bluuebunny/crossref_metadata_2025_split huggingface dataset:
1707-P: Maternal Smoking Around Birth, Offspring Genetic Susceptibility to Adiposity, and Risk of Type 2 Diabetes
Authors: SUN DIANJIANYI , ZHOU TAO , LI XIANG , HEIANZA YORIKO , QI LU 
Published: June 2019

Prenatal exposure to maternal smoking (MS) and genetic predisposition to obesity have been related to an increased risk of developing type 2 diabetes (T2D), individually; however, little is known about whether these risk factors may interact with each other. This study included 394867 European participants in UK Biobank. Three types of adiposity polygenetic score (PGS) were created based on 97, 66, and 12 genetic loci associated with BMI, waist-to-hip ratio adjusted for BMI (WHRadjBMI), and percentage of body fat (PBF). The adjusted odds ratio (OR) of MS for T2D was 1.25 (95% CI: 1.21-1.28), and ORs for T2D were 1.09 (1.08-1.11), 1.07 (1.05-1.08), and 1.02 (1.01-1.04) per one SD increment of BMI-, WHRadjBMI-, and PBF- PGS. The joint associations of MS and a higher adiposity genetic susceptibility for T2D were 1.52 (1.45-1.60), 1.43 (1.36-1.50), and 1.35 (1.28-1.41), respectively. The estimated proportions of the joint association were 45.1% for MS alone, 28.4% for genetic susceptibility to obesity alone, and 26.5% for their additive interaction. Our results indicate that the increased risk of T2D due to the joint association of MS and adiposity genetic predisposition was greater than each factor. Our findings extend our knowledge on the synergistic contribution of prenatal factors and genetic make-up to adiposity on T2D risk, and re-emphasize the importance of smoking cessation around pregnancy in women.

Disclosure
D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. L. Qi: None.

Funding
National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46200); United States-Israel Binational Science Foundation (2011036)
1708-P: Enteroendocrine Lineage Enriched microRNAs Regulate Intestinal Progenitor Cell Dynamics
Authors: SETHUPATHY PRAVEEN 
Published: June 2019

The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis and systemic energy balance. Notably, progenitors of EECs exhibit stem cell potential and contribute to intestinal epithelial proliferation and renewal; however, the molecular mechanisms are not well understood. In this study, we first report that miR-7 and miR-375 (previously thought to be specific to pancreatic beta cells) are very highly expressed along the EEC lineage trajectory and are among the most enriched miRNAs in Prox1+ EEC progenitors relative to Lgr5+ intestinal stem cells. Next, by studying intestinal stem/progenitor cell responses to microbiota, high-fat diet, and bariatric surgery, we show that miR-7 and miR-375 expression levels are inversely correlated with intestinal epithelial proliferative status. We then demonstrate by both loss- and gain-of function assays in ex vivo mouse enteroids that both miRNAs exert robust control of intestinal epithelial proliferation and enteroendocrine cell maturation. We also show by single cell RNA-sequencing, intestinal phenotyping, and metabolic phenotyping in a miR-375 knockout mouse model, that miR-375 controls intestinal stem/progenitor cell dynamics, especially with increasing age. Overall, this study demonstrates for the first time that two miRNAs highly enriched in the EEC lineage are critical regulators of intestinal epithelial proliferation and likely mediators of the effects of high-fat diet on the intestinal crypt. Ongoing studies are focused on the role of these two miRNAs in the rescue of intestinal crypt behavior after bariatric surgery.

Disclosure
P. Sethupathy: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-47)
1709-P: Assessing the Role of 211 “Established” Type 2 Diabetes Variants in American Indians
Authors: HANSON ROBERT L. , WEDEKIND LAUREN E. , HSUEH WEN-CHI , KOBES SAYUKO , BAIER LESLIE J. , BOGARDUS CLIFTON , KNOWLER WILLIAM C. 
Published: June 2019

