bluuebunny/crossref_metadata_2025_split huggingface dataset:
351-OR: Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes: Cost-Effectiveness Analyses of the CONCEPTT Randomized Controlled Trial
Authors: MURPHY HELEN R. , FEIG DENICE , PATEL NASHITA 
Published: June 2019

Aims: To evaluate the cost-effectiveness of continuous glucose monitoring (CGM) in type 1 diabetes (T1D) pregnancy.
Methods: Decision analytical models to compare T1D antenatal care with and without use of CGM. Probabilities, maternal health state utilities and healthcare resource utilization were obtained from individual patient-trial data. Costs and neonatal health state utilities were obtained from the literature. Primary outcome of interest was neonatal quality adjusted life years (QALY). The willingness to pay threshold was £30,000/QALY.
Results: Direct costs of CGM use were £2,045. From a neonatal perspective, CGM during was cost saving (- £2,613), and effective (75.43 vs. 73.77 QALYs), with an incremental cost effectiveness ratio (ICER) - 1,570.57/QALY (Figure 1). Sensitivity analyses demonstrated robustness of the model across ranges of variables including varying NICU care for preterm and term neonates, and health state utilities. From a maternal perspective, CGM was associated with additional cost (£330), but remained effective; QALYs 61.33 vs. 61.27 and ICER £5,508.00/QALY. CGM remained efficacious and the favored treatment strategy in the sensitivity analyses performed.
Conclusions: CGM use during T1D pregnancy is cost saving from a neonatal perspective and associated with improved cost effectiveness for both mother and neonate.

Disclosure
H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. N. Patel: None.

Funding
JDRF (17-2011-533); JDRF Canadian Clinical Trial Network (80-2010-585)
354-OR: Physiologic Pathways in Pregnancy Glycemic Regulation Implicated through Genetic Clustering Analysis
Authors: POWE CAMILLE E. , UDLER MIRIAM , ALLARD CATHERINE , KIM JAEGIL , PERRON PATRICE , BOUCHARD LUIGI , FLOREZ JOSE C. , HIVERT MARIE-FRANCE 
Published: June 2019

Background: Genetic determinants of glycemic regulation in pregnancy are poorly understood.
Methods: We studied 35 glycemia-related traits measured during pregnancy and 191 genetic variants identified in prior genome-wide association studies of type 2 diabetes (T2D) or gestational glycemia. Using linear regression, we quantified associations between glucose-raising alleles and traits measured in 582 women at 24-28 weeks gestation. We clustered traits and variants using Bayesian nonnegative matrix factorization (bNMF) to identify physiologic pathways involved in pregnancy glucose metabolism.
Results: In a plurality of bNMF iterations (22/50), 5 clusters emerged, with highly weighted traits and loci suggesting distinct physiologic pathways. Cluster 1: reduced insulin secretory response (lower insulin/c-peptide, greater insulin sensitivity); loci included several known or suspected to affect beta-cell function (ABO, CDKN2B, SLC30A8, CDKN1B). Cluster 2: obesity-related hyperglycemia (higher percent body fat, BMI, fasting/post-load glucose); loci included known obesity/T2D loci (MCR4, FTO) and loci previously tied to beta-cell function that associated with higher glucose and greater adiposity pregnant women (MTNR1B, GLP2R). Cluster 3: insulin resistance (reduced insulin sensitivity, higher fasting insulin/c-peptide, greater insulin secretory response); loci included LYPLAL1 and ANKRD55 (known to harbor insulin resistance variants). Cluster 4 traits suggested reduced adiposity with post-load glucose intolerance. Cluster 5 traits suggested a favorable metabolic profile (lower cholesterol and glucose, higher disposition index and insulin sensitivity).
Conclusion: Genetic variants can be grouped to identify physiologic mechanisms at play in gestational glycemic regulation. Associations between physiologically-informed variant clusters, gestational diabetes, and related perinatal outcomes await testing in well-powered cohorts.

