bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Resistin Was Inversely Associated with Physical Activity in the C/C Genotype of SNP-420 in the General Japanese Population—The Toon Genome Study
Authors: KAWAMURA RYOICHI , TABARA YASUHARU , TAKATA YASUNORI , TAKAKADO MISAKI , MATSUSHITA YUMI , HADATE TOSHIMI , ONUMA HIROSHI , MARUYAMA KOUTATSU , TANIGAWA TAKESHI , SAITO ISAO , OSAWA HARUHIKO 
Published: June 2018

In humans, resistin is predominantly expressed in monocytes and macrophages, and involved in insulin resistance, atherosclerosis, and cardiovascular diseases. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at -420 (rs1862513) in the human resistin gene increased susceptibility to type 2 diabetes. Genetically, serum resistin was positively associated with the number of the G-allele at SNP-420 in the general Japanese population. Epigenetically, serum resistin was inversely associated with methylation of the C-allele at SNP-420. However, interaction between SNP-420 and environmental factors remains to be elucidated. The aim of this study was to investigate the association between serum resistin and physical activity, and the effect of SNP-420 on this association. The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analyzed. Serum resistin was measured by ELISA. Physical activity was measured for 7 days using a waist-worn accelerometer (Lifecorder, Suzuken Co). Physical activity was also assessed using a questionnaire (the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire, JALSPAQ). Serum resistin was inversely associated with the quartile of moderate-intensity (3Mets or more) physical activity time (Q1 12.8, Q2 12.2, Q3 12.3, Q4 11.6 ng/ml; P for trend = 0.005; after adjustment for age, gender, and BMI). This inverse association was strongest in the C/C genotype of SNP-420. HOMA-IR was positively associated with serum resistin, and inversely associated with moderate-intensity physical activity time in the C/C genotype (Q1 1.51, Q2 1.52, Q3 1.36, Q4 1.32; P for trend = 0.01; after adjustment for age, gender, and BMI). Therefore, serum resistin and insulin resistance were inversely associated with physical activity in the C/C genotype of SNP-420 in the general Japanese population.

Disclosure
R. Kawamura: None. Y. Tabara: None. Y. Takata: None. M. Takakado: None. Y. Matsushita: None. T. Hadate: None. H. Onuma: None. K. Maruyama: None. T. Tanigawa: None. I. Saito: None. H. Osawa: None.
A Missense (c.T1424C:p.L475P) Mutation of ZYG11A Causes Maturity-Onset Diabetes of the Young
Authors: CHAROENSUK CHUTIMA , JUNGTRAKOON PRAPAPORN , TANGJITTIPOKIN WATIP , SUJJITJOON JATUPORN , PLENGVIDHYA NATTACHET , YENCHITSOMANUS PA-THAI 
Published: June 2018

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant mode. Approximately, 80% of Thai MODY families did not carry mutations of known MODY genes. This study aims, therefore, to identify an unknown causative gene of MODY in Thais. Exome sequencing was performed in DNA samples of two diabetic and one nondiabetic members of a MODY family with unknown genetic etiology. Only heterozygous non-synonymous variants with minor allele frequencies &lt;0.01%, which were shared between the two diabetic but not existed in nondiabetic family members, were selected for segregation analysis. Among these, a missense mutation (NM_001004339, c.T1424C:p.L475P) in a gene encoding zyg-11 family member A (ZYG11A) showed complete segregation with diabetes in three generations. This mutation is not present in any database and not detected in nondiabetic controls (n = 400) as well as other MODY-X probands (n = 90). The amino acid residue L475 of ZYG11A is evolutionally conserved among many species. Several prediction software tools suggested a deleterious effect of the L475P mutation. ZYG11A acts as a target recruitment subunit of an E3 ubiquitin ligase complex, which plays an important role in degradation of cyclinB1- a regulatory protein involved in mitosis. Suppression of ZYG11A in 1.1B4 β-cell line by specific small interfering RNA (siRNA) significantly reduced cell proliferation (p = 0.001) while increased cyclinB1 protein levels (p = 0.001). Moreover, 1.1B4 cells overexpressing ZYG11A showed a significant increase in proliferation as compared to the control cells (p = 0.019) whereas this effect was not observed in the cells overexpressing the mutant ZYG11A (p = 0.659). Taken together, this finding demonstrates the crucial role of ZYG11A in β-cell cycle regulation. It also suggests heterozygous ZYG11A-L475P mutation as a cause of MODY in the Thai family studied.

