bluuebunny/crossref_metadata_2025_split huggingface dataset:
1636-P: Transient Neonatal Diabetes: Clinical Differences between Patients Bearing KATP Mutations and 6q24 Defects May Guide Genetic Screening
Authors: BARBETTI FABRIZIO , BONFANTI RICCARDO , RABBONE IVANA , REINSTADLER PETRA , BIZZARRI CARLA , IAFUSCO DARIO 
Published: June 2020

Transient neonatal diabetes mellitus (TNDM) is a subtype of neonatal diabetes (diagnosis: ≤ 180 days of life) characterized by remission within months from onset. TNDM is almost invariably associated with mutations in genes encoding the two subunits of ATP-dependent potassium channel (KATP), ABCC8 and KCNJ11, or with defects in chromosome 6. We reviewed genetic data, family history and clinical features including age at diabetes onset, mode of diabetes presentation, birth weight, type of diabetes treatment, time to remission, and diabetes therapy at relapse in 23 patients with TNDM of the Italian collection. Italian data set of TNDM patients included 8 cases with ABCC8 mutation, 8 cases with KCNJ11 mutation and 7 patients with 6q24 defects. Ten patients with KATP/TNDM (62%) had a parent with diabetes or IFG/IGT who carried the mutation. In contrast, none of the parents of patients with 6q24/TNDM showed glucose derangement. Age at diabetes onset did not exceed 5 weeks from birth in patients with 6q24 defects, and ranged from 1 to 34 weeks in patients with KATP mutations. Seven patients with KATP/TNDM presented with diabetic ketoacidosis (DKA); in contrast, three other patients entered into remission without any pharmacological treatment. No patients with 6q24/TNDM had DKA. Age at remission was higher for probands with KATP/TNDM than those with 6q24/TNDM (median 28.5 vs. 8 weeks, respectively, p=0.0023), along with time to remission (20.5 vs. 6 weeks, p=0.0056). Four patients with TNDM who had relapse of diabetes were treated with sulfonylureas (SU), and one with insulin (refusal of SU).
Conclusions: TNDM patients with positive family history for diabetes, onset of diabetes beyond 6 weeks from birth and long time to remission should be screened for mutations in KATP genes first. Remission without therapy observed in 3 cases with KATP/TNDM suggests that in parents with diabetes onset in adolescence, mild TNDM could have been overlooked.

Disclosure
F. Barbetti: Consultant; Self; Amring. R. Bonfanti: Advisory Panel; Self; Abbott, Medtronic, Roche Diabetes Care. I. Rabbone: None. P. Reinstadler: None. C. Bizzarri: None. D. Iafusco: None.
1655-P: Genetic Risk Factors for Incident Cardiovascular Disease in Type 2 Diabetes Patients
Authors: KWAK SOO HEON , MERCADER JOSEP M. , LEONG AARON , PORNEALA BIANCA , WU PEITAO , COLE JOANNE B. , MERINO JORDI , PARK KYONG SOO , CHO NAM H. , DUPUIS JOSEE , FLOREZ JOSE C. , MEIGS JAMES B. 
Published: June 2020

Patients with type 2 diabetes (T2D) are at two-fold increased risk of cardiovascular disease (CVD). CVD is the leading cause of T2D morbidity and mortality. The aim of this study was to identify genetic risk factors associated with incident CVD in patients with T2D. We performed survival genome-wide association study (GWAS) with patients with T2D in the UK Biobank (UKBB), Partners HealthCare Biobank (PBB), and Korean Genome and Epidemiology (KoGES) studies. The primary outcome of the study was a composite of myocardial infarction and stroke that occurred at least one year after the diagnosis of T2D. We conducted survival GWAS using ’GWASTools’ R package adjusting for age, and sex. The results of the three cohorts were meta-analyzed using inverse variance weighted method. A total of 19,121 participants were included in the analyses (15,643 from UKBB, 1,161 from PBB and 2,317 from KoGES). The incidence rate of CVD was higher in the hospital-based study of PBB (33.5%) compared to population-based studies of UKBB (9.5%), and KoGES (8.0%). Although there was no genetic association reaching genome-wide significance, there were four genomic loci that had suggestive association evidence for incident CVD with P&lt;1.0x10-6. These include distinct variants in rs113067014 (intergenic) on chromosome 1 (chr1), rs1367414 (intron in PAX3) on chr2, rs11762253 (intron in AC004160.1) on chr7, and rs2837174 (intron in IGSF5) on chr21. When we investigated 184 previously validated coronary artery disease loci, 17 reached nominal significance of P&lt;0.05 with consistent direction of association. A polygenic score (PS) comprised of these 184 variants was significantly associated with risk of CVD in T2D patients (HR 1.20 per s.d. increase in PS, P=6.6x10-16).
In summary, we have implemented survival GWAS analysis to investigate genetic risk factors for incident CVD in patients with T2D. However, further increase in sample size is required to identify molecular features leading to increased CVD risk among individuals with T2D.

