bluuebunny/crossref_metadata_2025_split huggingface dataset:
29-LB: A Multicenter, Randomized Controlled Study of the Efficacy of Once-Weekly DPP-4 Inhibitor Omarigliptin in Patients with Type 2 Diabetes Undergoing Maintenance Hemodialysis
Authors: YOSHIZAWA YUTA , HOSOJIMA MICHIHIRO , KABASAWA HIDEYUKI , TANABE NAOHITO , KITAMURA TADAHIRO , NARITA ICHIEI , SAITO AKIHIKO 
Published: June 2019

Background: DPP-4 inhibitors are used widely in patients with type 2 diabetes (T2D) undergoing maintenance hemodialysis (HD), but the efficacy of the once-weekly DPP-4 inhibitor omarigliptin (O) is unknown.
Methods: This open, multicenter, randomized, non-inferiority trial compared glycemic control and safety of O and the daily DPP-4 inhibitor linagliptin (L) (UMIN000024284). We enrolled 33 T2D patients undergoing maintenance HD, who had been treated with L for at least 3 months at Niigata University Medical and Dental Hospital and three affiliated dialysis facilities between April 2017 and March 2018. The patients were randomized to receive O (n = 16) or L (n = 17). Primary endpoints were changes in HbA1c and glycoalbumin (GA) over 24 weeks from baseline (with non-inferiority margins of 0.25% and 0.75%, respectively). Secondary endpoints were changes in blood glucose and plasma glucagon measured by sandwich ELISA after single HD and the incidence of adverse events including hypoglycemia.
Results: In the full analysis set (n = 30), the difference in the mean change in primary endpoint values between the O and L groups was −0.6% for HbA1c and −1.7% for GA, with one-tailed upper 95% limits of −0.17% and 0.4%, respectively, below the respective non-inferiority limits. HbA1c reduction was significantly greater in the O group (−0.2% ± 0.6%) than in the L group (0.4% ± 0.8%, two-tailed p = 0.027). Blood glucose reduction after single HD was significantly greater in the O group (−18.4 ± 31.4 mg/dL) than in the L group (25.2 ± 59.5 mg/dL, two-tailed p = 0.025), but plasma glucagon reduction after single HD was not greater in the O group (−6.8 ± 14.1 pg/dL) than in the L group (2.6 ± 16.6 pg/dL, two-tailed p = 0.11). No subjects in the O group experienced hypoglycemia.
Conclusion: Omarigliptin is feasible for glycemic control in T2D patients undergoing maintenance HD. Further studies are needed to determine the mechanisms of its efficacy.

Disclosure
Y. Yoshizawa: None. M. Hosojima: Research Support; Self; Astellas Pharma Inc., Biotech Japan Corporation, Daiichi Sankyo Co.,Ltd., Eli Lilly Japan K.K., Forica Foods Co.,Ltd., Kameda Seika Co.,Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisc Pharma Ltd., Sato Foods Industries Co.,Ltd., Taisho Toyama Pharmaceutical.Co.,Ltd., Takeda Pharmaceutical Co.,Ltd. H. Kabasawa: Research Support; Self; Astellas Pharma Inc., Biotec Japan Corporation, Daiichi Sankyo Company, Limited, Forica Foods CO.,LTD., KAMEDA SEIKA CO., LTD., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K, Novo Nordisc Pharma Ltd, Sato Foods Industries CO.,LTD., Taisho Toyama Pharmaceutical.CO.,LTD., Takeda Pharmaceutical Company Limited. N. Tanabe: None. T. Kitamura: None. I. Narita: None. A. Saito: None.
29-OR: High Prevalence of Pathogenic Mutations in Genes Causing Monogenic Diabetes among Patients with Common Type 2 Diabetes
Authors: BONNEFOND AMELIE , FROGUEL PHILIPPE ,   LILLE-D.E.S.I.R. GENETICS STUDY
Published: June 2019

