bluuebunny/crossref_metadata_2025_split huggingface dataset:
1710-P: A Case with Monogenic Diabetes Caused by RFX6 Mutation in a 14-Year-Old-Girl
Authors: YU JEESUK , KWAK SOO HEON 
Published: June 2019

Introduction: It is worthwhile to find new causes of monogenic diabetes to understand glycemic regulation as well as the management of diabetes mellitus. In previous times, diabetes mellitus in children and adolescents was usually type 1 diabetes which was caused by autoimmune beta cell destruction, but due to the increased prevalence of obesity, the incidence of type 2 diabetes was explosively increased in children and adolescents. The underlying mechanism of childhood-onset type 2 diabetes mellitus may be different to the adult-onset type 2 diabetes. Therefore, it is useful to conduct genetic study in children with type 2 feature.
Case: A 14 year-old-girl was diagnosed as having type 2 diabetes mellitus. Initially, she was presented with glycosuria, polydipsia, and polyuria. Initial HbA1c was 11.7%. She had no specific past medical problems. Her mother was already diagnosed as diabetes mellitus and on medication. her weight was 66.3kg (95 pecentile) and height was 148.3cm (3 percentile). Acanthosis nigricans was detected in neck and axillary areas. Blood glucose was 345 mg/dL, insulin was 27.2 uIU/mL, and C-peptide was 8.7 ug/dL, implying the presence of insulin resistance. There was neither ketonuria nor acidosis. Blood lipid profile showed 200 mg/dL of cholesterol, 45 mg/dL of HDL cholesterol, and 144 mg/dL of triglyceride. Thyroid function was normal. She was managed with long-acting insulin and oral hypoglycemic agent (MetforminTM) and her HbA1c level became 9.3% at one year after the diagnosis. To find the candidate gene, targeted exome sequencing was performed which included 29 genes associated with monogenic diabetes. Nonsense mutation of the gene RFX6 was found (Tyr887*). The RFX6 gene mutation is known to contribute to beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels.
Conclusion: It may be recommended to perform the genetic test in childhood-onset type 2 diabetes mellitus to find the candidate gene of type 2 diabetes mellitus.

Disclosure
J. Yu: None. S. Kwak: None.
1715-P: Identifying Potentially Functional Variants in Regulatory Regions in KCNQ1 that Associate with Type 2 Diabetes in American Indians
Authors: MULLER YUNHUA L. , DAY SAMANTHA E. , KOBES SAYUKO , KNOWLER WILLIAM C. , HANSON ROBERT L. , BOGARDUS CLIFTON , BAIER LESLIE J. 
Published: June 2019

A prior genome-wide association study in 7701 Pima Indians utilized a custom Axiom array (Affymetrix) which contained 474,196 SNPs. These SNPs tagged 92% of common variants (R2≥0.85, minor allele frequency ≥0.05) identified in the Pima Indian genome. SNP rs79788804, which tags 38 additional SNPs in intron 15 of KCNQ1, achieved genome-wide significance in its association with type 2 diabetes (T2D; OR=1.31, p=2 x10-8). A 3 SNP haplotype (rs79788804, rs2237892 and rs2299620) with &gt;1 maternally-derived alleles strongly associated with T2D (ORM=2.05, p=2x10-12). ENCODE and Islet regulome databases mapped putative strong enhancers to 4 regions in intron 15 with multiple epigenetic marks and transcription factor binding sites. To validate these regulatory regions, we tested gene activation from the putative enhancers using CRISPR-CAS9-based acetyltransferase (dCas9p300) in human pancreatic beta cells (EndoC-βH3). Guide RNA specific acetylation by dCas9p300 at a 341 bp region spanning rs2299620, rs2237896, rs2237897 and rs74046911 resulted in a 1.5 fold gene activation for KCNQ1 and nearby gene TRPM5 (both p=0.001). A chromatin immunoprecipitation-qPCR assay confirmed that dCas9P300 acetylated chromatin at this targeted region. We further assessed the effects of 5 transcription factors (NKX2.2, MAFB, NKX6.1, FOXA2, PDX1) on transcriptional activity under control of these 4 enhancer regions. Mouse pancreatic β-cells (NIT1) were co-transfected with a vector expressing each transcription factor and a luciferase reporter construct containing the KCNQ1 SNPs. NKX2.2 had a 5.5 fold activation for the construct containing the same 341 bp KCNQ1 region, as compared to a 4.1 fold activation for the construct containing KCNQ1 promoter alone (p=0.02). Our data suggested that a 341 bp region containing rs2299620, rs2237896, rs2237897 and rs74046911 may harbor functional variant(s) which affect expression of KCNQ1 and TRPM5.