Disclosure
C. Charoensuk: None. P. Jungtrakoon: None. W. Tangjittipokin: None. J. Sujjitjoon: None. N. Plengvidhya: None. P. Yenchitsomanus: None.
TNF-α in Combination with Palmitate Enhances IL-8 Production via TLR4-Dependent Signaling Pathway—Potential Relevance to Metabolic Inflammation
Authors: AHMAD RASHEED , AKHTER NADEEM , KOCHUMON SHIHAB P. , ALROUB AREEJ ABU , THOMAS REEBY S. , SINDHU SARDAR T. 
Published: June 2018

Several chemokines produced by the adipose tissue in obesity are involved in metabolic inflammation. IL-8 or CXCL-8, a chemokine, is produced by immune cells and adipocytes and the increased levels of IL-8 are associated with several inflammatory disorders. Elevated IL-8 plasma levels have also been linked to insulin resistance (IR) and associated complications. It is still an open debate how does the obesity lead to an overwhelming production of IL-8. Not only the saturated free fatty acids and TNF-α are found to be elevated in obese humans but both have also been implicated with IR. Therefore, we sought to determine how these two obesity-associated factors could influence the production of IL-8 in human monocytic cells. Our data show that human monocytic cells/macrophages that were co-stimulated with palmitate and TNF-α synergistically increased IL-8 production. Of note, the synergistic production of IL-8 by TNF-α/palmitate was suppressed either by neutralizing TLR4 or by genetic silencing of TLR4. Moreover, inhibiting the clathrin-dependent endocytosis of TLR4 significantly suppressed the synergistic production of IL-8. This synergy between TNF-α and palmitate for IL-8 production was partly blocked by IRF3 knock down or TRIF inhibition. Both MyD88-deficient and MyD88-competent cells responded comparably to TNF-α/Palmitate co-stimulation. Interestingly, increased NF-κB/AP-1 activity was detected in the TNF-α/palmitate co-stimulated cells. Our human data show that increased adipose tissue TNF-α expression correlated positively with IL-8 expression (r=0.44, p=0.003). IL-8 also correlated positively with the fasting blood glucose (r=0.32, p=0.012), HBA1C (r=0.36, p=0.01 and HOMA-IR (r=0.30, p=0.05). These findings suggest that the cross-talk between saturated fatty acid palmitate and TNF-α signaling pathways is a key driver of the inflammatory response in obesity via an excessive production of IL-8.

Disclosure
R. Ahmad: None. N. Akhter: None. S.P. Kochumon: None. A. Abu Alroub: None. R.S. Thomas: None. S.T. Sindhu: None.
Pharmacological Inhibition of Neutrophil Elastase Attenuates Insulitis and Autoimmune Diabetes in Mice
Authors: LINGLING SHU , ZHONG LING , HOO RLC , XU AIMIN 
Published: June 2018