Disclosure
S. Kwak: None. J.M. Mercader: None. A. Leong: None. B. Porneala: None. P. Wu: None. J.B. Cole: None. J. Merino: None. K. Park: None. N.H. Cho: None. J. Dupuis: Consultant; Self; Merck Sharp & Dohme Corp. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. J.B. Meigs: Consultant; Self; Quest Diagnostics.
1664-P: Macrophage-Derived Lipid Signaling Contributes to Type 1 Diabetes Development
Authors: ALMUTAIRI ABDULAZIZ , GAI YING , LEI XIAOYONG Y. , PARK MARGARET A. , CHALFANT CHARLES , RAMANADHAM SASANKA , STEPHENSON DANIEL 
Published: June 2020

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells and the leading causes for this process are incompletely understood. Our previous work suggests the involvement of lipid signaling from immune cells on T1D development. Relevant lipids were shown to be generated by the Ca2+-independent phospholipase A2β (iPLA2β), which is ubiquitously expressed and hydrolyzes membrane phospholipids at the sn-2 position to release bioactive lysophospholipids and free fatty acids such as arachidonic acid. Arachidonic acid can be metabolized to generate eicosanoids, many of which are pro-inflammatory. We found that iPLA2β activation promotes pro-inflammatory M1 macrophage phenotype and that selective inhibition of iPLA2β preserves β-cell mass and reduces T1D incidence and insulitis in the NOD mice. Herein, we report that NOD macrophages generate significantly higher pro-inflammatory lipids and reduced anti-inflammatory lipids than C57 macrophages during the prediabetic phase. Such changes in the lipidome are mitigated with reduced expression of iPLA2β. Specifically, lipidomics analyses revealed that NOD.iPLA2β+/- macrophage production of multiple pro-inflammatory lipids (PGE2, leukotrienes, 12-HETE, DHETs) is decreased, and of anti-inflammatory lipids increased, relative to NOD-derived macrophages. The mitigated inflammatory lipid signature during the prediabetic phase the NOD.iPLA2β+/- contributed to a reduced T1D incidence. These findings suggest a role for macrophage iPLA2β-derived lipids (iDLs) in T1D development. In support, adoptive transfer of NOD.iPLA2β+/- macrophages reduced T1D incidence and improved glucose tolerance; and conditional knockout of iPLA2β in macrophages reduced T1D incidence in the NOD mice. We hypothesize that iDLs produced by macrophages contribute to T1D development and that these could be targeted to prevent onset/progression of T1D.

Disclosure
A. Almutairi: None. Y. Gai: None. X.Y. Lei: None. M.A. Park: None. C. Chalfant: None. S. Ramanadham: None. D. Stephenson: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
168-LB: Prediction for Risk-Stratified Care for Women with Gestational Diabetes: The PeRSonal GDM Study
Authors: COORAY SHAMIL , BOYLE JACQUELINE , SOLDATOS GEORGIA , ZAMORA JAVIER , FERNANDEZ-FELIX BORJA M. , ALLOTEY JOHN , THANGARATINAM SHAKILA , TEEDE HELENA 
Published: June 2020