Disclosure
Y.L. Muller: None. S.E. Day: None. S. Kobes: None. W.C. Knowler: None. R.L. Hanson: None. C. Bogardus: None. L.J. Baier: None.

Funding
National Institutes of Health
1720-P: The rs10423928 GIP Receptor “A” Allele Contributes to an Improved ß-Cell Response in Prediabetes Patients
Authors: BARBOSA-YAÑEZ RENATE LUZÍA , DAMBECK ULRIKE , HONSEK CAROLINE , KABISCH STEFAN , PFEIFFER ANDREAS F. 
Published: June 2019

The gut hormone GIP has become a novel target for T2DM and obesity research due to its glucose-dependent insulinotropic effect. GIP-receptor is therefore a biologically plausible candidate for T2DM treatment. A meta-analysis of genome-wide association studies identified a genetic variant in intron 12 of GIPR (rs10423928, A-allele) that is linked to impaired glucose metabolism. The aim of this study was to investigate the relationship between “A” allele carriers and T2DM susceptibility. Glucose challenge data of 424 prediabetes subjects was analyzed. Genotyping was performed using TaqMan™ SNP Genotyping Assay rs10423928. We extended previous data by showing that carriers of the A allele displayed increased fasting glucose. Unexpectedly, A carriers showed lower glucose levels 2 h after an oral glucose challenge and higher insulin sensitivity (assessed by Cederholm Index) compared to homozygous subjects for the T allele, indicating an enhanced ß-cell response. Furthermore, we found no link between rs10423928 variant and liver fat, total adipose tissue and visceral adipose tissue determined by MRI. Longitudinally, the SNP did not determine responses to dietary supplementation of oat fibers or low-fat vs. low-carb diets. The results suggest a partially advantageous effect of the minor allele A. Further investigation of the role of this gene, along with other SNPs in linkage with rs10423928 is required in larger study groups.

Disclosure
R. Barbosa-Yañez: None. U. Dambeck: None. C. Honsek: None. S. Kabisch: Research Support; Self; California Walnut Commission, Institute for Grain Processing, Nuthetal, J. Rettenmaier Söhne, Südzucker / Beneo. Other Relationship; Self; Berlin-Chemie AG, Sanofi. A.F. Pfeiffer: Advisory Panel; Self; Abbott, Berlin-Chemie AG, Novo Nordisk A/S. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG, Sanofi-Aventis Deutschland GmbH.

Funding
German Center for Diabetes Research
174-LB: Impact of Quality Improvement (QI) Program on 5-Year Risk of Diabetes-Related Complications
Authors: SHAO HUI , SHI LIZHENG , FURMAN ROY E. , MENEGHINI LUIGI , HARLAN TIMOTHY S. , FONSECA VIVIAN 
Published: June 2019

We have successfully implemented the ADA’s Diabetes INSIDE® QI program at a University hospital and safety-net health system (Tulane and Parkland), focused on system-wide improvement in poorly controlled type 2 diabetes (A1c&gt;8.0%). We extrapolated clinical outcomes of the QI program on a 5-year risk of complications, utilizing a validated risk prediction model: Building, Relating, Assessing, Validating of Outcomes (BRAVO) simulation model. We measured the differences between the baseline and post-intervention values of risk factors in 2,429 individuals with A1c &gt;8% at baseline and used the BRAVO model to project the 5-year risk reduction of diabetes-related complications under the assumption that intervention benefits diminished with time. The intervention period was defined as one year and the post-intervention period as the subsequent six months. The QI program was associated with reductions in A1c (-0.84%) and LDL-C (-5.94 mg/dl) among individuals with A1c level &gt;8.0%, with greater reduction in A1c (-1.67%) and LDL-C (-6.81 mg/dl) among those with A1c level &gt; 9.5% at baseline (all p&lt;0.05). The potential outcome of the QI program on 5-year risk of complications are presented in Fig 1. Our outcomes model suggests that the observed risk factor reduction is projected to lead to clinically significant 5-year risk of events - benefiting patients and population health as it relates to future complications burden."

