bluuebunny/crossref_metadata_2025_split huggingface dataset:
1371-P: Continuing Improvement of Diabetes Control after the Establishment of the Population-Based Childhood Diabetes Register ČENDA
Authors: SUMNIK ZDENEK , PAVLÍKOVÁ MARKÉTA , CINEK ONDREJ ,   ČENDA STUDY GROUP
Published: June 2019

Objectives: The Czech National Childhood Diabetes Register (ČENDA) is a web-based nationwide database that collects treatment and outcome data in children and adolescents with diabetes. Here we present data from the first five years of ČENDA (2013-2017).
Methods: Data include characteristics of disease onset and annual summaries of key clinical care parameters from every patient treated by participating pediatric diabetes outpatient clinics.
Results: The database contains data from 4361 children (aged 0 to 19 years) from 52 centers, which is estimated to be 85% of all Czech pediatric patients. Of these, 94% had type 1 diabetes (T1D), 4.5% had genetically proven monogenic or secondary, and 1.5% had type 2 diabetes. In children with T1D, median HbA1c decreased throughout the observed period from 66.3 to 61.0 mmol/mol (p &lt; 0.0001, 95% confidence interval for change -6 to -5). Consequently, the proportion of children reaching the ADA target therapeutic goal of 58.5 mmol/mol increased from 28% in 2013 to 40% in 2017. This improvement was significant for all categories of age and diabetes duration and was independent of gender. The overall proportion of children treated with continuous subcutaneous insulin infusion (CSII) remained stable over the observed period (25%). The main predictors associated with lower HbA1c were treatment with CSII, male sex and care provided at a large diabetes center (with &gt;100 patients in regular care).
Conclusions: A significant continuous decrease in HbA1c was observed in Czech children over the past five years. As this improvement was not accompanied by appreciable changes in the mode of therapy, we assume that the establishment of our nationwide register has itself constituted a stimulus towards improvement in the care process.

Disclosure
Z. Sumnik: None. M. Pavlíková: None. O. Cinek: None.

Funding
Ministry of Health of the Czech Republic
138-OR: Ablating Adipose CREB3l3 Preserves Metabolic Health during Obesity
Authors: MCCANN MAXIMILIAN A. , LI SHENGXIAN , LI YANLIANG , GIL VICTORIA , LIEW CHONG WEE 
Published: June 2019

During obesity, the adipose tissue becomes supersaturated with lipids, leading to inflammation, the release of free fatty acids into the bloodstream, and the development of metabolic syndrome. However, a small obese subpopulation does not develop metabolic syndrome and has been deemed to have “metabolically healthy” obesity (MHO). Our lab has created a mouse model that mimics MHO, via adipose-specific ablation of the ER-bound transcription factor cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3). We have discovered that CREB3L3 is not only expressed in adipose tissue, but selectively downregulated in the “metabolically protective” subcutaneous fat in obese mice and human patients. We hypothesized that CREB3L3 downregulation could contribute to the healthier metabolic profile of subcutaneous fat during obesity, so we created a CREB3L3 fat-specific knockout (KO) mouse. CREB3L3 KO mice had enhanced diet-induced obesity following 12 weeks of high-fat diet feeding and significantly larger inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) compared to wild type controls. Unexpectedly, the KO mice do not exhibit the reduction in glucose tolerance or insulin sensitivity that would be expected with their more obese phenotype, which is likely due to the enlarged adipose tissues. The KO mice do not exhibit the expected dyslipidemia or hepatic steatosis, suggesting that the KO adipose tissue sequesters lipids away from these spaces. Additionally, the KO iWAT and eWAT have reduced inflammatory marker expression, suggesting that CREB3L3 plays a role in adipose inflammation. Indeed, we observed that obese mice overexpressing CREB3L3 via direct injection of a CREB3L3 adeno-associated virus into the iWAT and eWAT had marked upregulation of IL-1B and MCP1 in both of these tissues. Together, these data suggest that adipose ablation of CREB3L3 preserves metabolic health during obesity by allowing the adipose tissue to meet the body’s lipid storage demands via healthy expansion.

Disclosure
M.A. McCann: None. S. Li: None. Y. Li: None. V. Gil: None. C. LIew: None.