Objective: To develop and validate a prediction model for adverse pregnancy outcomes at the time of gestational diabetes (GDM) diagnosis to stratify care.
Research Design and Methods: A prediction model development and validation study was conducted on data from a retrospective population-based study. The outcome to be predicted was a composite for adverse pregnancy outcome: hypertensive disorder of pregnancy, large-for-gestational (LGA) age neonate, neonatal hypoglycaemia requiring intravenous therapy, shoulder dystocia, perinatal death, neonatal bone fracture and nerve palsy.
Results: Predictors of the composite adverse pregnancy outcome were: fasting and 1 hour glucose from the diagnostic OGTT, gestational age of GDM diagnosis, previous macrosomia, previous pre-eclampsia or eclampsia, previous LGA, ethnicity, weight at GDM diagnosis and parity. The apparent performance of the model was reasonable: c-statistic was 0.691 (95% CI, 0.662 - 0.720) and the calibration plot showed near perfect agreement between predicted and observed risks (Figure 1).
Conclusions: A promising prediction model for adverse pregnancy outcomes in women with GDM was developed. Model estimation using the Least Absolute Shrinkage and Selection Operator method is currently underway to correct for over-optimism. External validation and decision curve analysis will determine suitability for clinical application.

Disclosure
S. Cooray: None. J. Boyle: None. G. Soldatos: None. J. Zamora: None. B.M. Fernandez-Felix: None. J. Allotey: None. S. Thangaratinam: None. H. Teede: Other Relationship; Self; Roche Diagnostics France.

Funding
National Health and Medical Research Council of Australia (APP1151242); Australian Academy of Science; Diabetes Australia Research Program; Medical Research Future Fund of Australia; Australian Government Department of Education and Training (7167_2019)
1683-P: Upregulation of Pancreatic Islet EGF Receptor Improves Beta-Cell Identity and In Vivo Vascularisation in a Directly Observed Transplant Model
Authors: SALEM VICTORIA , ALI USAMA , SUBA KINGA , BITSI STAVROULA , LOPES TATIANA , ALONSO ALDARA MARTIN , PATEL YATEEN S. , LECLERC ISABELLE , OWEN BRYN , RUTTER GUY A. , ROTHERY STEPHEN M. , TOMAS ALEJANDRA 
Published: June 2020

Aims: Long-term outcomes for islet transplantation remain suboptimal. An important determinant of islet transplantation success is vascularisation of engrafted islets. The epidermal growth factor receptor (EGFR) is a key angiogenic and pro-survival factor. In an in vivo mouse model, we investigated if EGFR overexpression in pancreatic islets improves engraftment.
Methods: Donor islets from C57BL/6 mice were infected with adenoviruses generated to encoding human EGFR alongside a GFP reporter. To assess the effects of EGFR over-expression on beta-cell identity and function, qPCR was run to determine expression of angiogenesis, beta-cell enriched and beta-cell disallowed genes compared with islets infected with control (empty vector) virus. To assess the effects of EGFR-overexpression on implantation in vivo, EGFR-overexpressing or control (empty vector) islets were transplanted into the anterior chambers of the eyes of syngeneic recipients. Using confocal microscopy, islet volume (GFP signal) and blood vessel density (following IV administration of dextran conjugated Texas Red) were assessed regularly and longitudinally over 30 days.
Results: qPCR results showed that EGFR-overexpressing islets had greater gene expression of angiogenic factors. Consistent with preserved beta-cell identity, beta-cell enriched genes were upregulated in EGFR-overexpressing islets compared to control islets, whilst beta-cell disallowed genes were repressed. EGFR-overexpressing islets demonstrating greater density compared to control islets at all time points (n=5 animals per group, 1-5 islets per eye, p&lt;0.05).
Conclusion: We are the first to demonstrate that EGFR overexpression can promote the vascularisation of transplanted islets in vivo. The transcriptional profiling of these islets suggests an improved potential for beta-cell regenerative capacity and function.