Disclosure
H. Shao: None. L. Shi: None. R.E. Furman: None. L. Meneghini: Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. Consultant; Self; Sanofi-Aventis. Other Relationship; Self; American Diabetes Association. T.S. Harlan: None. V. Fonseca: Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Abbott, Asahi Kasei Corporation, Novo Nordisk Inc., Sanofi US, Takeda Pharmaceutical Company Limited. Research Support; Self; Bayer US. Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health.

Funding
Lilly USA, LLC; Novo Nordisk; Sanofi
1743-P: Engineering Erythrocytes with the SQZ Cell Therapy Platform to Enhance Immunotolerance
Authors: RAMAKRISHNAN AMRITHA , LEE THOMAS , MOORE LINDSAY J. , SUAREZ ALFONSO VICENTE , MOORE FINOLA , BERNSTEIN HOWARD 
Published: June 2019

Current treatments for autoimmune disorders typically rely on the use of broadly immunosuppressive agents that increase the risk of adverse events in patients, such as cancer and opportunistic infections. Antigen (Ag)-specific immunotherapies have the potential to minimize these risks and improve efficacy by generating Ag-specific suppression to maintain immunohomeostasis. Several studies have established Ag-specific tolerance using red blood cells (RBCs) as a platform for delivery and Ag presentation in the context of eryptosis, a mechanism of RBC clearance. Here, we used the SQZ cell therapy platform to create Agloaded, pro-eryptotic RBCs to induce tolerance. In this approach, cells pass through constricted channels that cause transient permeation of the cell membrane and permit diffusion of cargo before the membrane reseals. In mice, we demonstrated that these highly delivered RBCs are rapidly cleared from circulation by splenic and liver-resident macrophages. The administration of ovalbumin (OVA)-SQZ’d RBCs led to a reduction of OVA-specific T cell proliferation and cytokine production in an OVA immunization model. In an autoimmune diabetes BDC2.5 T cell transfer model, mice treated with RBCs SQZ’d with 1040-p31 peptide mimetope delayed the onset of hyperglycemia in 80% of mice. Additionally, we developed mouse models for adenoassociated virus (AAV)-gene therapy and anti-drug antibody (ADA) to examine immunemediated clearance of exogenous Ag. In the AAV vector-specific model, mice treated with RBCs loaded with AAV-derived peptides abrogated the effector responses of AAV-specific CD8+ T cells upon restimulation. In a model of ADA responses, RBCs SQZ’d with a model drug also led to potent inhibition of ADA responses and preserved drug levels in circulation.
In summary, SQZ’d RBCs are a potentially exciting allogeneic cell therapy strategy to induce Ag-specific tolerance across a range of disease mechanisms and indications.

Disclosure
A. Ramakrishnan: None. T. Lee: None. L.J. Moore: None. A. Vicente Suarez: None. F. Moore: None. H. Bernstein: Employee; Self; SQZ Biotechnologies.