Funding
National Institutes of Health (R01DK109015)
1385-P: Associations between Maternal Metabolomic and Lipidomic Profiles across Gestation with Neonatal Birthweight in Type 1 Diabetes Pregnancy
Authors: STEWART ZOE A. , YAMAMOTO JENNIFER M. , MEEK CLAIRE L. , SANCHEZ J. JOHANNA , FEIG DENICE , MURPHY HELEN R. 
Published: June 2019

Aims/Objectives: To describe the maternal-fetal metabolomic and lipidomic profiles and examine associations with neonatal birthweight in type 1 diabetes pregnancy.
Methods: A longitudinal prospective study of 162 CONCEPTT mothers. 1049 maternal metabolites and 1041 lipids were analyzed at 12, 24 and 34 weeks gestation, in addition to 93 cord-blood samples using ultra-performance liquid chromatography-tandem mass spectroscopy. The effects on neonatal birth weight, classified as appropriate for gestational age (AGA) 10-90th percentile, large for gestational age (LGA) &gt;90th percentile and extreme LGA (ELGA) &gt;97.7th percentile were examined through ANOVA, principle component analysis and hierarchical clustering, adjusting for maternal BMI.
Results: Significant gestational changes in the maternal metabolome and lipidomic profiles were observed. Metabolite changes associated with birthweight were modest in LGA, albeit more apparent in ELGA. At 24 and 34 weeks, glucose levels were significantly elevated and 1,5-anhydroglucitol (1,5-AG) significantly reduced in ELGA mothers. Triglycerides did not differ between AGA and LGA. Throughout pregnancy, many lipid classes were lower in LGA mothers, with modest increases in free fatty acids and acylcarnitine species at 34 weeks in ELGA. The distribution of lipid classes was significantly different between maternal and cord-blood samples, with most cord-blood lipids comparable between AGA, LGA and ELGA. There were some differences in the cord-blood steroid hormones and acylcarnitine species of ELGA neonates.
Conclusions: Gestational changes in maternal-fetal metabolomic and lipidomic profiles are largely conserved across birthweight categories. Some differences in glucose handling, lipid homeostasis, steroid hormones and acylcarnitine species were apparent in maternal-fetal samples of ELGA neonates.

Disclosure
Z.A. Stewart: None. J.M. Yamamoto: None. C.L. Meek: None. J. Sanchez: None. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc.

Funding
Diabetes UK; JDRF
1387-P: Genotyping Cell-Free Fetal DNA to Decide whether to Treat Hyperglycemia during Pregnancy in Women with GCK Monogenic Diabetes—A Case Study
Authors: KWAK SOO HEON , JANG SE SONG , KANG SUNYOUNG , JANG HAK CHUL , LEE SEUNG MI , CHAE JONG HEE , PARK KYONG SOO 
Published: June 2019

Patients with inactivating glucokinase (GCK) mutation usually do not require treatment except for during pregnancy. The decision to treat hyperglycemia during pregnancy would depend on the fetal GCK genotype. However, it has not been able to noninvasively investigate the fetal genotype antenatally. In this study, we developed a method to determine cell-free fetal genotype of GCK and applied it in a case of pregnant woman with GCK mutation. A 40 years old woman in her second pregnancy presented with hyperglycemia. She was diagnosed with GCK p.Gly411Ser (chr7:44185121C&gt;T; NM_000162 c.G1228A) mutation prior to her second pregnancy. We used targeted linked-read deep sequencing to resolve the haplotypes of GCK for both the women and her husband. Cell-free DNA was extracted from maternal plasma at week 24 of gestation and were subjected to massively parallel sequencing. The allelic fraction of the heterozygous variants that were in maternal mutant-linked haplotype were analyzed. The fetal fraction of the maternal plasma cell-free DNA was 21.8%. In maternal plasma cell-free DNA, a total of 12 heterozygous variants, that were homozygous in paternal genomic DNA, were identified within 40 kb of the disease-causing mutation. The average allelic fraction of the 12 variants in the mutant-linked haplotype and the wild type-linked haplotype in the cell-free DNA was 44.1% and 55.9%, respectively. This significant difference in allelic fraction of the haplotypes suggested that the fetus did not inherit the GCK mutant-linked haplotype (P 0.0081). The inferred fetal genotype was available at week 30 of gestation and the patient was treated with basal-bolus insulin therapy until term at 38 weeks. The fetal birth weight was 2,980 g (25th percentile). The fetal genotype of GCK was confirmed by Sanger sequencing postnatally. This was the first study to use cell-free DNA to determine fetal genotype to guide treatment of hyperglycemia in pregnant women with GCK mutation.