Genome-wide association studies (GWAS) have identified many variants associated with type 2 diabetes (T2D), but there is little information on their effects in high risk populations such as American Indians. We analyzed 211 primary variants, associated with T2D (P&lt;5.0×10-8) in published GWAS, in 7659 American Indian participants in a population study (33.5% with T2D)- updating our previous study of 63 variants. Genotypes came from a custom Axiom array that captures common variation in American Indians; imputation was performed using whole genome sequence data from 266 Pima Indians. Variants were tested for association with T2D in a mixed model accounting for relatedness with adjustment for age, sex and the 1st 5 genetic principal components to account for population stratification. Heterogeneity was tested by comparing odds ratios (ORs) in American Indians with published ORs. A weighted polygenic risk score across all 211 variants was analyzed. Nominally significant (P&lt;0.05) and directionally consistent replication was observed for 21 of the 211 variants. Notable associations were with rs2237895 in KCNQ1 (OR=1.29, P=2.5×10-8) and rs4929965 in INS/IGF2 (OR=1.28, P=9.8×10-8). Significant heterogeneity was seen for 23 variants- 21 had weaker effects in American Indians than in published values. A summary test over all variants showed effects were generally weaker in American Indians (P=4.0×10-11). The polygenic risk score was strongly associated with T2D (OR=1.38 per SD, P=2.8×10-22). The risk score was also associated with reduced insulin secretion measured by a 25 g intravenous glucose tolerance test (by 10% per SD, P=0.005, n=300 all with normal glucose tolerance), but not insulin sensitivity measured by a hyperinsulinemic-euglycemic “clamp” (P=0.78, n=557 all nondiabetic). These findings suggest that established T2D risk variants generally also affect T2D risk in American Indians (although effects tend to be weaker) and that they act predominantly through diminished insulin secretion.

Disclosure
R.L. Hanson: None. L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. L.J. Baier: None. C. Bogardus: None. W.C. Knowler: None.
171-LB: A Pilot Study to Evaluate the Utility of an Interconnected Diabetes Management Solution in People with T2D
Authors: KLAFF LESLIE J. , MAIER THOMAS , RICHARDSON JAMES M. , PARDO SCOTT 
Published: June 2019

Use of remote monitoring/smartphones can lower HbA1c in T2D. This 12-week (W) single-arm pilot evaluated the utility of an investigational Interconnected Diabetes Management Solution (IDMS) using remote behavioral coaching from a certified diabetes educator (guide) and a mobile application (app). The app and call(s) allowed user (service member)-guide communication and monitoring of guide-directed tasks (short, time-limited behavioral interventions to improve testing, food choice, activity, stress and sleep). Members (adults: confirmed T2D; HbA1c 7-11%) provided quantitative and qualitative data. Members used a wireless enabled Contour® Next ONE blood glucose smart meter linked to the app on their mobile device. ∆HbA1c (0-12W) was evaluated. Baseline characteristics, n=58 (% or mean): male, 62%; age, 62 years; Caucasian, 88%; hypertension, 50%; BMI ≥30 kg/m2, 60%; hyperlipidemia, 48%; neuropathy, 28%; retinopathy, 12%; CVD, 10%; T2D for &gt;10 years, 71%. Mean %-HbA1c (±SEM) significantly decreased from 8.44 (0.08) to 8.01 (0.08) at W12: -0.43%, p&lt;0.0007 (Figure). A significant decrease in HbA1c was present in individuals with no change to diabetes medication(s). The investigator deemed all adverse events (n=59) unrelated to the IDMS. Conclusion: mean HbA1c significantly decreased independent of changes to medication(s), suggesting improved self-care and glycemic control. Figure.

Disclosure
L.J. Klaff: Research Support; Self; Abbott, Ascensia Diabetes Care, Cnoga Medical, Gan & Lee Pharmaceuticals, Lilly Diabetes, Medtronic MiniMed, Inc., Novo Nordisk Inc., REMD Biotherapeutics, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. T. Maier: Employee; Self; Ascensia Diabetes Care. J.M. Richardson: Employee; Self; Ascensia Diabetes Care. Employee; Spouse/Partner; Ascensia Diabetes Care. S. Pardo: Employee; Self; Ascensia Diabetes Care.
171-OR: Metformin Prevents Microvascular Insulin Resistance and Preserves Endothelial Function in High-Fat Diet-Fed Rats
Authors: LIU JIA , CHAI WEIDONG , GONG LIYING , AYLOR KEVIN W. , LIU ZHENQI 
Published: June 2019

