bluuebunny/crossref_metadata_2025_split huggingface dataset:
1089-P: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Multiple Ascending Dose Study of HD-6277, a Potent and Selective G-Protein-Coupled Receptor 40 (GPR40) Agonist, in Patients with Type 2 Diabetes Mellitus
Authors: KIM KI-HWAN , YANG HYE-JUNG , BAEK MYOUNGKI 
Published: June 2020

Previously, HD-6277 was reported about its safety and tolerability in healthy volunteers both in single ascending doses (SAD) and multiple ascending doses (MAD) study over all doses under fasting conditions. Based on these results, two doses with 25mg and 100 mg were selected and administered for 28 days in T2DM patients. 20 subjects were randomized (7:3) in two cohort as an exploratory study. No serious adverse events (AEs) or discontinuations as a result of AEs occurred in T2DM patients. The geometric mean Cmax values at day 1 were 2236 and 9422 ng/mL and the geometric mean AUC24 values were 26160 h*ng/mL and 111100 h*ng/mL, respectively, for the 25 and 100 mg dose levels. Following daily oral doses for 14 days, the geometric mean Cmax,ss values were 3993 to 17400 ng/mL and the geometric mean AUC24,ss values were 59270 h*ng/mL and 261300 h*ng/mL with time to median maximum plasma concentration of 1.0 and 1.5 hours, respectively. Results for multiple dose administration of 100 mg in T2DM patients were comparable to those observed in healthy subjects in SAD and MAD study. The geometric mean CL,ss/F was consistent across the dose levels and approximately 0.4 L/h. The geometric mean accumulation ratio for AUC was 2.27 and 2.35 for the 25 and 100 mg dose levels, indicating modest accumulation of HD-6277 following multiple dose administration, which showed comparable profile with that of healthy subjects ranged from 2.14 to 2.34 across the dose levels in MAD study. Therefore, HD-6277 was safe, well tolerated and showed dose-related plasma exposure when the drug is administered at doses ranging from 25 to 100 mg in T2DM patients.

Disclosure
K. Kim: None. H. Yang: Employee; Self; Hyundai Pharm. Co,.Ltd. M. Baek: None.

Funding
Korean Ministry of Health and Welfare (HI17C2529)
109-OR: Genetic Discrepancy of HLA Class I Alleles in Chinese Patients with Type 1 Diabetes at Different Onset Ages
Authors: JIANG ZIYU , REN WENQIAN , XIAN YINGXIN , YAN JINHUA , YANG DAIZHI , LUO SIHUI , ZHENG XUEYING , XU WEN , BEI JIN-XIN , GROOP LEIF , WENG JIANPING 
Published: June 2020

Association between HLA class I genes and onset ages of type 1 diabetes (T1D) has been reported in Europeans—risk A*2402 and B*3906 were associated with an earlier age at onset. However, there exists considerable heterogeneity in different populations and individuals of T1D. Its incidence varies dramatically by country and region, ranging from &gt; 60 per 100000 persons years in Finland to 1.01 per 100000 persons years in China. With latter, as many as 65% of the newly diagnosed patients occurred among adults. Furthermore, little is known about the distribution of HLA class I alleles in Chinese patients with T1D at different onset ages. To clarify the contribution of HLA class I genes to T1D with different onset ages in Chinese, 376 patients with T1D and 500 healthy controls were enrolled in this study to analyze HLA-A, B, C alleles conditioning on DRB1-DQA1-DQB1 haplotypes. Among them, 159 patients with an onset age &lt; 15 years were assigned into early-onset group (EG) while the rest 217 patients constituted the late-onset group (LG). After adjustment for linkage disequilibrium with HLA class II, A*24:02:01 (OR 2.7), B*54:01:01 (OR 4.1) and C*15:02:01 (OR 7.8) were associated with susceptibility in EG patients, while A*24:02:01 (OR 2.3), B*15:02:01 (OR 2.5), B*54:01:01 (OR 3.6) and C*08:01:01 (OR 2.0) were predisposing in LG patients when compared with control subjects. Besides, B*46:01:01 (OR 0.4) conferred protection against T1D in EG patients, while B*46:01:01 (OR 0.5) and A*02:07:01 (OR 0.6) were protective in LG patients. When comparing the distribution of HLA class I genes between EG and LG, the data showed that the frequency of A*11:01:01 was higher in LG than EG. When A*11:01:01 was analyzed in patients at all ages using linear regression, it showed a positive correlation between A*11:01:01 and T1D onset age.
In conclusion, the data showed that HLA class I alleles play a role in susceptibility to T1D with different onset ages among Chinese patients, which is independent from DR-DQ haplotypes.

Disclosure
Z. Jiang: None. W. Ren: None. Y. Xian: None. J. Yan: None. D. Yang: None. S. Luo: None. X. Zheng: None. W. Xu: None. J. Bei: None. L. Groop: None. J. Weng: None.