Funding
JDRF
1753-P: Foot Ulceration in the Immunosuppressed Population: Surgeon Beware!
Authors: WALTERS ELLIOT , TERMANINI KAREEM M. , JACKSON BRANDON T. , CHADAB TARA M. , WANG JESSICA , KIM PAUL J. , EVANS KAREN 
Published: June 2019

Background: Over the past 3 decades, advances in transplant surgery have allowed life-saving renewal of solid organ function. Many of these patients are predisposed to the development of lower extremity wounds. There is a paucity of data describing treatment and outcomes of this complex patient population. The purpose of this study is to examine the surgical outcomes of these patients and overall limb salvage rates in a tertiary care center with a multi-disciplinary team focused on limb salvage.
Methods: Medical records were reviewed for all patients with a foot wound and functioning solid organ transplant who received surgery (including debridement or toe/foot/limb amputation) at our institution from 2010-2017.
Results: We identified 59 patients with lower extremity wounds and a prior transplant, 40 with a kidney transplant, 13 with combined kidney-pancreas transplant, and 6 with a liver transplant. The average solid organ transplant patient received 6.5 (±4.8) procedures during the follow-up period (46mos, 6.8-149.4). There were 32 patients (54.2%) who required toe amputations, 15/32 (46.9%) of these healed, 14 (43.8%) required a midfoot amputation, and 8 (25%) progressed to a below-knee amputation (BKA). Of patients with hind foot wounds 11/15 (73.3%) required calcanectomy, of these 7/11 (63.6%) progressed to a BKA. Overall, there were 19/59 (32.2%) patients who required below knee amputations, including the 15 which progressed from lesser procedures; two of the patients requiring BKA progressed to an above knee amputation.
Conclusions: This retrospective study highlights the morbidity associated with foot ulceration in the immunosuppressed patient with an overall BKA rate of 32.2%. Solid organ transplant patients who develop lower extremity wounds require a high level of surgical care. A large proportion of these patients will eventually require a major lower extremity amputation. Further investigation is needed to develop better strategies for lower extremity salvage in the immunosuppressed patient.

Disclosure
E. Walters: None. K.M. Termanini: None. B.T. Jackson: None. T.M. Chadab: None. J. Wang: None. P.J. Kim: Consultant; Self; Acelity, Integra LifeSciences. K. Evans: None.
176-OR: ApoC3 Related with Postprandial Hyperlipidemia Independently of ANGPTL3 and ANGPTL4 in Type 2 Diabetes
Authors: GOTO SATOSHI , HAYASHI TOSHIYUKI , NAGAIKE HIROE , KUSHIMA HIDEKI , HIROMURA MUNENORI , OHARA MAKOTO , YAMAMOTO TAKESHI , MORI YUSAKU , FUKUI TOMOYASU , HIRANO TSUTOMU 
Published: June 2019

Aims: While the angiopoietin-like protein (ANGPTL) has attracted recent attention for its causative role in hypertriglyceridemia, the relationship between postprandial hyperlipidemia and ANGPTL has yet to clarified. In this study we sought to investigate how the pre-heparin lipoprotein lipase mass (LPL), ANGPTL3 and ANGPTL4 relates to postprandial hyperlipidemia in patients with type 2 diabetes.
Methods: Thirty-eight type 2 diabetics (M/F: 15/23) were enrolled. Blood samples were drawn from the patients just before and at 2h after every meal and measured the triglyceride (TG) levels. LPL, ANGPTL3 and ANGPTL4 were determined by the enzyme-linked immunosorbent assay method in the fasting samples. The TG incremental area under the curve (TG-iAUC) and area under the curve (TG-AUC) were calculated to investigate how they related to the lipid parameters.
Results: The findings were as follows: mean age, 65.9±12.3 years; BMI, 24.5±4.5 kg/m2; HbA1c, 8.4±1.0 %; LPL, 55.1±23.5 ng/mL; ApoCII, 5.6±1.6 mg/dL; ApoCIII, 10.4±3.1 mg/dL; ANGPTL3 409.5±114.8 ng/mL; ANGPTL4, 254.1±120.2 pg/mL; circadian variation of TG just before every meal/2h after every meal, 141.1±78.5/148.4±86.4-160.7±93.6/172.9±94.5-153.9±80.1/149.5±74.3 mg/dL; TG-AUC, 1889.2±1011.2 mg•h/dL; TG- iAUC, 196.6 ± 241.9 mg•h/dL. The TG-AUC was significantly correlated with LPL (r=-0.44, p&lt;0.05), ApoCIII(r=0.83, p&lt;0.0001), and logANGPTL3 (r=-0.45, p&lt;0.05). There was confirmed to be no significant correlation, however, between the TG-AUC and logANGPTL4. The TG-iAUC was confirmed not to be significantly correlated with either LPL, logANGPTL3, or logANGPTL4. The TG-iAUC was significantly correlated with ApoCIII(r=0.41, p&lt;0.05).
Conclusions: ApoCIII related with Postprandial hyperlipidemia independently of ANGPTL3 and ANGPTL4 in T2DM.

