bluuebunny/crossref_metadata_2025_split huggingface dataset:
17-OR: Efficacy and Safety of Chiglitazar, a Novel PPARα/γ/d Pan-Agonist, in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Superiority Trial (CMAP)
Authors: JI LINONG , SONG WEIHONG , FANG HUI , LI WEI , GENG JIANLIN , XU YAN CHENG , WANG YANGANG , GUO LIAN , CAI HANQING , YANG TAO , LI HONG-MEI , YANG GANGYI , LI QIFU , LIU KUANZHI , LI SHUYING , LIU YANJUN , SHI FUYAN , LI XIN SHENG , GAO XIN , JI QIUHE , TIAN HAOMING , SU QING , ZHOU ZHIGUANG , WANG WENBO , ZHOU ZUNHAI , LI XUEJUN , XU YAN CHENG , NING ZHIQIANG , LU XIANPING , JIA WEIPING 
Published: June 2019

Chiglitazar showed favorable effect on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to further compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes inadequately controlled with lifestyle interventions (ClinicalTrials.gov NCT02121717). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. After 24-week treatment, patients in placebo group were randomly assigned to receive chiglitazar 32 mg or 48 mg, while others remained on the planned treatment till to 52 weeks. The primary endpoint was change in HbA1c at week 24 with superiority of each chiglitazar dose versus placebo. Analysis was done in all randomized patients who received at least one dose of study drug (n= 535). Chiglitazar was superior to placebo in HbA1c reduction at 24 weeks (LS mean difference -0.87% [95% CI -1.10 to -0.65] and -1.05% [95% CI -1.29 to -0.81] for 32 mg and 48 mg, respectively) and achieved sustainable effect till to 52 weeks. Overall adverse events were comparable across groups. The incidences of weight gain, edema, and hypoglycemia were relatively higher in chiglitazar groups. Chiglitazar showed superior and sustainable HbA1c lowering effect with well tolerated safety profile in patients with type 2 diabetes.

Disclosure
L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. W. Song: None. H. Fang: None. W. Li: None. J. Geng: None. Y. Xu: None. Y. Wang: None. L. Guo: None. H. Cai: None. T. Yang: None. H. Li: None. G. Yang: None. Q. Li: None. K. Liu: None. S. Li: None. Y. Liu: None. F. Shi: None. X. Li: None. X. Gao: None. Q. Ji: None. H. Tian: None. Q. Su: None. Z. Zhou: None. W. Wang: None. Z. Zhou: None. X. Li: None. Y. Xu: None. Z. Ning: None. X. Lu: None. W. Jia: None.

Funding
Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)
1702-P: Fine-Scale Haplotype Mapping of PPM1K Gene Reveals New Genetic Markers for the Study of Insulin Resistance at Clinical Scale
Authors: HAYDAR SARA , LAUTIER CORINNE , GRIGORESCU FLORIN 
Published: June 2019

Branched chain amino acids (BCAA) plasma levels represent potential biomarkers for development of type 2 diabetes (T2D). Mendelian randomization and prospective studies indicated causal relationship between SNPs in PPM1K (protein phosphatase Mg2+/Mn2+ dependent 1K) gene (Chr 4q22.1) and increased risk of incident T2D while other studies, including ours suggested the contribution of MUT (metylmalonyl-CoA mutase) gene (Chr 6p12.3) in insulin resistance (IR). To define genetic markers we performed fine-scale haplotype mapping of PPM1K in two populations (French and Romanians) with metabolic syndrome (n = 465). SNPs were genotyped with Affymetrix and enriched by imputation at 1000 genome density (BEAGLE 4.1). Haplotype association was performed by sliding window (4 SNPs windowing) and analyzed in HAPLOVIEW and PHASE 2.1. Previous leader SNPs in PPM1K (rs7678928 and rs1440581) were not associated with IR in our population but haplotype mapping revealed two major signals downstream (GGGC) and upstream (ACAG), centered by rs71609524 and rs4423843 with P &lt; 3.76 x 10-3 (OR 1.59, 95% CI [1.13 - 2.23]) and &lt; 4.72x10-3 (OR 1.50, 95% CI [1.12 - 2.01]), respectively. Values were weaker that those from MUT gene (P-value of the most significant haplotype, centered by rs2167284 was &lt; 10-5). Total BCAA plasma levels were associated with PPM1K by several SNPs, including rs7656367 and rs4693955 with P &lt; 5 x 10-3, OR of 0.41 and 3.22, respectively. Interestingly, correlation trend test with leucine, isoleucine and valine were better correlated with SNPs in the MUT gene: rs10948396 was associated with P &lt; 7.91 x 10-5 (Bonferroni 6 x 10-2) and confirmed by correlation with total BCAA levels (P &lt; 1.60 x 10-6, Bonferroni 1.22 x 10-3). These data suggest synergistic effects and indicate that new valuable genetic markers can be defined for clinical trials using fine-scale haplotype mapping, thus revealing complex relationship between genes in the determinism of IR and BCAA metabolism.