In contrast to monogenic diabetes, the genetic investigations of common forms of type 2 diabetes (T2D) have led to modest advances in precision medicine. We aimed to assess the prevalence in common T2D of pathogenic mutations across 33 genes causing monogenic diabetes, and to compare it to the prevalence found in normoglycemic individuals. Through next-generation sequencing, genes were sequenced in a case-control study including more than 6,000 individuals. We then applied stringent quality control steps before the analyses. The pathogenicity of variants was assessed using the American College of Medical Genetics and Genomics criteria. Primary outcome was the prevalence of pathogenic or likely pathogenic mutations in the case-control study. Secondary outcomes included age of T2D diagnosis, body mass index, T2D treatment and T2D family history. We found a significant association between pathogenic or likely pathogenic variants and T2D risk (p&lt;0.001; 6.5% of carriers among cases). This association was explained in part by pathogenic mutations of two actionable genes, GCK and HNF1A. Overall, among cases, carriers were leaner (β=-1.5±0.5 kg/m²; p&lt;0.01) and tended to develop T2D earlier (β=-1.2±0.7 years; p=0.05) compared to non-carriers, but use of antidiabetic drugs and T2D family history were not different. We reported a high prevalence of pathogenic mutations in monogenic diabetes genes among common T2D patients who did not present with clinical characteristics of monogenic diabetes (i.e., MODY). These results could lead to precision diabetic medicine, and to significant savings in health expenditure via systematic molecular diagnosis of newly diagnosed patients.

Disclosure
A. Bonnefond: None. P. Froguel: None.

Funding
European Research Council; French National Research Agency
298-LB: GLP-1 Secretion Enhancement after H. Pylori Eradication Treatment Is Related to Gut Microbiota Modification
Authors: CORNEJO-PAREJA ISABEL , MARTIN-NUÑEZ GRACIA MARÍA , MORENO-INDIAS ISABEL , CARDONA-DÍAZ FERNANDO F. , ROCA-RODRIGUEZ M. MAR , COIN-ARANGüEZ LETICIA , MANCHA-DOBLAS ISABEL , TINAHONES FRANCISCO 
Published: June 2019

Introduction: Antibiotic treatments modify gut microbiota. Microbiota alterations (in composition and biodiversity) are fundamental pieces in the development of metabolic disorders (T2DM and obesity).
Objective: To evaluate the relationship between microbiota changes due to antibiotic treatment in patients colonized by H. pylori and GLP-1 secretion.
Methods: A prospective case control study was assessed. We evaluated a H. pylori positive patient model before and two months after a short-term eradication therapy and a control group. Anthropometric measurements, carbohydrate and lipid metabolisms, GLP-1 levels and fecal microbiota composition (determined by 16S rRNA gene (V3-V4) sequencing with an Illumina Miseq) were analyzed.
Results: We studied 40 cases and 20 controls (60% women, respectively). Average age was 47.0±2 vs. 43.6±2.7 years. 42.5% vs. 40% had clinical history of gastrointestinal disease. After eradication treatment, we found significant changes in microbiota profile at phylum, family, genus and species levels. The Chao1 and Shannon indices showed a decreased in bacterial richness and diversity in patients (pre and post H. pylori eradication) compared to controls. GLP-1 secretion and carbohydrate metabolism were improved after antibiotic treatment. GLP-1 changes were related to microbial community disturbances through correlation analysis, specifically with Bifidobacterium adolescentis (r=0.354, p=0.034), Lachnobacterium (r=-0.332, p=0.048) and Coriobacteriaceae (r=0.372, p=0.026).
Conclusions: Antibiotic treatment to eradicate H. pylori increased the secretion of GLP-1 and improved the carbohydrate metabolism. This GLP-1 secretion improvement was related to changes in microbial community because of the antibiotic treatment, particularly in Bifidobacterium adolescentis, Lachnobacterium and Coriobacteriaceae. These taxa could play their roles through the production of short chain fatty acids (SCFA) and/or bile acid metabolism.

Disclosure
I. Cornejo-Pareja: None. G. Martin-Nuñez: None. I. Moreno-Indias: None. F.F. Cardona-Díaz: None. M. Roca-Rodriguez: None. L. Coin-Arangüez: None. I. Mancha-Doblas: None. F. Tinahones: Advisory Panel; Self; Lilly Diabetes, Novo Nordisk A/S, Regeneron Pharmaceuticals, Sanofi-Aventis. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Danone Nutricia Research, Lilly Diabetes, Novo Nordisk A/S, Regenerative Medical Solutions, Sanofi-Aventis.
30-LB: Diabetes Complications Including Nephropathy, Neuropathy, and Retinopathy Can Now Be Studied in a New Spontaneous Autoimmune Diabetes Transgenic Model
Authors: IMAM SHAHNAWAZ , JAUME JUAN C. , ALFONSO-JAUME MARIA A. 
Published: June 2019