Funding
National Natural Science Foundation of China (81530025); National Key Research and Development Program of China (2017YFC1309603); Sun Yat-sen University (2007030)
1093-P: Association between First-Line Monotherapy with Metformin and the Risk of Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus
Authors: TEKIN ZEHRA , MILINOVICH ALEX , JI XINGE , BAUMAN JANINE , KATTAN MICHAEL , PANTALONE KEVIN M. , ZIMMERMAN ROBERT S. , CHUNG MINA K. , KASHYAP SANGEETA 
Published: June 2020

Background: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is associated with an increased risk of thromboembolic events, heart failure, and frequent hospitalizations. Type 2 diabetes mellitus (T2DM) has one of the strongest associations with AF with an overall 35% increased risk. Metformin is the first-line medication for T2DM and it has been proposed to have anti-inflammatory, pro-metabolic and cardioprotective benefits, but its effect on AF is not well studied.
Our objective was to investigate whether the initial metformin monotherapy was associated with reduced AF rates compared to other non-insulin agents.
Methods: This retrospective cohort analysis involved adults with newly diagnosed T2DM between 2007 and 2017, without any history of arrhythmias or contraindications to metformin use including GFR less than 30 ml/min who initiated a single antidiabetes therapy (except insulin). A multivariate analysis was performed to control for other variables that may have impacted the association between initial therapy with metformin and the outcomes of interest.
Results: Out of 42384 cases with newly diagnosed diabetes, 5664 patients met the inclusion criteria. The majority of patients initiated monotherapy with metformin (81%), followed by sulfonylureas (13%) and thiazolidinediones (4%). The 10-year cumulative incidence of AF in the metformin group was 5.2% vs. 8.1% with others. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92 95% CI 0.69 to 1.21; P = 0.55). Increased age and the presence of CHF were associated with significantly higher risk of AF (HR: 1.29, 95% CI: 1.21 to 1.37; P&lt;0.001; HR: 2.73, 95% CI: 1.62 to 4.61; P&lt;0.001, resp).
Conclusion: In this observational study following patients with newly diagnosed T2DM, first-line therapy with metformin, when compared to other non-insulin antidiabetes therapies, was not found to be associated with a decreased risk of developing AF.

Disclosure
Z. Tekin: None. A. Milinovich: Research Support; Self; Novartis AG, Novo Nordisk Inc. X. Ji: Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. J. Bauman: None. M. Kattan: Consultant; Self; GlaxoSmithKline plc. Research Support; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc. K.M. Pantalone: Consultant; Self; Bayer Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. R.S. Zimmerman: Research Support; Self; Bayer U.S., Merck & Co., Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; LifeScan, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Baxter, Bristol-Myers Squibb, Pfizer Inc., Procter & Gamble Company. M.K. Chung: None. S. Kashyap: Other Relationship; Self; GI Dynamics Inc.
1095-P: Exendin 4 Decreases Tumor Volume through Attenuation of psma-Induced Activation of NfκB Pathway in HPV-Induced Diabetes/Cancer Model
Authors: MAO DANDAN , CHAN JULIANA C. 
Published: June 2020

Background: The diabetes-cancer link may be mediated by inflammation due to infection such as Human Papilloma Virus (HPV). Exendin 4, a Glucagon-like-peptide 1 agonist, has anti-hyperglycemic and anti- inflammatory effect and can attenuate certain cancer growth.
Methods: We used RNA microarray analysis to detect the gene expression after Exendin 4 treatment in the db/db mouse tumor, which was established by inoculation of mouse PV cancer cells (CUP-1). The latter originates from the kidney of baby C57BL/6J mice expressing HPV-16 E7 oncogene. We examined the effect of Exendin 4 on cell proliferation, apoptosis and gene expression along the inflammatory pathway in CUP-1 under different glucose environment. We developed CUP-1 cells with or without target gene overexpression (OE) or downregulation (DR) for inoculation into the db/db mouse. We compared RNA expression of the target gene in cervical cancer specimen from patients with or without diabetes.
Results: RNA expression of proteasome 20s (psma) was decreased after Exendin 4 treatment in the db/db mouse tumor. High glucose environment increased cell proliferation in CUP-1 cells, which was enhanced after OE of psma but attenuated after DR of psma. Exendin 4 suppressed NFκB P65 and IκB activation in CUP-1 cells under high glucose medium. After inoculation of CUP-1 cells with DR and OE of psma, the tumor size was decreased and increased in db/db mice respectively. Exendin 4 decreased the tumor volume in the db/db mice of psma OE group. In human cervical cancer specimen, RNA expression of psma was increased in patients with diabetes versus those without diabetes.
Conclusion: High glucose increased expression of psma, which activated NFκB inflammation pathway and promoted carcinogenesis. Exendin 4 suppressed the NFκB pathway activation and decreased tumor volume with corroborative evidence from human samples, suggesting that the anti-cancer effect of Exendin 4 might be mediated by the psma-NFκB pathway.