Background: Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic beta-cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Our previous studies demonstrated that increased circulating neutrophil elastase (NE) is closely associated with beta-cell autoimmunity in patients with T1D. Here we investigate the role and mechanism whereby NE participates in the pathogenesis of T1D, and to explore the therapeutic potential of the pharmacological NE inhibitors for autoimmune diabetes.
Method: Biochemical and immunological analysis were adopted to determine the dynamic change in the infiltration and activation of neutrophils in pancreas of NOD mice. NE-specific endogenous (pre-elafin/elafin) or pharmaceutical (sivelestat) inhibitors were supplemented into NOD mice to evaluate their effects on diabetes incidence and insultitis. Flow cytometry was employed to explore the effects of NE in mediating the crosstalk of immune cells.
Results: A dynamic change in the infiltration of neutrophils was observed in pancreatic islets of NOD mice, leading to a transient elevation of local NE activity. Supplementation of NE-specific inhibitors rectified the elevated pancreatic NE activity, alleviated insulitis and reduced the development of T1D in NOD mice. Inhibition of NE activity significantly attenuated the infiltration of pro-inflammatory macrophages into pancreas, reduced the production of inflammatory cytokines. In vitro studies showed that NE directly induced inflammatory responses in both min6 beta-cells and RAW264.7 macrophages through the activation of TLR4-IκB-NFκB pathway.
Discussion: NE-mediated crosstalk between beta-cell and macrophages forms a vicious feedback loop, resulting in the exaggerated beta-cell damage in NOD mice. Pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

Disclosure
S. Lingling: None. L. Zhong: None. R. Hoo: None. A. Xu: None.
The MultiPepT1De Study—Examining the Safety of Peptide Immunotherapy Using Multiple Islet Antigens in Recent-Onset Type 1 Diabetes
Authors: LIU YUK-FUN , POWRIE JAKE K. , ARIF SEFINA , FOUNTOULAKIS NIKOLAOS , JOSHI MAMTA , SMITH EMMA L. , STRIMENOPOULOU FOTEINI , THOMSON MOIRA , PEAKMAN MARK 
Published: June 2018

Background: Peptide immunotherapy (PIT) aims to modulate immune responses to specific antigens in order to restore immune tolerance. Recently, we reported outcomes of a phase 1b study of PIT at type 1 diabetes onset, showing safety, tolerability and changes in immune regulation pathways, following up to 12 doses of 10μg of a single proinsulin peptide that is naturally processed and presented by HLA-DR4 (DRB1*0401). Preclinical PIT studies show that multiple peptides in combination enhance tolerance induction.
Aims: To evaluate the safety and clinical effects of PIT using a mix of multiple islet autoantigen peptides in adults with recent-onset type 1 diabetes.
Methods: The MultiPepT1De study was a single centre, double-blind placebo-controlled, ascending dose, randomized trial recruiting adults aged 18-45 years within 4 years of diagnosis with HLA-DRB1*0401 genotype, positive islet autoantibodies and stimulated C-peptide &gt;0.2pmol/mL. Study drug comprised of 6 naturally processed and presented, islet-derived peptides (MultiPepT1De). Participants were enrolled into 3 cohorts for monthly intradermal injections for 6 months. In each cohort, subjects were randomized to receive placebo (n=2) or MultiPepT1De (n=6) at 10µg (Cohort 1), 100µg (Cohort 2) or 500µg (Cohort 3) doses.
Results: Twenty-seven participants were randomized; 3 participants withdrew for non-clinical reasons and were replaced. There were no episodes of systemic hypersensitivity, anaphylaxis or serious adverse reactions linked to MultiPepT1De administration. Analysis of changes in stimulated C-peptide, HbA1c and insulin dose per kg showed no evidence of disease acceleration following dosing compared with placebo. Mild transient injection site erythema was observed in all cohorts, with no increase on repeated dosing.
Conclusions: Intradermal administration of multiple islet-derived peptides up to a cumulative dose of 3000µg, is well tolerated with no safety concerns.