We have developed a spontaneous humanized transgenic mouse model of autoimmune diabetes chronically develops diabetic complications.
Our humanized mouse develop diabetic nephropathy. The basal glomerular membrane thickness was doubled in size at 4 months of age as shown by electron microscopy. The manifestation of glomerulopathy subsequently correlates with microalbuminuria. At 6 month, mice show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. The typical features of Kimmelstiel-Wilson are seen when severe chronic kidney disease develops.
Our humanized mice develop diabetic retinopathy. We have noted a significant increase in acellular capillaries of the retina at the age of 6 months. Ocular tomography revealed a significant reduction in total retinal thickening. Fundoscopic retinal images revealed a classic vascular leakage as observed in humans.
Our humanized mice also show diabetic neuropathy. We have observed an impaired sciatic and optic nerve conduction. Specifically, optic nerves at 6-months old diabetic mice showed an increased refractory period of the second compound action potential (CAP). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity. However, a limb vasculopathy has not been observed so far.
In our mouse model, the mouse MHC-II was replaced with human DQ8 in all antigen-presenting cells. The mouse also expresses human GAD65 in pancreatic beta cells. The diabetic phenotype of our mouse mimics the human disease progression. Importantly, our mouse model has a genetic background that compromises beta-cell neogenesis and/or regeneration (1).
Our humanized mice model has the closest known phenotype to human diabetes and is most suitable for addressing physiopathology and treatment of diabetes complications. (U.S. Provisional Patent #62/713,827).

Disclosure
S. Imam: None. J.C. Jaume: None.

Funding
University of Toledo
302-OR: Causes of Blinded CGM Failure during Clinical Trials in Patients with T2D
Authors: SALDIVAR-SALAZAR SERGIO , TESTA MARCIA A. , HAYES JOHANNA F. , SIMONSON DONALD C. 
Published: June 2019

Blinded CGM is useful in clinical trials to preserve the validity of outcomes. However, lack of real-time feedback about performance of the system generates a significant number of failed sessions. We analyzed causes of such failed CGM sessions in 453 T2D subjects (mean age 55.2±9.6 years, 51.9% males) using the Medtronic iPro2 to obtain a 6-day baseline CGM during two randomized clinical trials of oral agents and insulin. At the end of the CGM session, non-calibrated data (ISIG - electric signals) were immediately reviewed by a third party to determine the completeness and quality of the dataset (at least 72 continuous hours of ISIG between 10-200 nA) and the need for a new CGM session. If data were not acceptable, clinical sites were promptly contacted to ascertain the conditions of the study subject, insertion technique and technical problems that could cause the failed session, and to recommend other approaches to CGM reinsertion. Subjects who failed the first CGM sessions were reinserted a second or third time when possible. Eighty-two of 453 subjects failed their first CGM insertion, 9 of 56 failed the second insertion, and one of four subjects failed all three insertions (cumulative success rate = 99.8%). The causes of failure were discernible in 38 (41.3%) of the 92 failed cases, including sensor detachment (19.6%), insufficient BG for calibration (17.4%), user error (3.3%), and intentional removal (1.1%). For the remaining 58.7% of cases, the non-calibrated ISIG patterns were analyzed and most likely causes found to be undetermined (25.0%), disconnection (20.7%), sensor failure (8.7%) and device failure (4.3%). Upon clinical review, most failed sessions of undetermined cause or probable disconnection were attributable to patient characteristics (morbid obesity, profuse sweating) or improper insertion technique.
Conclusions: 1) Most identifiable causes of failed CGM can be potentially corrected by proper user/subject training, and 2) only a minimal portion of failed sessions are secondary to faulty devices.

Disclosure
S. Saldivar-Salazar: Speaker's Bureau; Self; Medtronic MiniMed, Inc. M.A. Testa: Stock/Shareholder; Spouse/Partner; GI Windows, Inc. Stock/Shareholder; Self; Phase V Technologies, Inc. J.F. Hayes: None. D.C. Simonson: Stock/Shareholder; Self; GI Windows, Inc. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc.
303-LB: Accelerated Hepatic Fibrosis in Western Diet-Fed Nonalcoholic Steatohepatitis Mice Model by Small Dosage of Carbon Tetrachloride
Authors: ZHANG GUODONG , CHNG KEEFE , WANG YIXIN 
Published: June 2019