Disclosure
S. Haydar: None. C. Lautier: None. F. Grigorescu: None.

Funding
MEDIGENE (FP7-279171)
172-OR: Perfusion Controls Insulin-Stimulated Glucose Uptake in Skeletal Muscle by Altering the Rate of Glucose Dispersion In Vivo
Authors: MCCLATCHEY PENN MASON , WILLIAMS IAN M. , MIGNEMI NICHOLAS A. , HUGHEY CURTIS C. , MCGUINNESS OWEN P. , BECKMAN JOSHUA A. , WASSERMAN DAVID 
Published: June 2019

Objective: It has been proposed that the microcirculation contributes to insulin-stimulated muscle glucose uptake (MGU) by recruiting capillaries and thus enhancing the dispersion of insulin from capillaries into interstitium. This theory contrasts with intravital microscopy (IVM) measurements showing near-complete capillary recruitment at baseline, and it does not address the possibility that dispersion of glucose, rather than insulin, could limit MGU. This study tests the hypotheses that perfusion effects on MGU are 1) capillary recruitment-independent and 2) critical more so for the interstitial dispersion of glucose, rather than insulin.
Methods: In one experiment, microvascular perfusion was measured using IVM before and after intravenous insulin injections. In a second experiment, mice were treated with vasoactive drugs. Microvascular perfusion, dispersion of fluorophores approximating insulin size (10 kDa dextran) and glucose (2-NBDG), and muscle accumulation of a radioactive glucose analogue (phospho-2[14C]DG) were measured.
Results: The first experiment showed ∼95% recruitment of capillaries before insulin with no recruitment following insulin. In the second experiment, perfusion-limited delivery indices (calculated from capillary blood flow and its distribution) and 2-NBDG dispersion, but not diffusion-limited delivery indices (calculated from perfused surface area and permeability) or 10 kDa dextran dispersion, predicted phospho-2[14C]DG accumulation.
Conclusions: These findings show that the role of perfusion in insulin-stimulated MGU is mediated by blood flow rather than capillary recruitment, and that the rate of glucose dispersion into the interstitium overrides insulin dispersion as a determinant of muscle insulin sensitivity in vivo.

Disclosure
P.M. McClatchey: None. I.M. Williams: None. N.A. Mignemi: None. C.C. Hughey: None. O.P. McGuinness: None. J.A. Beckman: Consultant; Self; AstraZeneca, Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Bayer AG, Novartis AG. D. Wasserman: None.

Funding
National Institutes of Health (DK059637, DK054902, DK050277, T32DK101003, F32DK120104, P30DK020593); American Heart Association
1732-P: ERK1 and ERK2 Are Required for Lipopolysaccharide-Induced Production of Cytokines and Chemokines by Macrophages
Authors: CHANG PHOEBE F. , REYNA SARA M. 
Published: June 2019

Low-grade chronic inflammation may be a factor in the development of insulin resistance. Studies suggest that chronic inflammation may be due in part to changes in composition and function of gut microflora, which provide an intestinal barrier preventing bacterial lipopolysaccharide (LPS) release. Animal and human studies demonstrate that obesity increases gut permeability leading to elevated plasma LPS levels resulting in inflammation and metabolic dysfunction. We hypothesized that insulin resistance could be produced by inflammatory factors secreted by macrophages when exposed to gut-released LPS. We examined the extracellular signal-regulated kinase (ERK) signaling pathway, which may be responsible for the macrophage inflammatory response. We examined whether inhibition of ERK activity blocked LPS-mediated responses in bone marrow derived macrophages (BMDM). To determine which ERK isoform is involved in the regulation of inflammatory factor production, we used siRNA to knockdown ERK1, ERK2, or both. BMDM were treated with LPS (100 ng/ml, 6hr). LPS induced TNF-α, RANTES, MCP-1, and IFN-β production of 106371±18250 pg/ml, 11827 ± 1168 pg/ml, 851 ± 73 pg/ml, and 454 ± 46 pg/ml, respectively. Knockdown of ERK1 decreased the release of TNF-α and RANTES to 26534 ± 1471 pg/ml and 5938 ± 806 pg/ml, respectively. Knockdown of ERK2 decreased the release of TNF-α and RANTES to 11600±3610 pg/ml and 7289 ± 265 pg/ml, respectively. Knockdown of either ERK1 or ERK2 did not decrease the release of MCP-1 and IFN-β. However, double knockdown of ERK1 and ERK2 had the greatest inhibition of TNF-α, RANTES, MCP-1, and IFN-β release (not detected, 1540 ± 240 pg/ml, 549 ± 32 pg/ml, and 31 ± 1 pg/ml, respectively).
In summary, knockdown of both ERK isoforms is necessary to completely abrogate the LPS effect in macrophages. We propose that ERK positively regulates LPS-mediated inflammatory responses and inhibition of ERK signaling may protect against development of insulin resistance.