Disclosure
S. Goto: Research Support; Spouse/Partner; DENKA SEIKEN CO., LTD. T. Hayashi: Research Support; Spouse/Partner; DENKA SEIKEN CO., LTD. H. Nagaike: None. H. Kushima: None. M. Hiromura: None. M. Ohara: None. T. Yamamoto: None. Y. Mori: None. T. Fukui: None. T. Hirano: None.

Funding
Denka Seiken Co., Ltd.
177-LB: Use of Online Diabetes Management Programs among Patients with a New Diabetes Diagnosis
Authors: HUANG JIE , GRAETZ ILANA , REED MARY 
Published: June 2019

Objective: Online wellness programs offer a convenient way for newly diagnosed patients to engage with targeted health education and self-management tools, but there is limited evidence on use rates and user characteristics. We examined patient characteristics associated with use of an online diabetes self-management program among patients with a new diabetes diagnosis in a large integrated health system.
Research Design and Methods: A diabetes self-management program was introduced on the health system's patient portal website in 2010 without formal clinician promotion. Using the health system clinical diabetes registry, we identified patients newly diagnosed with diabetes in 2010-2018 and examined the use of diabetes care tool in the same year they joined the registry. We examined use of the online diabetes program and used multivariable logistic regression model to examine the association between use and patient characteristics including age, gender, race/ethnicity, neighborhood socioeconomic status (SES) and baseline HbA1c.
Results: Among 277,032 total patients diagnosed with diabetes 2010-2018, 1,734 (0.63%) patients used the diabetes management program in that same year. Patients of older age (OR=0.34, 95% CI: 0.27-0.43 for age 75+ vs. &lt;45), male (OR=0.48, 95% CI:0.44-0.53), non-white (e.g., OR=0.32, 95% CI: 0.28-0.37 for Asian vs. white), living in a low SES neighborhood (OR=0.71, 95% CI: 0.63-0.81) were less likely to use the online diabetes wellness program. Patients with higher baseline HbA1c were more likely to use the program (OR=1.29, 95% CI: 1.04-1.59 for A1c 9+ vs. A1c &lt;7).
Conclusions: Few newly diagnosed diabetes patients used the diabetes management program on their own, with evidence of a digital divide in use. It is encouraging, however, that patients with higher baseline A1c were more likely to use the program. Efforts to promote patient-facing online tools use in clinical care delivery from providers may increase use, and research is needed on clinical impacts.

Disclosure
J. Huang: None. I. Graetz: None. M. Reed: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1770-P: Further Evidence Supporting a Potential Role for ADH1B in Obesity
Authors: JENKINSON CHRIS , MORALES LIZA D. , TRIPATHY DEVJIT , HU SHIRLEY L. , LOPEZ-ALVARENGA JUAN C. , DUGGIRALA RAVINDRANATH , DEFRONZO RALPH A. , MUMMIDI SRINIVAS , ARYA RECTOR , NORTON LUKE , BLANGERO JOHN , DIAZ-BADILLO ALVARO 
Published: June 2019