Carbon Tetrachloride (CCl4) is a common hepatotoxin used in liver injury and fibrosis animal models, but it is rare to observe obesity and liver fat accumulation in CCl4-induced liver fibrosis models since weight loss is also provoked. Nonalcoholic Steatohepatitis (NASH) is an epidemic disease coincides with obesity and type 2 diabetes (T2D) causing liver steatosis and inflammation. There are no perfect animal models that capture all steatosis, inflammation and following fibrosis stages of NASH disease, our recent study developed an accelerated fibrotic model in previously established NASH model of western diet fed FATZO/pco mice. Using a dose of 0.08 mL/kg (IP, 2/week) CCl4 on 8-week western diet fed FATZO/pco mice, the average histology fibrosis score increased from 1.2±0.2 to 3.0±0.0, average lobular inflammation score increased from 1.4±0.7 to 1.9±0.1, while average steatosis score remained stable. Hepatotoxicity of CCl4 affected the hepatocyte ballooning score due to increased necrosis, reducing ballooning score from 1.6±0.4 to 1.0±0.0. It is also interesting to find out the FATZO/pco strain tolerated CCl4 challenges better than the control C57Bl/6 strain.
Conclusion: The study developed an accelerated NASH mice model with balanced performance in all stages of histopathology and provides better translational values in comparison with human patients.

Disclosure
G. Zhang: None. K. Chng: None. Y. Wang: None.
304-OR: Polygenic Risk Score Predicts Type 2 Diabetes Susceptibility in a Diverse Consumer Genetic Database
Authors: MULTHAUP MICHAEL L. , KITA RYOSUKE , ERIKSSON NICHOLAS , ASLIBEKYAN STELLA , SHELTON JANIE , TENNEN RUTH I. , KIM ESTHER , KOELSCH BERTRAM 
Published: June 2019

With the rise in the prevalence of type 2 diabetes (T2D), as well as undiagnosed cases of T2D and prediabetes (25% and 90%, respectively), early detection is imperative to minimize individual and societal burden. T2D is highly heritable, and personal genetic information is increasingly available to the general public. Studies have suggested that T2D risk reduction strategies may be more effective for individuals with high T2D genetic risk, supporting the use of genetics as a screening tool to inform cost-effective interventions.
We trained a polygenic risk score (PRS) for T2D based on &gt;1,200 genotyped variants in &gt;600,000 European consented research participants from a consumer genetic database who self-reported if they had been diagnosed with T2D. We tested the PRS' performance in separate sets of participants covering five different ancestries (African-American, East-Asian, European, Latino, and South-Asian; ~ 600,000 participants).
The area under the receiver-operator curve of this PRS varied from 0.65 to 0.57, performing best in European and worst in African ancestries. The PRS was calibrated separately in each ancestry to account for differences in T2D prevalence. European participants with a PRS in the top 5% of the distribution have a T2D odds ratio of more than 3, and lifetime risk for this group exceeds 65%. Our PRS is strongly correlated with an independently derived T2D PRS from (Scott et al. 2017 GWAS, Spearman rho=0.44, p &lt; 1x10^-200) but is more predictive in our dataset (AUC 0.65 vs. 0.59). Lastly, we defined an "increased likelihood" result based on the PRS threshold at which risk of T2D from genetics alone exceeds the risk of T2D due to being overweight. In our database, 19% of individuals met this criterion.
We find that personalized PRS' have the potential to identify large numbers of individuals with increased T2D susceptibility equal to or greater than known risk factors and could prove useful in evaluating T2D risk at individual as well as population levels.

Disclosure
M.L. Multhaup: Employee; Self; 23andMe. R. Kita: Employee; Self; 23andMe. N. Eriksson: None. S. Aslibekyan: Employee; Self; 23andMe. J. Shelton: None. R.I. Tennen: Employee; Self; 23andMe. E. Kim: Employee; Self; 23andMe, inc. B. Koelsch: Employee; Self; 23andMe.
305-OR: Genomic Basis to Shared Influences on Pubertal Timing and Type 2 Diabetes
Authors: COUSMINER DIANA L. , MISHRA RAJASHREE , ARGENZIANO MARIANA A. , MANDUCHI ELISABETTA , HODGE KENYAITA M. , SU CHUN , LEONARD MICHELLE , LU SUMEI , PIPPIN JAMES A. , JOHNSON MATTHEW , WELLS ANDREW D. , CHESI ALESSANDRA , VOIGHT BENJAMIN F. , GRANT STRUAN F. 
Published: June 2019