Disclosure
C.E. Powe: None. M. Udler: None. C. Allard: None. J. Kim: None. P. Perron: None. L. Bouchard: None. J.C. Florez: None. M. Hivert: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-15-ACE-26 to M-F.H.); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218, K24DK110550); Robert Wood Johnson Foundation; Fonds de la recherche du Québec en santé
357-OR: Early Pregnancy Trace Element Mixtures and Gestational Glucose Levels Late in the 2nd Trimester
Authors: ZHENG YINNAN , ZHANG CUILIN , WILLIAMS PAIGE L. , WEISSKOPF MARC , PARSONS PATRICK J. , PALMER CHRISTOPHER D. , BUCK LOUIS GERMAINE M. , JAMES-TODD TAMARRA 
Published: June 2019

Background: A number of essential trace elements are involved in glucose metabolism, but the associations between these elements and glucose levels among pregnant women are unclear. Furthermore, little is known about the joint association of these trace elements.
Methods: We used data from 1857 women enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Study, for whom trace element status (Zn, Se, Cu, Mo) was determined using plasma collected during the 1st trimester. Non-fasting glucose levels were measured during the GDM screening test. Three approaches were used to assess the joint effects of these trace elements on glucose levels. First, all four trace elements were included in a multivariable linear model and adaptive lasso was performed for model selection. Second, generalized additive models (GAMs) with model selection were fitted to allow non-linear associations. Lastly, a novel method, Bayesian Kernel Machine Regression (BKMR) was used to model the dose-response relationships of the trace element mixture in a non-parametric fashion.
Results: In the multivariable linear model, we observed significant associations of glucose levels with plasma Cu (2.4 mg/dL increase per 1 SD increase on the log scale; 95% CI: 1.1, 3.7) and plasma Mo (-1.4 mg/dL decrease per 1 SD increase on the log scale; 95% CI: -2.6, -0.1). The GAM showed suggestive evidence of non-linear positive interaction between Zn and Cu in plasma (p-value = 0.052). Similar results were observed using the BKMR approach.
Conclusion: Employing different statistical methods to study the effect of early pregnancy trace element mixtures on glucose levels, we found consistent evidences of hyperglycemic effect of Cu and hypoglycemic effect of Mo, as well as potential synergism between Zn and Cu. Future work is needed to better understand the joint effects of these elements in the context of the increasingly insulin-resistant state of pregnancy.

Disclosure
Y. Zheng: None. C. Zhang: None. P.L. Williams: None. M. Weisskopf: None. P.J. Parsons: None. C.D. Palmer: None. G.M. Buck Louis: None. T. James-Todd: None.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development
360-OR: A Novel Genetic Syndrome of Early-Onset Diabetes, Microcephaly, and Epilepsy Due to Homozygous YIPF5 Mutations
Authors: LYTRIVI MARIA , FRANCO ELISA DE , PATEL KASHYAP A. , ESTEVE MARIANA IGOILLO , COSENTINO CRISTINA , WAKELING MATTHEW N. , HALILOGLU BELMA , YILDIZ MELEK , GODBOLE TUSHAR , HATTERSLEY ANDREW T. , CNOP MIRIAM 
Published: June 2019

Neonatal diabetes is caused by single gene mutations affecting fundamental β-cell function pathways. 20% of cases of neonatal diabetes remain genetically unexplained. Our aim was to explore the genetic basis of a syndrome characterized by neonatal diabetes, microcephaly and epilepsy, present in 2 unrelated patients. The Turkish and Indian patients were born to consanguineous parents. Using whole genome sequencing, we found that they had homozygous likely deleterious variants (missense, p.(Ala181Val) and in-frame deletion p.(Lys106del)) in YIPF5. We then performed replication studies in 112 patients with neonatal diabetes by targeted next generation sequencing. These identified 2 homozygous YIPF5 mutations (p.(Trp218Arg) and p.(Ile98Ser)) in 3 patients (2 siblings) with early-onset diabetes, epilepsy and microcephaly. In functional studies, YIPF5 was expressed in human islets and fetal brain cortex, as evaluated by qPCR and in situ hybridization. Because YIPF5 is involved in endoplasmic reticulum (ER)-to-Golgi trafficking, we examined the impact of YIPF5 loss-of-function on β-cell survival during ER stress. YIPF5 was silenced in the human β-cell line EndoC-βH1 and in human islets. YIPF5 silencing sensitized β cells to apoptosis induced by the ER stressors thapsigargin and brefeldin A. The ER stressors enhanced CHOP, BiP and spliced XBP1 expression in YIPF5-depleted cells, indicating increased ER stress signaling. Expression of the proapoptotic proteins PUMA and DP5 was also enhanced by YIPF5 silencing. CHOP and DP5 knockdown partially protected YIPF5-deficient cells from apoptosis, suggesting that they mediate apoptosis.
In conclusion, homozygous loss-of-function mutations in YIPF5 are a novel cause of early-onset diabetes, microcephaly and epilepsy. This syndrome unveils a critical role of YIPF5 and ER-to-Golgi trafficking in the function and survival of human β-cells and neurons.