Disclosure
S. Kwak: None. S. Jang: None. S. Kang: None. H. Jang: None. S. Lee: None. J. Chae: None. K. Park: None.

Funding
Korean Ministry of Health and Welfare (HI15C3131, HI13C1468)
1388-P: Umbilical Cord Blood-Derived Exosomal LRG1 and ECM1 Induce Abnormal Placental Angiogenesis in Women with Gestational Diabetes Mellitus
Authors: YAO JULEI , DUAN TAO , WANG KAI 
Published: June 2019

Background: Gestational diabetes mellitus (GDM) is characterized by a high risk of fetal macrosomia and placenta hypervascularization. There is a need to investigate the underlying mechanism to explain these associate complications. Exosomes had been known participating in the regulation of various angiogenic processes. However, the effects of exosomes from cases of GDM on placental vascular network formation remain unclear.
Methods and Results: Capillary branching per placental villi and protein level of CD31 were identified to be increased in GDM. Exosomes derived from umbilical cord blood (UE) enhanced endothelial cell vascularization significantly, especially in GDM pregnancies. The proteome of 10 normal exosomes and 10 GDM exosomes showed different profiles and uncovered two up-regulated proteins in GDM cases, namely leucine-rich alpha-2-glycoprotein-1 (LRG1) and extracellular matrix protein 1 (ECM1). Genetically engineered exosomes that overexpressed LRG1 or ECM1 resulted in hyper vascularization, including proliferation and migration.
Conclusions: Our results demonstrate for the first time the expression of LRG1 and ECM1 in normal and GDM UE and their role in regulating pathological placental angiogenesis. These findings support the potential role of LRG1 and ECM1 in monitoring placental pathologies in this increasingly prevalent condition and novel insights into the causes.

Disclosure
J. Yao: None. T. Duan: None. K. Wang: None.

Funding
National Natural Science Foundation of China; National Key Research and Development Program of China
1398-P: Augmented Insulin Secretory Response in Early Pregnancy Is Independent of Gestational Insulin Resistance
Authors: POWE CAMILLE E. , PRESLEY LARRAINE , LOCASCIO JOSEPH J. , CATALANO PATRICK 
Published: June 2019

Background: Augmentation of insulin secretory response (ISR) in pregnancy has been attributed to a pregnancy-associated reduction in insulin sensitivity. We hypothesized that ISR in pregnancy increases prior to and independent of decrements in insulin sensitivity.
Methods: In 34 women, ISR (by intravenous glucose tolerance test) and insulin sensitivity (by euglycemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation), and in late pregnancy (34-36 weeks gestation). In a secondary analysis of data from a prior study, we used mixed effects models to compare ISR and insulin sensitivity in early pregnancy to the same parameters prior to pregnancy and in late pregnancy, with adjustment for age, obesity, and GDM status. We next explored the relationship between ISR and circulating hormones.
Results: ISR increased from prior to pregnancy to early pregnancy (unadjusted mean [standard deviation] 1st phase insulin response 465.1 [268.5] to 720 [358.2], P&lt;0.001) and from early pregnancy to late pregnancy (to 924 [494.6], P=0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], P=0.001) and decreased in late pregnancy (to 0.06 [0.03], P&lt;0.001). Adjustment for insulin sensitivity did not attenuate observed augmentation in ISR in early pregnancy (P &lt;0.001), but did eliminate the augmentation of ISR between early pregnancy and late pregnancy (P=0.30). Adjustment for age, obesity, and GDM status did not affect longitudinal changes in physiologic parameters. Leptin was positively associated with ISR, independent of insulin sensitivity and adiposity (P=0.004). Adjustment for leptin attenuated the augmentation of ISR in early pregnancy (adjusted mean change 121.5, P=0.13).
Conclusion: ISR increases markedly in early pregnancy, prior to and independent of the late pregnancy decrement in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation.