Endothelial dysfunction and vascular insulin resistance coexist and both contribute to the development of type 2 diabetes mellitus (T2DM) and increased cardiovascular risks. Insulin relaxes precapillary arterioles to increase insulin delivery to and action in muscle via recruiting muscle microvasculature and this action is impaired in the insulin resistant states. Metformin is the first line therapy for T2DM and has been shown to improve endothelial function beyond its hypoglycemic effects. Here we aim to examine whether metformin could restore vascular insulin responses in the setting of insulin resistance induced by high fat diet (HFD) feeding via the modulation of endothelial function. Adult, male Sprague-Dawley rats were fed on HFD with or without metformin treatment for 2 weeks. A chow fed group served as control. After dietary intervention, rats were fasted overnight and received a euglycemic-hyperinsulinemic clamp for 120 min. Insulin-mediated muscle microvascular recruitment was assessed before and during insulin infusion using contrast-enhanced ultrasound. Distal saphenous artery was isolated and used for determination of endothelial function and vascular insulin responses. Compared with controls, HFD feeding abolished insulin-induced muscle microvascular recruitment in muscle, decreased insulin-mediated whole body glucose disposal and blunted the vasodilatory response to insulin in small resistance vessel. Metformin treatment significantly enhanced insulin’s microvascular action, effectively rescued small arteriole endothelial function, but did not improve insulin-stimulated whole body glucose disposal in HFD rats. We conclude that metformin could reverse microvascular insulin resistance and attenuate endothelial dysfunction induced by HFD feeding. There findings may provide a novel mechanistic insight into metformin’s cardiovascular protective effect in patients with diabetes.

Disclosure
J. Liu: None. W. Chai: None. L. Gong: None. K.W. Aylor: None. Z. Liu: None.

Funding
American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)
1711-P: Pancreas Single-Cell Patch-Seq Links Physiologic Dysfunction in Diabetes to Transcriptomic Phenotypes
Authors: SOLER JOAN CAMUNAS , DAI XIAOQING , HANG YAN , KIM SEUNG , MACDONALD PATRICK 
Published: June 2019

Pancreatic islet-cells regulate glucose levels in the body through insulin and glucagon secretion; dysfunction of these cells leads to severe disease such as diabetes. Several single-cell transcriptome studies have shown heterogeneous gene expression in major islet cell-types such as beta and alpha cells. However, it has remained an open challenge to reconcile the heterogeneity in transcriptomic signatures with physiological observations of functional heterogeneity. Here we combined electrophysiological profiling and single-cell RNA sequencing of the same cells (pancreas patch-seq) to link transcriptomic phenotypes of islet cells to their physiologic properties. We collected 1,369 pancreas patch-seq cells from fresh and cryopreserved tissue and assessed function-gene expression networks in nondiabetic, type 1 diabetic (T1D) and type 2 diabetic (T2D) humans. We discovered that ‘hub’ genes and pathways drive functional heterogeneity in nondiabetic beta-cells and show that specific transcriptional programs correlate with physiologic dysfunction early in T2D. We have also found evidence that alpha-cell transcriptional plasticity acts as a driver of dysfunction in T1D.

Disclosure
J. Camunas Soler: None. X. Dai: None. Y. Hang: None. S. Kim: None. P. MacDonald: None.

Funding
Chan Zuckerberg Biohub; California Institute for Regenerative Medicine; National Institutes of Health
1716-P: MODY5 and Serous Ovarian Carcinoma in 17q12 Recurrent Deletion Syndrome
Authors: HOLLAR LAURA , SALAM MAAMOUN , THAKER PREMAL H. , MCGILL JANET B. 
Published: June 2019

Background: Maturity onset diabetes of the young type 5 (MODY5) is due to a mutation in the hepatocyte nuclear factor 1b (HNF1b) gene on chromosome 17q12. HNF1b mutations have been found in clear cell ovarian carcinomas (CCOC) while non-CCOC express this mutation rarely. 17q12 recurrent deletion syndrome presents with urogenital anomalies, MODY5, neurodevelopmental and psychiatric disorders. We report a patient with 17q12 recurrent deletion syndrome with MODY5, uterine abnormalities and low grade serous ovarian cancer.
Clinical Case: The female proband was diagnosed with diabetes at age 12. GAD65, islet cell and insulin auto-antibodies were negative, C-peptide was 2.7 ng/mL. Childhood history included strabismus, depression and chronic transaminitis with unremarkable liver biopsy. Mother’s medical history was notable for single kidney, partially-septated uterus, and diabetes. At age 25, the patient presented with abdominal pain. CT showed pancreatic atrophy, ascites, omental and peritoneal nodularity and calcifications. Tumor markers were normal except an elevated CA-125 of 240 U/mL. Short stature was noted, height 147 cm, BMI 27 kg/m2. Laparoscopy revealed bicornuate uterus, 2 cervices and vaginal septum. She underwent TAH-BSO, lymph node dissection and omentectomy for a stage IIIC low grade serous ovarian carcinoma. Chromosomal microarray analysis of the tumor revealed a pathogenic ∼1.8 Mb loss of 17q12, denoted arr[hg19] 17q12(34477479_36283807)x1.
Conclusion: While 17q12 has been described as a susceptibility locus in some ovarian cancers, ovarian cancer predisposition is not a reported feature of MODY5 or 17q12 recurrent deletion syndrome. The disease association reported here suggests that women with MODY5 should have periodic evaluation for ovarian cancer in addition to screening for gut and urogenital tract abnormalities. Patients with diabetes plus urogenital tract abnormalities or 17q12 deletion in an ovarian tumor should have genetic evaluation for MODY5.