Disclosure
P.F. Chang: None. S.M. Reyna: None.

Funding
National Institutes of Health; University of Texas Rio Grande Valley
1733-P: Cross Talk between Palmitate and LPS Leads to a Synergistic IL-6 Production in Human Monocytic Cells: Implications for Metabolic Inflammation
Authors: AHMAD RASHEED , KOSHY MERIN SERA , KOCHUMON SHIHAB PUTHIYAVEETTIL , THOMAS REEBY SARA , AL-MULLA FAHD 
Published: June 2019

IL-6 concentrations are positively correlated with the level of obesity and associated proinflammatory state that promotes the development of insulin resistance. The metabolic stimuli that regulate IL-6 production has not been fully revealed. Since metabolic concentrations of plasma LPS and palmitate (free fatty acid) are increased in obesity and are considered as potent inducers of IL-6. Therefore, we have examined whether interaction of palmitate with LPS trigger the production of IL-6 in human monocytic cells. THP-1 and primary human monocytic cells incubated with palmitate and LPS together produced more biological active IL-6 compared to monocytes incubated with palmitate or LPS alone. Synergistic IL-6 induction was blocked either by silencing the expression of TLR4 or MyD88. However, IRF3 did not have impact on this synergism. Non-metabolizable analog as well as specific metabolic pathway inhibitors of palmitate showed that esterification of palmitate with coenzyme A (CoA) involved, in part, in this synergism. Furthermore, synergistic upregulation of IL-6 was suppressed by histone acetyltransferase inhibitor (anacardic acid). Histone deacetylase (HDAC) inhibitor (sodium butyrate) enhanced IL-6 production.
In conclusion, our results show that an interaction between palmitate and LPS depends on TLR4/MyD88, lipid metabolism and epigenetic signaling pathways, which leads to the elevation of IL-6, providing interesting pathophysiological connections among FFAs, LPS, and IL-6 in settings such as obesity or metabolic inflammation.

Disclosure
R. Ahmad: None. M.S. Koshy: None. S.P. Kochumon: None. R.S. Thomas: None. F. Al-Mulla: None.

Funding
Kuwait Foundation for the Advancement of Science
1734-P: A Considerable Mismatch of Measurements between Radioimmunoassay and Enzyme-Linked Immunosorbent Assay Tests for Anti-Glutamic Acid Decarboxylase Antibody
Authors: OIKAWA YOICHI , KONDO TAKUMA , SHIMADA AKIRA , SEINO YUTAKA , KITAOKA MASAFUMI 
Published: June 2019

Most cases of type 1 diabetes mellitus are considered to be caused by pancreatic β-cell destruction through islet cell autoimmunity. Anti-glutamic acid decarboxylase antibody (GADA) is an important islet cell-associated autoantibody in the diagnosis of autoimmune type 1 diabetes mellitus. In Japan, the GADA assay kit was changed from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) in 2015. Thereafter, a mismatch of measurements between the two tests became apparent in clinical situations. The aim of this study was to clarify the extent of the mismatch between the two tests on a larger scale. In this cross-sectional non-local/non-hospital-based study, we collected anonymized data on GADA levels of 598 randomly selected participants in whom GADA levels were simultaneously measured by GADA-RIA and GADA-ELISA tests. We found that 34% (= 162/477) of the GADA-RIA-positive participants showed negative results in the GADA-ELISA test; the mismatch was predominantly observed in participants with relatively low GADA-RIA levels. Concretely, when considering lower GADA-RIA levels alone (1.5-32 U/mL), GADA-ELISA-negative participants accounted for 44.8% (= 162/362) of the GADA-RIA-positive participants. These findings suggest that a single application of the GADA-ELISA test may affect the precise diagnosis of type 1 diabetes mellitus, and cause physicians’ confusion on the diagnosis. Therefore, the cause for the mismatch should be promptly identified.