Disclosure
Y. Liu: Other Relationship; Self; Novo Nordisk Limited. Research Support; Self; Bristol-Myers Squibb Company. J.K. Powrie: None. S. Arif: None. N. Fountoulakis: None. M. Joshi: None. E.L. Smith: Employee; Self; UCB, Inc. F. Strimenopoulou: Employee; Self; UCB, Inc. M. Thomson: Employee; Self; UCB, Inc. M. Peakman: Research Support; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Bristol-Myers Squibb Company. Consultant; Self; UCB, Inc.. Research Support; Self; UCB, Inc.. Advisory Panel; Self; T1D Exchange.
A Cut-Off Value for Anti-GAD Ab ELISA Test for Predicting Future Insulin Dependency in SPIDDM May Not Exist
Authors: OIKAWA YOICHI , KATSUKI TAKESHI , KAWAI TOSHIHIDE , SHIMADA AKIRA 
Published: June 2018

We previously demonstrated that patients initially diagnosed with slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) using a radioimmunoassay (RIA) test for anti-glutamic acid decarboxylase antibody (GADA) (GADA-RIA), who were also positive on a GADA enzyme-linked immunosorbent assay (ELISA) test (GADA-ELISA), showed a reduced insulin secretory capacity early in the SPIDDM disease process [Endocr J. 2017;64:163]. When we used GADA-RIA test, in SPIDDM with non-insulin dependent state, a GADA-RIA value ≥10 U/mL(GADA-RIA-High) was believed to indicate a higher risk for future insulin dependency than a value &lt;10 U/mL(GADA-RIA-Low). In our previous study also, the insulin secretory capacity may be lower in “GADA-RIA-High and GADA-ELISA-positive SPIDDM patients” (A group) than those with “GADA-RIA-Low and GADA-ELISA-positive SPIDDM patients” (B group) early in the disease process, but this point was not yet confirmed. Therefore, we have now performed additional analysis to compare serum C-peptide levels in these two patient groups (group A vs. B). When restricted to a shorter disease duration, &lt;11 years based on our previous study, serum C-peptide levels were 0.73 ± 0.61 ng/mL in group B (n = 9) and 0.68 ± 0.65 ng/mL in group A(n = 15). There was no significant difference between the two measures, but each of these two measurements was significantly lower than those for patients with type 2 diabetes (2.20 ± 0.85 ng/mL; n = 15) and those for “GADA-RIA-Low and GADA-ELISA-NEGATIVE SPIDDM patients” (2.60 ± 1.66 ng/mL; n = 6). These findings suggest that, regardless of their GADA-RIA titer, GADA-ELISA-positive patients with SPIDDM may show a reduced insulin secretory capacity early in the disease process.
In conclusion, unlike GADA-RIA test, a cut-off value for GADA-ELISA test for predicting future insulin dependency in SPIDDM may not exist.

Disclosure
Y. Oikawa: None. T. Katsuki: None. T. Kawai: None. A. Shimada: Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis, Novo Nordisk A/S.
Alpha-1 Antitrypsin (AAT) Promotes Islets Graft Survival by Modulating Macrophage Activation
Authors: GOU WENYU , WANG JINGJING , KIM DO-SUNG , SONG LILI , STRANGE CHARLIE , ADAMS DAVID , MORGAN KATHERINE , WANG HONGJUN 
Published: June 2018

Infiltrating macrophages can induce inflammation by secretion of proinflammatory cytokines and contribute to islet graft loss shortly after islet transplantation. In this study, we tested the mechanistic effects of AAT in mitigating macrophage mediated inflammation in an intrahepatic islet transplantation model in which human islets (2500 islet equivalent numbers) were transplanted into NOD-SCID mice that had been rendered diabetic (blood glucose &gt;350mg/dl) by streptozotocin treatment. AAT (Prolastin-C, Grifols) was given to recipients intraperitoneally at 4 mg/mouse, every two days for 14 days, beginning before transplantation. In those recipients receiving AAT (n=29), 69.0% reached normoglycemia, compared to 35.7% in controls (n=28, p=0.002, logrank test) at 30 days post transplantation. Compared to mice treated with vehicle, AAT-treated mice had lower serum levels of interleukin 1 β (IL-1β), interferon- γ (IFN-γ) and interleukin 6 (IL-6), at day 1 post transplantation. To explore potential cell target(s) of AAT action, we analyzed activation of macrophages infiltrated into the liver after transplantation. Fewer M1 macrophages were observed in AAT-treated mice than in controls. To measure the effects of AAT on macrophage activation, we added AAT to Raw264.7 cells stimulated with IFN-γ in vitro. Expressions of M1 markers (iNOS, CD11c, TNFα, and IL-6) were dramatically decreased in AAT-treated cells compared to vehicle-treated controls. Co-culture of IFN-γ activated macrophages with islets led to islet cell apoptosis. Addition of AAT in the co-culture system reduced macrophage activation and protected islet cells from apoptosis.
In summary, AAT treatment significantly enhances human islet graft survival and function after transplantation into the liver of NOD-SCID mice, in part by suppression of macrophage activation and pro-inflammatory cytokine production.