Disclosure
L. Hollar: None. M. Salam: None. P.H. Thaker: Advisory Panel; Self; Clovis. Consultant; Self; AbbVie Inc., Celsion, Tesaro, UpToDate. Research Support; Self; Celsion, Merck & Co., Inc. Speaker’s Bureau; Self; Merck & Co., Inc., Tesaro. J.B. McGill: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk Inc., Sanofi US. Research Support; Self; Dexcom, Inc., Medtronic, Novartis AG, Sanofi US. Speaker's Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation.
173-LB: Using a Diabetes Kidney Disease (DKD) Registry to Treat to Multiple Targets (TMT)—A JADE Technology-Based RCT
Authors: CHAN JULIANA C.N. , NGUYEN KHUE THY , TAN ALEXANDER , CHIA YOOK C. , HWU CHII-MIN , HONG EUN-GYOUNG , THEWJITCHAROEN YOTSAPON , DU JIAN , YOO SOON JIB , MIRASOL ROBERTO C. , LAU ERIC S. , LAU VANESSA , FU AMY W.C. , MOHAMED MAFAUZY , YOON KUN-HO , TSANG CHIU CHI , LUK ANDREA 
Published: June 2019

DKD causes co-morbidities made preventable by attaining multiple targets. Patient empowerment, regular feedback and team-based care assisted by JADE Technology with risk stratification and decision support may improve targets attainment and clinical outcomes. In 2014-2018, 2435 patients1 with DKD2 (age:67.6±9.9 years, DM duration:16.5±9.7 years; BMI:26.9±4.7 kg/m2; A1c:7.9±1.6%; SBP:139±18 mmHg; LDL-C:2.35±1.05 mmol/L; TG:1.92±1.29 mmol/L; RASi:70.0%; statin:74.8%; CVD:32.0%, cancer:5.0%, heart failure:3.9%, ≥3 targets3:33.6%), were randomized to usual care (UC=809), empowered care (EC=819) and team-based empowered care (TEC=807) for 1 year with endpoints defined at year 1 and when study ends. After structured assessment, EC and TEC received JADE report, with EC receiving 3-monthly phone calls by nurses and TEC, additional 3-monthly review by a doctor-nurse team with JADE follow-up reports. Amongst 1837 returnees at 1 year, TEC had the lowest HbA1c and LDL-C and highest proportion with ≥3 targets (TMT)4. Non-returnees had worse risk profiles and were less likely to have familial DM and received prior DM education. At study end (2019)5, TMT group (27/408) had fewer CV-renal-cancer endpoints than non-TMT group (66/676) with RR of 0.678 (95% CI: 0.668-0.687). Empowerment, information support and continuing team-based care improve risk factor control and clinical outcomes in DKD.

Disclosure
J.C.N. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare. K.T. Nguyen: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novo Nordisk A/S, Sanofi-Aventis. A. Tan: None. Y.C. Chia: None. C. Hwu: None. E. Hong: None. Y. Thewjitcharoen: None. J. Du: None. S. Yoo: None. R.C. Mirasol: None. E.S. Lau: None. V. Lau: None. A.W.C. Fu: None. M. Mohamed: None. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. C. Tsang: None. A. Luk: None.