Disclosure
V. Salem: None. U. Ali: None. K. Suba: None. S. Bitsi: None. T. Lopes: None. A. Martin Alonso: None. Y.S. Patel: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. S.M. Rothery: None. A. Tomas: None.

Funding
Diabetes UK (15/0005317)
1702-P: PRDM1 Is a Novel Regulator of Angiogenesis in Adipose Tissue
Authors: LIU YAO , QU SHEN , LI JIN 
Published: June 2020

Adipose tissue is highly vascularized, and angiogenesis is a key process involved in regulation of tissues homeostasis and remodeling. Studies in the past have shown the importance of adipose angiogenesis in glucose and lipid metabolism. Prdm1 is a transcription factor participating immune response. Recent studies suggest Prdm1 is regulated by VEGF and important for the heart development. To test the changes of Prdm1 in adipose tissue under different physiological conditions, we challenged the C57BL/6 mice with fasting, coldness or high fat diet (HFD). Our results showed that Prdm1 mRNA level of inguinal fat was downregulated by fasting, coldness and long-term HFD. But it was upregulated when the mice were exposed to a short-term HFD. Overexpression of Prdm1 in Human Umbilical Vein Endothelial Cells (HUVEC) leads to alteration of angiogenic capabilities in vitro.
In conclusion, we propose Prdm1 as a novel regulator of angiogenesis. Prdm1 may play important roles in glucose and lipid metabolism.

Disclosure
Y. Liu: None. S. Qu: None. J. Li: None.

Funding
National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Natural Science Foundation (18ZR1435800)
1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients
Authors: MICHURINA SVETLANA , STAFEEV IURII , SKLYANIK IGOR , SHESTAKOVA EKATERINA , YURASOV ANATOLIY , YAHYAEV KAMIL , RATNER ELIZAVETA , MENSHIKOV MIKHAIL , SHESTAKOVA MARINA V. , PARFYONOVA YELENA V. 
Published: June 2020

Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT).
Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI&gt;35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy.
Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation.
Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance.

Disclosure
S. Michurina: None. I. Stafeev: None. I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None.

Funding
Russian Science Foundation (17-15-01435)
1706-P: Ginsenoside Rb2 Improves Insulin Resistance by Inhibiting Adipocyte Pyroptosis
Authors: GU XUEJIANG 
Published: June 2020

Pyroptosis plays a critical role in the development of obesity-associated inflammation and insulin resistantance (IR). Ginsenoside Rb2 (Rb2), the main component of ginsenosides has drawn appreciable interest in the context of glucose metabolism. In the present study, we investigated Rb2-mediated protection against obesity-induced IR and the related mechanisms. Rb2 could significantly reduce high-fat diet (HFD)-induced body weight changes, fat accumulation and IR. In addition, Rb2 treatment inhibited pyroptosis-related genes and proteins,such as caspase-1, ASC, NLRP3, IL-1β and GSDMD in HFD-fed mice. The above results were recapitulated in 3T3-L1 adipocytes and demonstrated that Rb2 improved TNF-α induced IR and pyroptosis in 3T3-L1 adipocytes. Furthermore, Rb2 reduced the phosphorylation levels of p65 and IκBα both in vitro and in vivo. The present study showed that Rb2, which could serve as a promising agent for the treatment of IR and obesity, ameliorated IR by inhibiting pyroptosis in adipocytes in vivo and in vitro through the NF-κB pathway.

Disclosure
X. Gu: None.

Funding
Zhejiang Provincial Natural Science Foundation (LY20H070003, LQ12H07003); Wenzhou Science and Technology Bureau (Y20170047); National Key Research and Development Program of China (2016YFC1305202)
1710-P: Maternal Supplementation of Tetrahydrobiopterin Regulates Differentiation of Fetal Brown Adipose Tissue and Contributes to Offspring Metabolic Health
Authors: MINAMINO HIROTO , FUJITA YOSHIHITO , OGURI YASUO , GOTO TSUYOSHI , OHASHI AKIKO , FURUYA FUTOSHI , ISOMURA NOZOMI , KOHEI TAKESUE , LI YING , KAWARASAKI SATOKO , KAWADA TERUO , HASEGAWA HIROYUKI , INAGAKI NOBUYA 
Published: June 2020