Disclosure
D. Mao: None. J.C. Chan: None.
110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)
Authors: REDONDO MARIA J. , WARNOCK MEGAN V. , BOCCHINO LAURA E. , GEYER SUSAN , PUGLIESE ALBERTO , STECK ANDREA , LIBMAN INGRID , EVANS-MOLINA CARMELLA , BECKER DOROTHY J. , SOSENKO JAY , BACHA FIDA ,   TYPE 1 DIABETES TRIALNET STUDY GROUP
Published: June 2020

In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% &lt;18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values &lt;0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity.

Disclosure
M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1103-P: Balancing the Risk of DKA and Severe Hypoglycemia with Sotagliflozin in Adults with Type 1 Diabetes
Authors: PETTUS JEREMY , CARIOU BERTRAND , SAWHNEY SANGEETA , BANKS PHILLIP L. , DAVIES MICHAEL J. , LAPUERTA PABLO 
Published: June 2020

Background: DKA and severe hypoglycemia (SH) are the 2 most important acute complications of type 1 diabetes (T1D). SGLT inhibitors are associated with an increased risk of ketosis and DKA. Sotagliflozin (SOTA), a dual SGLT 1 and 2 inhibitor, has been shown to reduce the incidence of documented hypoglycemia and SH as adjunct to insulin therapy in T1D. The objective was to determine if the increased risk of DKA with SOTA was offset by the reduction of SH.
Methods: Data were pooled from the inTandem 1 and 2, 52-week, placebo (PBO)-controlled studies in adults with T1D (N=1575). Events of DKA and SH were adjudicated by an IRC. Incidence and exposure-adjusted incidence rates (EAIR) were calculated along with numbers needed to treat or harm (NNT/NNH).
Results: A higher incidence of adjudicated DKA was seen with SOTA 200 and 400 mg (2.9 and 3.8%) compared to PBO (0.2%). However, SOTA was associated with a lower rate of hypoglycemia events with blood glucose levels ≤55 mg/dL and a lower incidence of adjudicated SH with SOTA 200 and 400 mg (5.7 and 4.4%) compared with PBO (7.4%). The absolute risk difference in EAIR between SOTA and PBO was 2.9 to 4.0 events per 100 patient-yr for DKA and -1.9 to -3.4 events per 100 patient-yr for SH (Figure). NNH for DKA (28) was similar to the NNT for SH (33) with SOTA 400 mg.
Conclusions: With SOTA added to insulin, the increase in DKA was similar in magnitude to the decrease in SH in adults with T1D.

Disclosure
J. Pettus: Consultant; Self; Diasome Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc., Sanofi. B. Cariou: Advisory Panel; Self; Bristol-Myers Squibb, Gilead Sciences, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Board Member; Self; GENFIT. Research Support; Self; Amgen, Regeneron Pharmaceuticals. Speaker’s Bureau; Self; Abbott, AstraZeneca. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M.J. Davies: Employee; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.
1106-P: Effects of Long-Term Dapagliflozin Treatment on Hemorheology (D-PATH Study)
Authors: ONO SHOYA , NAKATANI YUKI , KAWABE ATSUHIKO , MIYASHITA YASUSHI , MATSUMURA MIHOKO , BANBA NOBUYUKI , ASO YOSHIMASA , YASU TAKANORI 
Published: June 2020

Introduction: Hemorheology (blood viscosity) was reported to be a strong predictor of cardiovascular events in the Edinburgh Artery Study. However, deterioration in hemorheology through microvessels is a potential adverse effect of Sodium-glucose cotransporter-2 (SGLT2) inhibitors. This study aimed to clarify the effect of dapagliflozin on blood fluidity.
Method: This multi-center, open-label, randomized, comparative study included 90 patients with type 2 diabetes mellitu. Patients were randomly divided into treatment groups with and without dapagliflozin treatment, and each item was investigated. The primary endpoint was the whole blood transit time, based on the difference from the baseline to 16 weeks after enrollment, as measured by a microchannel array flow analyzer (MC-FAN). To assess this outcome, a 15% noninferiority margin (clinically significant cut-off value) was used. To test the noninferiority of the treatment, a t-distribution was used to calculate the 95% confidence interval to assess the difference from the baseline.
Results: The whole blood transit time in the dapagliflozin group was 41.8 ± 6.1 sec (mean ± SD) before administration, and 43.4 ± 6.8 sec at 16 weeks after dapagliflozin administration. In the control group, the whole blood transit time was 40.5 ± 3.0 sec before administration and 39.9 ± 3.8 sec after 16 weeks. The difference between groups from the baseline to 16 weeks after enrollment was 1.7 sec [0.2, 3.5] (95% C.I), confirming the noninferiority of dapagliflozin administration. Futher, the analysis Results of the differences between groups according to the some items (the baseline of hematocrit, HbA1c levels and the whole blood transit time) for baseline, demonstrating the noninferiority of dapagliflozin administration in these items.
Conclusion: Dapagliflozin was unlikely to have negative effects on blood fluidity after administration irrespective of the baseline Hematocrit, HbA1c levels and the whole blood transit time.