Disclosure
C.E. Powe: None. L. Presley: None. J.J. Locascio: None. P. Catalano: None.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD22965); National Center for Research Resources (UL1RR024989); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218); Robert Wood Johnson Foundation; National Center for Advancing Translational Sciences (UL1TR002541)
140-OR: Dermal Adipose Tissue—A Unique Fat Pad Undergoes Dynamic Changes by Reversible Dedifferentiation
Authors: ZHANG ZHUZHEN , SHAO MENGLE , GUPTA RANA K. , SCHERER PHILIPP E. 
Published: June 2019

Dermal adipose tissue is a layer of adipocytes residing under the reticular dermis. Recent data have revealed a difference between the dermal adipose tissue and subcutaneous adipose tissue. Dermal adipocytes show dramatic changes in synchrony with hair cycling. Beyond hair cycling, many additional stimuli can modulate the volume of dermal adipose tissue. However, dermal adipose tissue remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the re-appearing dermal adipocytes after they de-differentiate are still unclear. Here we isolated dermal adipocytes and characterized dermal fat as a fat pad with unique identity. Using pulsed lineage tracing of dermal mature adipocytes, as well as single cell sequencing, we reveal that mature dermal adipocytes can de-differentiate into fibroblast-like cells or even myofibroblast-like cells. Upon various stimuli, the de-differentiated fibroblasts proliferate and re-differentiated into adipocytes. Similar to other skin fibroblasts, the de-differentiated fibroblast-like cells showed two distinct clusters, and totally lose their mature adipocyte characteristics. In addition, manipulation of dermal adipose tissue highlights an important role of adipocytes for hair cycling and wound healing. This study advances our knowledge of dermal adipose tissue and implicates dermal adipocytes as essential components for normal skin morphology and function.

Disclosure
Z. Zhang: None. M. Shao: None. R.K. Gupta: None. P.E. Scherer: None.
1400-P: Adverse Perinatal and Long-Term Outcomes Differ among Physiologic Subtypes of Gestational Glucose Intolerance
Authors: EDELSON PAULA , CORELLI KATIE , JAMES KAITLYN , HIVERT MARIE-FRANCE , THADHANI R. , ECKER JEFFREY L. , POWE CAMILLE E. 
Published: June 2019

Background: Gestational diabetes mellitus (GDM) is associated with adverse perinatal and long-term outcomes; it is unclear if these outcomes are equally distributed among all affected women. We aimed to define physiologic subtypes of gestational glucose intolerance using beta-cell (BC) function and insulin sensitivity (IS) parameters and characterize adverse outcomes associated with each subtype.
Methods: We used homeostasis model assessment to estimate BC function and IS from fasting glucose and insulin levels at 16-20 weeks gestation. We defined BC and IS defects using the 50th percentile in 1369 women with normal subsequent 50g glucose load tests (GLTs, performed at 24-30 weeks gestation). We categorized 158 women whose GLTs were abnormal (1-hour glucose ≥130 mg/dl) according to the predominant physiologic defect. We compared hyperglycemia-associated adverse outcomes across physiologic subtypes. We used logistic regression to adjust for potential confounders.
Results: Among 158 women, 59 (37%) had BC defects, 83 (53%) had IS defects, 10 (6%) had both, 6 (4%) had neither. Women with IS defects (vs. those with BC defects) were more likely develop GDM (13% vs. 2% by Carpenter-Coustan criteria, P=0.03), while women with BC defects were more likely to develop pregnancy-associated hypertension (20% vs. 7%, P=0.02). Women with IS defects (vs. women with BC defects) were more likely to develop postpartum glucose intolerance (prediabetes/type 2 diabetes) (29% vs. 3%, P&lt;0.001) during a mean follow-up of 12 years. Differences persisted after adjustment for BMI, age, and GDM. There were no differences in other pre-specified outcomes (macrosomia, cesarean delivery, neonatal intensive care unit admission) across subtypes.
Conclusion: Distinct underlying physiologic mechanisms leading to gestational glucose intolerance are associated with distinct hyperglycemia-associated adverse outcomes. This may inform risk stratification and allow for targeted management approaches.