Disclosure
Y. Oikawa: None. T. Kondo: None. A. Shimada: Advisory Panel; Self; Terumo Medical Corporation. Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Y. Seino: Research Support; Self; Arkray, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. M. Kitaoka: Research Support; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd.
1735-P: Oral Exposure to Air Pollutants Mediates Diabetes via Innate Immunity
Authors: BOSCH ANGELA J.T. , ROHM THERESA V. , ALASFOOR SHEFAA , BAUMANN ZORA , CAVELTI-WEDER CLAUDIA 
Published: June 2019

Background: Besides classical risk factors such as sedentary lifestyle and unhealthy diet, air pollution has emerged as an unexpected risk factor for type 2 diabetes. However, the causal mechanism remains poorly understood. Air pollution particles are known to reach the gastrointestinal tract by mucociliary clearance. Underlining the clinical relevance of oral exposure, air pollution has been associated with a variety of gastrointestinal diseases. Therefore, we aim to study the effects of oral air pollution exposure on glucose metabolism and a potential immune-mediated mechanism.
Research Design and Method: Male C57B6/N, Rag2-/- and CCR2-/- mice or mice on a diet supplemented with a Csfr1-inhibitor were exposed to diesel exhaust particles (DEP; 12µg 5 days/week) or PBS by gavage for up to 6 months. Glycemia, tissue inflammation and immune cells were assessed.
Results: Mice orally treated with DEP developed impaired glucose tolerance with reduced insulin secretion, while insulin resistance, systemic, adipose tissue and liver inflammation were not induced. This effect was independent of the adaptive immunity as Rag2-/- mice, which are devoid of B and T cells, also became glucose intolerant. In contrast, glucose intolerance did not develop in CCR2-/- mice and mice treated with a Csfr1-inhibitor. Supporting a causative role of intestinal macrophages in air pollution-induced diabetes, wild type mice exposed to oral DEP had reduced anti-inflammatory, resident macrophages in the lamina propria of the gut.
Conclusion: Oral exposure to air pollutants results in impaired glucose tolerance, which is mediated by innate immunity as we found a loss of anti-inflammatory, resident macrophages in the gut. Moreover, mice devoid of macrophages are protected from air pollution-induced diabetes. Our findings provide a new understanding how environmental pollutants affect metabolic health, which is crucial for preventing the worldwide disease burden of air pollution-induced diabetes.

Disclosure
A.J.T. Bosch: None. T.V. Rohm: None. S. AlAsfoor: None. Z. Baumann: None. C. Cavelti-Weder: None.
1740-P: Gene-Editing of FOXP3 in Antigen-Specific CD4+ T Cells for Restoration of Immune Tolerance in Type 1 Diabetes
Authors: XIANG YUFEI , SOMMER KAREN , HONAKER YUCHI , SMITH JESSICA , TORGERSON TROY R. , BUCKNER JANE , RAWLINGS DAVID 
Published: June 2019

Clinical trials for type 1 diabetes (T1D) using expanded, autologous natural regulatory T cells (nTreg) have demonstrated safety and sustained engraftment. Limitations to this approach include the requirement for potential instability in vivo, lack of antigen specificity, and intrinsic Treg defects in some patients. As an alternative strategy, we used gene editing to convert primary human or mouse CD4+T cells into immunosuppressive Treg-like cells. Our approach utilizes co-delivery of designer nucleases and AAV6 homology-directed repair templates to enforce the expression of FOXP3, a transcription factor determining Treg development. These edited (ed)Treg exhibit a phenotype and functional activity similar to nTreg and ameliorate the inflammatory xenograft response of effector T cells in NOD-scid-Il2rgnull (NSG) mice. In the current study, we hypothesized that antigen-specific edTreg would exhibit increased potency in treatment of autoimmune diseases including T1D. As an initial test of feasibility, we generated edTreg from flu- or tetanus-specific human CD4+ T cells and demonstrated antigen-specific suppressive activity. Next, we show proof-of-concept for antigen (Ag)-specific edTreg in a T1D mouse model. Using mouse-specific nucleases and donor templates, we edited CD4+T cells from transgenic NOD mice expressing the diabetogenic, BDC2.5, TCR. BDC2.5 edTreg were similar to nTreg on the basis of key cell markers and cytokine production. BDC2.5 edTreg or polyclonal edTreg from NOD mice were co-transferred with effector BDC2.5 T cells (CD4+CD25-) into NSG mice. Recipients of only effector cells exhibited rapid diabetes onset. In contrast, edTreg delayed disease and, as hypothesized, Ag-specific edTreg exhibited much greater suppression and longer delays in T1D onset. Together, our findings demonstrate the capacity to generate functional, Ag-specific, edTreg with potential therapeutic application in promoting immune tolerance in T1D.