Brown adipose tissue (BAT) is a key organ that produces heat and dissipates energy, and may be clinically relevant to the treatment of obesity and diabetes. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis including that of norepinephrine (NA) and nitric oxide (NO) synthase. Although both NA and NO are well-known factors in BAT differentiation, the role of BH4 in the differentiation of BAT is poorly understood. We investigated the role of BH4 in differentiation of BAT using a mouse model of BH4 deficiency, the Hph-1 mouse. Hph-1 neonatal mice exhibit dysplasia of BAT as well as attenuated thermogenesis-related gene expressions (UCP1, Dio2, Pgc1a) compared with control mice. As differentiation capacity is considered to be at maximum during late gestation, we administered BH4 to fetal Hph-1 mice via placental transfer using intraperitoneal injection to pregnant Hph-1 mice for 6 days just before birth. Maternal BH4 supplementation ameliorated dysplasia of neonatal BAT and restored thermogenesis-related genes expression. Intriguingly, offspring of the maternal BH4-supplementation group showed less weight gain, ameliorated glucose intolerance, and improved cold tolerance after growth under high fat chow diet. We then evaluated the direct effect of BH4 on brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Compared with control mice, brown pre-adipocytes from Hph-1 mice showed reduced differentiation capacity, while BH4 supplementation in brown pre-adipocytes from Hph-1 mice ameliorated differentiation capacity nitric oxide-dependently. Taking these findings together, BH4 plays an integral role in the differentiation of BAT, especially in the fetal period, and may represent a novel target for prevention of metabolic disorders such as obesity and diabetes.

Disclosure
H. Minamino: None. Y. Fujita: None. Y. Oguri: None. T. Goto: None. A. Ohashi: None. F. Furuya: None. N. Isomura: None. T. Kohei: None. Y. Li: None. S. Kawarasaki: None. T. Kawada: None. H. Hasegawa: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
1715-P: Impaired Postprandial Adipose Tissue Microvascular Blood Flow in Healthy People with a Family History of Type 2 Diabetes
Authors: ROBERTS-THOMSON KATHERINE , RUSSELL RYAN D. , HU DONGHUA , GREENAWAY TIMOTHY M. , BETIK ANDREW C. , PARKER LEWAN , RICHARDS STEPHEN M. , PREMILOVAC DINO , KESKE MICHELLE 
Published: June 2020

Microvascular blood flow (MBF) enables the delivery of key nutrients (e.g., lipids and glucose) and hormones (e.g., insulin) to adipose tissue. We have demonstrated that adipose tissue MBF is impaired in people with type 2 diabetes (T2D), postprandially. Whether this also occurs in people at risk of T2D (having a family history of T2D) is unknown. Eighteen healthy people with no family history of T2D for two generations (FH-), and sixteen healthy people with at least one parent with T2D (FH+) were recruited. Overnight-fasted participants had a blood sample taken for clinical chemistries, a DEXA scan performed for body composition and underwent a mixed meal challenge (MMC, 300kCal; 54% carbohydrate, 29% protein and 16% fat). Microvascular blood volume (MBV), velocity (β) and MBF in truncal subcutaneous adipose tissue was assessed by contrast-enhanced ultrasound before and 60 min post-MMC. Both groups were matched for age, BMI, clinical chemistries and post-MMC area under the glucose time curve (Table 1). FH+ had higher truncal fat (Table 1). Increases in adipose tissue MBF post-MMC were lower in FH+ which was mostly attributed to a lower MBV (Table 1). Despite having normal clinical chemistries and blood glucose regulation, FH+ have impaired post-prandial adipose tissue MBF coinciding with greater central obesity which might in part explain their heightened risk for developing T2D.

Disclosure
K. Roberts-Thomson: None. R.D. Russell: None. D. Hu: None. T.M. Greenaway: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; AstraZeneca, Sanofi-Aventis. A.C. Betik: None. L. Parker: None. S.M. Richards: None. D. Premilovac: None. M. Keske: None.