Earlier pubertal onset in girls is associated with later-life type 2 diabetes (T2D) risk. Studies have shown that age at menarche (AAM), a marker of girls’ pubertal timing, and T2D are genetically correlated genome-wide. Since both AAM and T2D also correlate with BMI, the biological link between the two traits could be mediated via BMI. As the most recent genome-wide association study (GWAS) for T2D also adjusted for BMI, we queried if AAM and T2D remain correlated after removing the effect of BMI on T2D. Leveraging such large-scale GWAS data, LD Score Regression revealed that the genetic correlation between AAM and T2D (rg (SE)=-0.24 (0.02) P=2.2x10-22) was only partly attenuated after BMI adjustment (rg (SE)=-0.1 (0.03) P=0.0002), suggesting that BMI does not entirely explain the puberty-T2D link. Five of the 13 significant GWAS-implicated loci associated with both AAM and T2D do not associate with BMI, further supporting that BMI is not the only mediator between the two traits. Given that causal effector genes are unknown at most GWAS loci, identification of target genes at these shared loci should provide key biological insights. To implicate effector genes, we first identified all SNPs in LD with the sentinel SNPs. We then extracted the subsets of proxy SNPs in open chromatin, determined by ATAC-seq, in primary cells or cell lines relevant to this trait area [beta cells (EndoC-βH1), adipose (SGBS and MSC-derived adipocytes), and—given recent findings in both AAM and BMI studies—brain (neural precursors, microglia, astrocytes and hypothalamic neurons)]. Using high resolution Capture-C, we detected consistent physical contacts between open-proxy SNPs and candidate effector genes. Our results support direct SNP-to-gene promoter contacts for at least four of these shared loci (one not associated with BMI) including TSPAN3 at ‘AC046168.1’ and TFAP2D at ‘TFAP2B’, along with leads at the ‘MTCH2/CELF1’ and ‘MAP2K5’ loci. Follow-up experiments are needed to determine the physiological roles of implicated target genes.

Disclosure
D.L. Cousminer: None. R. Mishra: None. M.A. Argenziano: None. E. Manduchi: None. K.M. Hodge: None. C. Su: None. M. Leonard: None. S. Lu: None. J.A. Pippin: None. M. Johnson: None. A.D. Wells: Research Support; Self; GlaxoSmithKline plc. A. Chesi: None. B.F. Voight: None. S.F. Grant: None.

Funding
American Diabetes Association (1-17-PDF-077 to D.L.C.); National Institutes of Health
309-LB: Cell-Permeable Truncated SOCS3 Competitively Inhibits the Interaction Between Endogenous SOCS3 and Leptin Receptor (ObR) to Overcome Leptin Resistance on JAK/STAT Signaling
Authors: LEE KUYSOOK 
Published: June 2019

Aim: The abnormal control of leptin, an adipocyte-derived hormone controlling appetite, chronically enhances obesity. On binding to leptin receptor (ObR) expressed in hypothalamic neurons, leptin evokes JAK/STAT signaling, and induces the expression of suppressor of cytokine signaling 3 (SOCS3) as a negative feedback regulator to maintain the homeostatic balance between food intake and energy expenditure. However, due to excess leptin in obesity, increased levels of endogenous SOCS3 promotes leptin resistance and disables the appetite-control by leptin. We aim to develop cell-/tissue-permeable form of a truncated, trans-dominant SOCS3 protein (CP-?SOCS3) to antagonize leptin resistance caused by binding of endogenous SOCS3 to ObR and test its use as an anti-obesity and antidiabetic agent.
Method: We have developed CP-?SOCS3 by fusing truncated SOCS3 with a hydrophobic cell-penetrating peptide, namely advanced macromolecule transduction domain. CP-?SOCS3 was tested using in vitro and in vivo leptin resistance models (in which endogenous SOCS3 is highly expressed) for the ability to intervene in JAK/STAT signaling and promote leptin sensitivity.
Results: CP-?SOCS3 competitively bound at the p-Y985 of ObR against endogenous SOCS3 and significantly promoted leptin-induced JAK/STAT signaling in vitro. Diet-induced obese (DIO) mice treated with CP-?SOCS3 showed 12.1% body weight loss in 14 days (15 mg/kg, IV, daily injection). In addition, CP-?SOCS3 reduced blood cholesterol by 31% and improved glycemic control by 67% in the DIO mice. CP-?SOCS3 was delivered into brain by penetrating brain blood barrier.
Conclusion: CP-?SOCS3 competitively suppressed the inhibitory action of endogenous SOCS3 on JAK/STAT signaling to enhance leptin sensitivity. Therefore, these results suggest that CP-?SOCS3 has a therapeutic potential as a protein-based anti-obesity and antidiabetic agent.

Disclosure
K. Lee: None.