Disclosure
M. Lytrivi: None. E. De Franco: Other Relationship; Self; Novo Nordisk Foundation. K.A. Patel: None. M. Igoillo Esteve: None. C. Cosentino: None. M.N. Wakeling: None. B. Haliloglu: None. M. Yildiz: None. T. Godbole: None. A.T. Hattersley: None. M. Cnop: None.

Funding
Fonds Erasme for Medical Research; European Union (667191); Fonds National de la Recherche Scientifique; Brussels-Capital Region Innoviris
363-OR: ChREBP-Beta Controls Both Proliferation and Cell Death of Pancreatic Beta Cells
Authors: KATZ LIORA S. , BRILL GABRIEL , HERMAN MARK A. , SCOTT DONALD 
Published: June 2019

Glucose is a key physiological driver of adaptive beta cell mass expansion, promoting beta cell proliferation both in vitro and in vivo. Carbohydrate response element binding protein β (ChREBPβ) is upregulated in response to glucose and is required for glucose-stimulated beta cell proliferation. To study the role of ChREBPβ in beta cells, we knocked out (KO) or overexpressed (OE) ChREBPβ in mouse pancreatic beta cells using Cre LoxP approaches with either MIP-CreERT (induced by tamoxifen at 3 months of age), or the RIP-Cre model which leads to recombination specifically in β cells, early during embryogenesis (E9). We performed intraperitoneal glucose tolerance tests (IPGTTs) and assessed pancreata for proliferation (Ki67), cell death (TUNEL) and beta cell mass in the 4 mouse models. ChREBPβ MIP-CreERT KO mice displayed impaired glucose tolerance, with an increase of 25.3 ± 7.9% (N=3-4, P&lt;0.05) in the area under the curve (AUC) of IPGTT. Heterozygous or complete Chrebpβ KOs in the RIP-Cre model resulted in an increase in the AUC of IPGTT compared with control littermates (20.1 ± 13.7% and 56 ± 7.1%, respectively; n=2-4). Beta cells from isolated ChREBPβ KO islets had 60.4 ± 17.4% less proliferation compared to control islets in 6 mM glucose, and 22.9 ± 2.4% (P&lt;0.05, N=5) less in 20 mM glucose. Inducible OE of ChREBPβ resulted in 97.7 ± 6% increase in AUC of IPGTT (N=3, p&lt;0.01) and fasting blood glucose levels were increased by 89 ± 13.2% (P&lt;0.01). Similarly, when ChREBPβ was OE early in the embryogenesis of β cells, we observed AUC for GTT was increased by 2.4 ± 0.5 fold compared to non-Cre expressing litter mates (N=5, p&lt;0.05). In both mouse models, the OE of ChREBPβ resulted in β cell death as assessed by TUNEL along with increased in Ki67 staining. Remarkably, the RIP-Cre mice had almost no remaining β cells at 4 months of age and were overtly diabetic. Taken these data together, we propose a molecular regulatory mechanism where ChREBPβ controls both beta cell proliferation and cell death depending on its abundance.

Disclosure
L.S. Katz: None. G. Brill: None. M.A. Herman: None. D. Scott: None.

