescence was significantly increased, suggesting the change of mitochondrial membrane potential. These data suggest that SGLT2 inhibitor Ipra induces apoptosis in the breast cancer cell via membrane hyperpolarization and mitochondria dysfunction.

Disclosure
S. Komatsu: None. T. Nomiyama: Research Support; Self; MSD K.K., Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.T. Numata: None.T. Kawanami: None.Y. Hamaguchi: None.T. Tanaka: None.R. Inoue: None. T. Yanase: Research Support; Self; MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.
Regulation of Systemic Energy Metabolism by a Human-Specific Long Noncoding RNA In Vivo
Authors: RUAN XIANGBO , LI PING , CAO HAIMING 
Published: June 2018

Long non-coding RNAs (lncRNAs) are widely expressed in mammals and play critical roles in a broad array of physiological processes. We have recently demonstrated that lncRNAs sense and regulate lipid and glucose metabolism in mice. However, it remains to be determined whether human lncRNAs regulate metabolism in vivo and whether they play a role in the pathogenesis of human metabolic disorders. The lack of knowledge of lncRNA’s functions in human metabolism is partly caused by the extremely low sequence conservation between human and mouse lncRNAs, which makes it difficult to apply the functional information of mouse lncRNAs to human physiology. To overcome this limitation, we have produced liver-specific humanized mice in which over 80% of mouse hepatocytes in the liver can be replaced by human ones and have confirmed that human metabolic genes in these mice maintain proper responses to metabolic cues. Using the liver-specific humanized mice, we identify a Fasting induced, Human-specific, and Liver-enriched lncRNA (lncFHL). Knocking down of lncFHL in humanized mice results in decreased expression of genes in Peroxisome Proliferator Activated Receptor Alpha (PPARalpha) pathway, which leads to decreased fasting plasma glucose and ketone levels. We further find that lncFHL interacts with and affects the mRNA interactions of HuR, a RNA binding protein that suppresses hepatic PPARalpha pathway in human. Finally, by analyzing published genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data, we find the hepatic expressions of lncFHL are associated with human metabolic diseases including diabetes and coronary artery disease. These studies not only provide a proof of principle that the humanized mice could sever as a suitable model to study the metabolic function of human lncRNAs but also demonstrate that regulatory mechanism mediated by human-specific lncRNAs contributes significantly to physiological and pathophysiological metabolic homeostasis.

Disclosure
X. Ruan: None. P. Li: None. H. Cao: None.