Disclosure
W. Gou: None. J. Wang: None. D. Kim: None. L. Song: None. C. Strange: Research Support; Self; Grifols, CSL Behring, Shire. Consultant; Self; Shire. Stock/Shareholder; Self; Abeona. Consultant; Self; CSL Behring. Research Support; Self; Adverum. Consultant; Self; Adverum. Research Support; Self; MatRx. D. Adams: None. K. Morgan: None. H. Wang: None.
Protective Effect of NecroX-7 on Islets against Oxidative Stress and Inflammation
Authors: KWON YOUNGSANG , LEE HAN SIN , KIM HYUNJIN , KIM GYURI , JIN SANG-MAN , LEE MOON-KYU , KIM JAE HYEON 
Published: June 2018

Oxidative stress generated during islet isolation, culture, and transplantation causes islet cell damage mediated by hypoxia, reactive oxygen species (ROS) and inflammatory responses. We investigated the protective effects of NecroX-7, a novel ROS scavenger, during isolation and/or culture of islets. For ex vivo studies, islets from heterozygote human islet amyloid polypeptide (hIAPP+/-) mice and C57BL/6J mice were isolated by collagenase with and without supplementation with 20 uM of NecroX-7. Supplementation with NecroX-7 provided markedly increased islet viability and ATP contents, and attenuated ROS, transcription of c-Jun N-terminal kinases, high mobility group box-1 (HMGB1) and proinflammatory cytokines including interleukin-1beta (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a). Transplantation of islets, which is derived from islet isolation method using supplementation with NecroX-7, into syngeneic subrenal subcapsular of hIAPP+/- mice also improved post-transplant blood glucose levels. Also, NecroX-7 protected RINm5F cells from t-BHP-induced and serum deprivation induced toxicity in in vitro culture by dose-dependent manner from 0.1 uM to 20 uM. Supplementation of medium with NecroX-7 during serum-deprived culture condition also improved impaired viability and serum deprivation-induced ROS in islets from hIAPP+/- mice by dose-dependent manner from 0.1 uM to 20 uM. These findings suggest that NecroX-7 supplementation during the islet isolation and/or culture process suppressed inflammatory responses and ROS induced by serum deprivation and provides a potential benefit to improve post-transplantation outcomes.

Disclosure
Y. Kwon: None. H. Lee: None. H. Kim: None. G. Kim: None. S. Jin: None. M. Lee: None. J. Kim: None.
Synergistic Effect of Islet Magnetic Resonance Imaging Using Direct Linking of Ferumoxytol to Surface of PEGylated Islet
Authors: LEE HAN SIN , KWON YOUNGSANG , KIM HYUNJIN , HAQUE MUHAMMAD R. , KIM GYURI , JIN SANG-MAN , LEE MOON-KYU , BYUN YOUNGRO , KIM JAE HYEON 
Published: June 2018