Disclosure
Y. Xiang: None. K. Sommer: None. Y. Honaker: None. J. Smith: None. T.R. Torgerson: Consultant; Self; CSL Behring, Grifols, Shire, UCB, Inc. Research Support; Self; CSL Behring. J. Buckner: None. D. Rawlings: None.

Funding
Seattle Children’s Research Institute, Seattle Children's Center for Immunity and Immunotherapies; Seattle Children's Program in Cell and Gene Therapy; Seattle Children's Guild Association (to D.R.); The Leona M. and Harry B. Helmsley Charitable Trust (to D.R.); National Institutes of Health (DP3DK111802-01 to D.R.)
1741-P: Overexpression of the Type 1 Diabetes-Associated IFIH1 A946T Single Nucleotide Polymorphism in Coxsackievirus B Infection
Authors: TAYLOR JARED P. , TSE HUBERT M. 
Published: June 2019

Type 1 diabetes (T1D) is a multifactorial autoimmune disease with a strong genetic basis. However, evidence suggests a role for environmental factors such as viral infections in triggering disease onset. One viral infection that is highly correlated with T1D is the Coxsackievirus B (CVB) serotype. Sensing of CVB is mediated by the melanoma differentiation-associated protein 5 (MDA5), a cytosolic sensor of dsRNA, which is encoded by the IFIH1 gene. Stimulation of the MDA5 signaling pathway activates the transcription factors IRF3 and NFκB p65, which induce type I IFNs synthesis. Type I IFNs can signal in an autocrine manner through the JAK/STAT pathway to initiate an antiviral transcriptional program. Single nucleotide polymorphisms (SNP) in the IFIH1 gene such as rs1990760, which results in a non-synonymous mutation that changes alanine at position 946 to a threonine, is highly associated with increased risk for T1D. Studies in human PBMCs and mice have demonstrated that the A946T SNP results in an increased sensitivity to viral ligands and subsequently a stronger downstream IFN response. We hypothesize that cells overexpressing the type I diabetes-associated variant 946T will have enhanced downstream signaling and subsequent type I IFN secretion in response to viral ligands and CVB infection. To test this, we stably overexpressed MDA5 with the 946A or 946T variants in HeLa cells. We anticipate that signaling events downstream of CVB infection and synthetic ligand poly (I:C) treatment, such as levels of phosphorylated IRF3 and NFκB p65 will be increased in cells expressing the T1D-associated allele 946T in contrast to cells overexpressing the non-risk allele 946A. Corroborating the increase in IRF3 and NFκB p65 pathway activation, we expect to observe enhanced production and secretion of type I IFNs were measured using HEK Blue IFN reporter cells that may partly explain how CVB infections can trigger autoimmune diabetes.

Disclosure
J.P. Taylor: None. H.M. Tse: None.

Funding
National Institutes of Health
1742-P: Blockade and Reversal of Autoimmunity and Type 1 Diabetes through Gene-Therapeutic and Nutritional Intervention of Elevating ω-3 PUFAs
Authors: BI XINYUN , LI XIAOXI , ZHAO ALLAN ZIJIAN 
Published: June 2019

Despite the benefit of insulin injection, blockade of autoimmune attack and regeneration of pancreatic islets remain to be the ultimate sought-after goal for the complete cure of type 1 diabetes(T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for both prevention and amelioration of autoimmune diseases. Herein, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, readjusted the population of Th1, Th2, Th17 and Treg, balanced the ratio of Th1/Th2, decreased the levels of such cytokines as IFN-γ, IL-17, IL-6 and TNF-α. In T1D patients, ω-3 PUFAs also regulated CD4+ T-cell differentiation isolated from peripheral blood mononuclear cells (PBMCs) in a manner similar to that observed in NOD mice. The regulation of CD4+ T-cell differentiation was mediated at least in part through some of their eicosanoid derivatives and by inhibition of mTORC1. Importantly, therapeutic intervention in NOD mice through nutritional or gene-therapeutic supplementation completely normalized blood glucose and insulin levels for at least 182 days, blocked autoimmune development, prevented lymphocyte infiltration into regenerated islets, and sharply elevated expression of Pdx1 and Pax4. The findings revealed herein can potentially become a novel and cost-effective therapeutic modality in the cure of T1D.

Disclosure
X. Bi: None. X. Li: None.

Funding
National Natural Science Foundation of China