Disclosure
S. Ono: None. Y. Nakatani: None. A. Kawabe: None. Y. Miyashita: None. M. Matsumura: None. N. Banba: None. Y. Aso: None. T. Yasu: None.

Funding
AstraZeneca
1108-P: Resveratrol Inhibits Dapagliflozin-Induced Renal Gluconeogenesis through Modulating the PI3k/Akt/Foxo1 Pathway in HK-2 Cells
Authors: SUN XIAOYA 
Published: June 2020

Aims: Dapagliflozin(Dapa) improves glycemia by increasing glucosuria, but it enhances renal gluconeogenesis, thus reducing its efficacy. Resveratrol (RSV) inhibits hepatic gluconeogenesis by increasing insulin sensitivity. Our study aims to determine if RSV can reduce dapa-induced renal gluconeogenesis via modulating the PI3K/Akt/FoxO1 pathway.
Methods: Glucose produced via gluconeogenesis was tested by glucose assay kit. Changes in insulin signaling and gluconeogenic key enzymes were detected by RT-PCR and western blot.
Results: Dapa induced glucose production and the expression of gluconeogenic enzymes (PEPCK, G6Pase) via increasing the expression of FoxO1 in HK-2 cells. RSV treatment reversed all these findings by up-regulating pFoxO1 expression. The PI3K inhibitor LY294002 restained the pFoxO1 expression and subsequently inhibited PEPCK and G6Pase expression via PI3K/Akt-mediated FoxO1 inactivation.
Conclusion: Our data show that RSV ameliorates gluconeogenesis via modulating the PI3K-Akt-FoxO1-PEPCK/G6Pase pathway in dapa-treated HK-2 cells. This mechanism provides a basis for pharmaceutial intervention in order to achieve better hypoglycemic effect in future animal and human research.

Disclosure
X. Sun: None.
112-OR: Integrative Analysis of Chromatin Accessibility and Genetic Risk in T1D Patients and Controls
Authors: ROBERTSON CATHERINE C. , CHEN WEI-MIN , ONENGUT-GUMUSCU SUNA , CONCANNON PATRICK J. , RICH STEPHEN S. 
Published: June 2020

Motivation: Twin studies estimate 50% of type 1 diabetes (T1D) risk is genetic. Genetic association has implicated T cells as central to the disease process. Thus, we generated chromatin accessibility profiles from CD4+ T cells isolated from 135 T1D cases and 144 controls and investigated whether (1) there are patterns of chromatin accessibility that differ from T1D patients compared to healthy controls; (2) established T1D risk variants influence chromatin accessibility.
Methods: Frozen PBMCs were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). CD4+ T cells were isolated using bead purification and Assay for Transposase Accessible Chromatin (ATAC-seq) was performed. ATAC-seq samples were processed using the PEPATAC pipeline and R packages edgeR and limm.
Results: We tested for differences in accessibility between individuals with and without T1D adjusting for sex, age, and experimental variability. We identified 516 chromatin regions peaks with differential accessibility by T1D status (2 with increased and 514 with decreased accessibility at FDR&lt;0.05). Enrichment analysis with the software LOLA indicated these regions are enriched for ETS-1, AP1, and Maf transcription factor binding motifs. Next, we tested for association between T1D-associated variants and chromatin accessibility using available T1DGC genotypes. For each T1D variant with an observed chromatin accessibility quantitative trait locus effect (caQTL), we tested for colocalisation between the two signals and used publicly available expression QTLs (eQTL) to identify potential target genes. We identified six regions where data were consistent with a single variant driving association with T1D risk, chromatin accessibility in CD4+ T cells, and gene expression in whole blood, highlighting several candidate T1D genes: ANKRD55, IL6ST, BACH2, CENPW, SUOX, GDF11, GSDMB, ORMDL3, IKZF3, ERBB2, PNMT.
Conclusion: These results provide hypotheses about molecular mechanisms of T1D in CD4+ T cells.

Disclosure
C.C. Robertson: None. W. Chen: None. S. Onengut-Gumuscu: None. P.J. Concannon: Stock/Shareholder; Self; Amgen. Other Relationship; Self; 10x Genomics. S.S. Rich: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK111906)