Funding
Asia Diabetes Foundation
1731-P: The Involvement of Glutaminolysis in ß-Cell Differentiation and Its Clinical Application for Type 1 Diabetes
Authors: HAJIME MAIKO , IWATA SHIGERU , ZHANG MINGZENG , NAKAYAMADA SHINGO , OKADA YOSUKE , TANAKA YOSHIYA 
Published: June 2019

Objective: B cells play a crucial role in type 1 diabetes (1DM). Recently, “Immunometabolism” attract much attention. In this study, we examined the role of mitochondrial function and glutaminolysis in B cell differentiation and its relevance to 1DM.
Methods: Peripheral blood mononuclear cells were obtained from healthy controls (HCs) and 1DM patients and assessed by FACS. In addition, CD19+ cells were isolated from HCs and change of mitochondrial function and glutaminolysis were assessed in the absence of glucose or glutamine, by metformin in vitro.
Results: Initially, mitochondrial function in B cells from 1DM patients was assessed using DiOc6 as a marker of depolarization-activated mitochondrial membrane. CD24-DiOc6+ cells in IgD-CD27- memory B cell from 1DM patients were significantly higher than those of HCs. Next, we assessed the role of mitochondrial function and glutaminolysis in human B cell differentiation in vitro. Stimulation with CpG (TLR9 ligand) and IFN-α, 1) increased the area of cytoplasm including many expanded mitochondrial cristae with slightly wider and loosely organized intermembrane space in electric microscopy, accompanied with ROS production and DiOc6 up-regulation, 2) induced CD27hiCD38hi plasmablasts differentiation and immunoglobulin production. Interestingly, ROS production and DiOc6 expression were significantly decreased in the absence of glutamine, leading to inhibition of plasmablasts differentiation and immunoglobulin production. This tendency was not shown in the absence of glucose. Metformin, which is known as AMPK activator, abrogated glutamine uptake, resulting in suppression of ROS production, DiOc6 expression, plasmablast differentiation and immunoglobulin production.
Conclusion: These results suggest that mitochondrial activation via glutaminolysis may play an important role in the differentiation from IgD-CD27- double negative B cells to plasmablasts and production of immunoglobulins in 1DM patients.

Disclosure
M. Hajime: None. S. Iwata: None. M. Zhang: None. S. Nakayamada: None. Y. Okada: None. Y. Tanaka: None.
1736-P: Significance of Anti-insulin Immune Responses in Autoimmune Diabetes with HLA DR9
Authors: SHIMADA AKIRA , SATOMURA ATSUSHI , HAISA AKIFUMI , OIKAWA YOICHI 
Published: June 2019

Previously we reported that CXCL10 in type 1 diabetes (T1D) is higher than controls, and the level reflects islet associated antigen specific T cell responses and disease activity in T1D (Diabetes Care, 2001). However, little is known regarding the relationship between CXCL10 level and autoantibody levels in T1D. Therefore, we investigated relationship between the marker of cellular immunity including CXCL10 levels and islet associated autoantibody levels in T1D. We obtained informed consent and blood samples from 101 T1D patients, and examined HLA (DRB1*04:05, *09:01; susceptible HLA types in Japanese), serum CXCL10, insulin peptide (B9-23, 10-24, 11-25, 12-26) and PPD reactive T cell responses by using ELISPOT (IFNg), GAD, IA-2, ZnT8 Abs and insulin antibody. Because it has been reported that BCG administration might affect the autoimmune responses in T1D, we assessed the PPD responses in these patients as well. Among them, we focused to GAD Ab positive T1D including acute onset (n=28, 13 male and 15 female, mean age 43.1 years, disease duration 5.9 years), and slowly progressive type (n=17, 9 male and 8 female, mean age 56.9 years, disease duration 9.1 years); i.e., autoimmune diabetes subjects. We found significant positive correlation between serum CXCL10 and insulin antibody levels in the autoimmune diabetes with DRB1*09:01 (p&lt;0.05), but it was not the case in those with DRB1*04:05. Interestingly, there was significant positive correlation between insulin peptide reactive T cells and PPD responses in the autoimmune diabetes with DRB1 09:01 (p&lt;0.05), but it was not the case in those with DRB1 04:05. The observation was still true when we focused to acute onset subjects. These results suggest that insulin antibody levels seem to reflect higher disease activity in the autoimmune diabetes with DR9, and modulation of PPD responses may affect insulin peptide T cell responses in those patients.

Disclosure
A. Shimada: Advisory Panel; Self; Terumo Medical Corporation. Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. A. Satomura: None. A. Haisa: None. Y. Oikawa: None.