Disclosure
P. Edelson: None. K. Corelli: None. K. James: None. M. Hivert: None. R. Thadhani: Consultant; Self; Thermo Fisher Scientific. J.L. Ecker: None. C.E. Powe: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218); Robert Wood Johnson Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094150)
1406-P: Associations between Indices of Glycemic Variability (GV) and Gestational Outcomes among Pregnant Women with Type 1 Diabetes (T1D)
Authors: POLSKY SARIT , PYLE LAURA , GARCETTI RACHEL , JOSHEE PRAKRITI , DEMMITT JAMIE K. , VIGERS TIM B. , SNELL-BERGEON JANET K. 
Published: June 2019

Pregnancies associated with diabetes are at high risk of adverse health outcomes. We examined associations between indices of glycemia and GV, assessed by continuous glucose monitoring, and maternal and fetal outcomes in women with T1D.
Women with T1D were stratified to groups during preconception or the 1st trimester: (1) CGM Alone (n=13): women without Apple devices, or (2) CGM Share (n=15, DexCom, San Diego, CA): women with iPhone and followers with data viewing devices. Association between change in GV indices over time and gestational outcomes were measured with linear mixed models.
Preeclampsia developed in 28.6% (8/28) of women. Preeclampsia was significantly associated with higher estimated A1C, mean sensor glucose, and time spent &gt;140 mg/dL, and with lower time spent &lt;65 mg/dL and 65-140 mg/dL (Table 1). Gestational age at delivery was 36.7 ± 1.7 weeks (mean ± SD). Gestational age at delivery was associated with lower estimated A1C (0.11% decrease A1C per 1 week increased gestational age, p=0.02), mean sensor glucose, and time spent &gt;140 mg/dL, and with higher time in range (Table 2). There were no associations found between GV indices and cesarean delivery, delivery &lt;37 weeks, large-for-gestational age infants, birth weight, and neonatal hypoxemia.
Preeclampsia and gestational age at delivery were associated with worse A1C and CGM metrics, but not with GV indices.

Disclosure
S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children's Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona & Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US. L. Pyle: None. R. Garcetti: None. P. Joshee: None. J.K. Demmitt: None. T.B. Vigers: None. J.K. Snell-Bergeon: None.

Funding
Dexcom, Inc.; National Center for Research Resources/Colorado Clinical and Translational Science Institute (UL1RR025780)
1408-P: Seasonal Variations in Incidence and Neonatal Outcomes of Gestational Diabetes: A Retrospective Cohort Study
Authors: MEEK CLAIRE L. , DEVOY BENJAMIN O. , SIMMONS DAVID , PATIENT CHARLOTTE , MURPHY HELEN R. , AIKEN CATHERINE 
Published: June 2019

Objective: Gestational diabetes (GDM) incidence reportedly demonstrates seasonal variation. We aimed to assess if season also affects maternal-fetal outcomes in GDM.
Methods: 23,735 women who consecutively delivered singleton, live-born, term infants in a tertiary obstetrics center (2004-08; 4.6% GDM) were included. Additive dynamic regression models (age, BMI, parity, ethnicity adjusted) compared GDM incidence and outcomes (GDM diagnosis, birth weight, delivery mode) over annual cycles.
Results: GDM incidence varied by 30% from peak (October births) to nadir (March births; p&lt;0.05). Temperature at time of test (28 weeks) was strongly positively associated with diagnosis (p&lt;0.001). Birth weight in GDM-affected pregnancies showed marked seasonal variation (mean: 58th centile June - Sept; 67th centile Dec-Mar; p&lt;0.05; fig). Emergency Caesarean rates (50% variation, p&lt;0.05), closely temporally correlated with birth weight.
Conclusions: Substantial seasonal variation exists in GDM diagnoses and maternal-fetal outcomes in GDM-affected pregnancies. Birth weight is highest when GDM diagnoses are lowest, implying either over-diagnosis in summer or more challenging glycemic control in winter. Considering seasonal variation gives new opportunities for intensive individualized therapy to improve outcomes.
Figure: Effect of season on birthweight centiles in GDM; p&lt;0.05.

Disclosure
C.L. Meek: None. B.O. Devoy: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. C. Patient: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. C. Aiken: None.

Funding
Diabetes UK (17/0005712 to C.L.M.)