We previously showed that expression of the human cytosolic enzyme, alcohol dehydrogenase 1B (ADH1B), was inversely correlated with measures of obesity and insulin resistance in subcutaneous adipose tissue in Mexican Americans. Here, we sought to determine the relationship between ADH1B RNA, protein expression, adipogenesis and insulin action in human subcutaneous primary adipocytes in culture, derived from lean (BMI &lt; 28 kg.m-2) and obese (BMI ≥ 30 kg.m-2) donors. ADH1B expression increased ∼160-fold during adipogenesis as preadipocytes differentiated into mature adipocytes, reaching maximal levels at 14 days whereas the expression of two homologous genes, ADH1A and ADH1C was relatively unchanged. This indicates that ADH1B may play a role in adipocyte differentiation and proliferation. Adipocytes from lean donors expressed ADH1B at higher levels compared with those from obese donors. Given the multiple passaging of these cells, this indicates likely epigenetic regulation of expression. We performed a meta-analysis of the relationship between ADH1B expression and obesity using data from four populations (Mexican Americans, African Americans, Europeans and Pima Indians). The results showed that BMI was increased by 0.56 standard deviations for each standard deviation of decreased ADH1B expression. This finding illustrates the global relevance of the inverse correlation of ADH1B expression with obesity. Insulin stimulated ADH1B expression dose dependently, with higher levels in the “lean adipocytes.” Phosphorylation of AKT, an important mediator of insulin signaling, was lower in “obese adipocytes” compared with “lean adipocytes” (p&lt;0.01) demonstrating that the “obese adipocytes” were relatively insulin resistant. Knockdown of ADH1B expression resulted in a decrease in insulin-stimulated glucose uptake of 35% (p&lt;0.05). Taken together, these findings show that ADH1B is involved in insulin signaling and action in human subcutaneous adipocytes and that this activity is suppressed in obesity.

Disclosure
C. Jenkinson: None. L.D. Morales: None. D. Tripathy: None. S.L. Hu: None. J.C. Lopez-Alvarenga: None. R. Duggirala: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. S. Mummidi: None. R. Arya: None. L. Norton: None. J. Blangero: None. A. Diaz-Badillo: None.

Funding
National Institutes of Health
1776-P: Gut Microbiota Remodeling and Intestinal FXR Inhibition Mediate the Antimetabolic Syndrome Properties of Gynostemma Pentaphyllum
Authors: XIE ZHIFU , HU LIHONG , LI JINGYA , LI JIA 
Published: June 2019

Gynostemma pentaphyllum (G. pentaphyllum) is widely used as a traditonal chinese medicine with anti-metabolic syndrome properties in Asian countries, however, the critical mechanism with the metabolic benefits of G. pentaphyllum remained unclarified. Herein, we performed metabolomic analysis (LC-MS/MS) of samples from obese mice treated with G. pentaphyllum, and identified 2α-OH-PPD (GP2) may be the principal bioactive constituent responsible for the anti-metabolic syndrome effect of G. pentaphyllum. In mouse model of high fat diet-induced obesity, GP2 prevented diet-induced obesity, along with hepatic steatosis and insulin resistance after 5 weeks treatment. The metabolic benefits of GP2 treatment were abrogated in the antibiotic treated DIO mice, which indicated GP2 improves metabolic syndrome dependent on gut microbiota remodeling. Mechanically, GP2, play as an inhibitor of bile salt hydrolase (BSH) in the gut microbiota, increased the bile acid tauro-α/β-muricholic acid (Tα/βMCA) and tauroursodeoxycholic acid (TUDCA) in the gut through decrease in level of the genus Clostridium, but not the genus Lactobacillus (LefSe Analysis for gut microbiota composition). The expression of FGF-15 and shp gene were dramatically decreased in the ileum, and the expression of pro-glucagon in the L cell and glucose induced GLP-1 secretion were markedly increased in the GP2 treated mice, which were accompanied by farnesoid X receptor (FXR) signaling inhibition in the intestine. Finally, after transplanted the fecal microbiota of mice treated by GP2 into recipient mice pretreated with antibiotics, the mice reflected much more GLP-1 secretion after glucose stimulated and high Tα/βMCA level in the gut than the mice received control microbiota. These results indicated that GP2 as well as G. pentaphyllum improved metabolic syndrome in part through intestinal FXR inhibition induced by gut microbiota remodeling.

Disclosure
Z. Xie: None. L. Hu: None. J. Li: None. J. Li: None.

Funding
National Natural Science Foundation of China