Purpose: We previously reported the feasibility of islet magnetic resonance imaging (MRI) using ferumoxytol, which is the only clinically-available ultrasmall superparamagnetic iron oxide. However, the labeling efficacy was not sufficient for its clinical use in islet transplantation. We aimed to evaluate the feasibility of islet MRI using direct linking of ferumoxytol to islet surface through PEGylation.
Method: Islets were labeled by surface modification with up to 4% PEG-heparin-ferumoxytol. We compared islet function and viability of control islets and ferumoxytol-heparin-PEGylated islets. Efficacy of labeling with ferumoxytol-heparin-PEGylation and ferumoxytol alone was assessed in both ex vivo and in vivo models.
Results: Labeling of islets with up to 2% PEG-heparin-ferumoxytol did not derange ex vivo islet viability and function. The T2* relaxation time was optimal when islets were labeled with 1 to 4% PEG-heparin-ferumoxytol. The labeling intensity in the ex vivo MRI of ferumoxytol-heparin-PEGylated islets was stronger than islets labeled with ferumoxytol alone. In syngeneic renal subcapsular islet transplantation, labeling with ferumoxytol-heparin-PEGylation showed better in vivo labeling efficacy than that of islets labeled with ferumoxytol alone. After labeling with ferumoxytol-heparin-PEGylation, there was a correlation between the total area of visualized islets and the transplanted islet mass in syngeneic mouse intraportal islet transplantation, and the visibility was also confirmed in the preliminary analysis of non-human primate intraportal islet transplantation model.
Conclusion: Direct linking of ferumoxytol to islet surface through PEGylation improved the labeling efficacy and it could be used for the islet MRI in clinical islet transplantation.

Disclosure
H. Lee: None. Y. Kwon: None. H. Kim: None. M.R. Haque: None. G. Kim: None. S. Jin: None. M. Lee: None. Y. Byun: None. J. Kim: None.
Intraperitoneally Administered Neo-islets, Aggregates of Mesenchymal Stem Cells, and Cultured Islet Cells Improve Glycemic Control of Spontaneously Occurring Insulin-Dependent Diabetes Mellitus in Pet Dogs—A Pilot Study, INAD 012-776
Authors: WESTENFELDER CHRISTOF , GOOCH ANNA , LOY SON NATASHA K. , AVILA NICOLE , FISCHER JULIE R. 
Published: June 2018

The clinical need for novel technologies that effectively treat patients with T1DM and render them insulin-independent is great. Endogenous insulin replacement by pancreas or islet transplants is currently the only treatment that can achieve insulin-independence and provide significant end organ protection in patients with autoimmune-mediated T1DM. However, the shortage of pancreas donors and the need for repeated islet transplants, requiring up to five donors each, continue to limit the availability of these expensive therapies. Both transplant modalities depend on the permanent use of potentially toxic antirejection drugs. We previously reported that allogeneic, i.p. administered “Neo-Islets” (NIs), composed of cultured islet cells coaggregated with high numbers of immunoprotective and cytoprotective Adipose Derived Stem Cells (ASCs) reestablished normoglycemia in autoimmune T1DM NOD mice without the use of encapsulation devices or immunosuppressive agents. With FDA guidance, we are currently testing this NI technology in a pilot study of insulin-dependent, spontaneously diabetic pet dogs by the i.p. administration of 2x10e5 NIs/kg bw to metabolically controlled (blood glucose, triglycerides) dogs under light anesthesia and ultrasound guidance. Dogs are continued on insulin as needed and are to be followed for 3 years for adverse events, glycemic control, insulin need. Two dogs have been treated. One has been followed for 6 months, the other for 3 months. While decreasingly insulin dependent with significantly improved glycemic control, and no IgG response to the allogeneic NIs, no adverse events have been observed.
In conclusion, these data demonstrate that this novel technology is safe, feasible and holds promise for the treatment of dogs with insulin dependent DM, but that further protocol/dosing optimization is required.

Disclosure
C. Westenfelder: Consultant; Self; SymbioCellTech, LLC. A. Gooch: Other Relationship; Self; SymbioCellTech, LLC. N.K. Loy Son: None. N. Avila: None. J.R. Fischer: None.