Funding
National Institutes of Health
372-P: Activation of the Nrf2 Pathway Provides Protection against Hypoglycaemia-Induced Cognitive Impairment in a Rodent Model of Type 1 Diabetes
Authors: MCNEILLY ALISON D. , GALLAGHER JENNIFER , DINKOVA-KOSTOVA ALBENA T. , MCCRIMMON RORY J. 
Published: June 2019

Whether recurrent mild-moderate hypoglycaemia (RH) has pathological effects on the brain in the long-term remains unknown, but is of major concern to people with type 1 diabetes (T1D). We have previously demonstrated in a rodent model of T1D that RH is associated with impaired cognitive function resulting from a reduced ability to cope with enhanced oxidative stress and that this was associated with activation of the Nrf2 pathway. This study sought to investigate whether pre-treatment with sulforaphane (SFN), a potent Nrf2 inducer would ameliorate the impact of RH on cognitive function in the T1D rodent model. A chronic stable model of chronic insulin-treated T1D was achieved using streptozotocin (125mg/kg i.p) and insulin implants (Linbit®). Diabetic (male C57bl6 mice n=8-10/group) mice were randomly allocated to one of 3 groups: (i) T1D, (ii) T1D+RH, (iii) T1D+RH+SFN and subjected to repeated episodes of insulin-induced moderate hypoglycemia (3 episodes/week for 4 weeks; mean glucose 2.9±0.6 mmol/l). SFN (50mg/kg i.p.) or Vehicle (1% DMSO/PBS) was administered 24 hour prior to each hypoglycemic episode. Cognition was assessed by novel object recognition (NOR) and spontaneous alternation tasks. Data are mean±SEM. Pre-treatment with SFN had no impact upon body weight (p=ns) or fasting blood glucose (p=ns). SFN significantly improved cognitive performance in the 24 hour NOR task in T1D+RH animals when compared to vehicle (80% improvement; p&lt;0.01). Furthermore, performance in the spontaneous alternation task was enhanced to Control levels in T1D+RH following treatment with SFN (25% improvement; p&lt;0.01). The beneficial effects of SFN on cognition were not observed in Nrf2 null mice. Treatment with the SFN significantly improves RH-induced cognitive impairments in a rodent model of T1D. Therefore, activation of the Nrf2 antioxidant pathway offers a novel therapeutic target for the treatment of cognitive impairments associated with RH in T1D.

Disclosure
A.D. McNeilly: None. J. Gallagher: None. A.T. Dinkova-Kostova: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust.

Funding
Diabetes UK
373-P: Recurrent Insulin-Induced Hypoglycaemia Leads to Weight Gain in Association with Increased Adiposity and Reduced Basal Metabolic Rate
Authors: MCNEILLY ALISON D. , GALLAGHER JENNIFER , MCCRIMMON RORY J. 
Published: June 2019

Intensification of insulin therapy in type 1 diabetes is associated with significant weight gain. Several mechanisms have been proposed to account for this weight gain including reduced glucosuria and suppression of hepatic gluconeogenesis and glucose production however the precise mechanisms responsible for this remain unclear. This study examined the hypothesis that recurrent hypoglycaemia (RH) might contribute, at least in part, to this phenomenon.
Male C57BL6J mice (n=12/group) received either RH (1mU/g insulin i.p. 3 per week for 12 weeks to achieve glucose of approximately 2.8mmol/l) or Vehicle (saline i.p in equivalent volume). Body composition and energy homeostasis were assessed using EchoMRI and CLAMS systems respectively. Hypothalamic transcript abundance was assessed using Taqman real time PCR. Data are expressed as mean+/-SEM.
RH animals were 43% heavier and had increased fat mass compared to Control animals (8.49+/-0.64 v 16.6+/-1.38% body weight) despite comparable food intake (p=ns). Energy expenditure was significantly lower (53% decrease) in RH animal (0.414+/-0.006 v 0.218+/-0.004 kcal/min; p&lt;0.01) and was associated with a decrease in the respiratory exchange ratio (RER: 0.98+/-0.01 v 0.96+/-0.01;p&lt;0.05). There was no difference in locomotor activity. These changes were associated with suppression of genes involved in thermogenesis, mitochondrial energetics and lipolysis within the brown adipose tissue.
Consistent with our hypothesis, RH leads to increased accumulation of fat stored which is associated with reduced energy expenditure and RER. These results suggest that RH induces a state of hypometabolism that may contribute to weight gain observed with intensification of insulin therapy in type 1 diabetes.

Disclosure
A.D. McNeilly: None. J. Gallagher: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust.

Funding
JDRF; Diabetes UK
378-P: Human Voice Is Modulated by Hypoglycemia and Hyperglycemia in Type 1 Diabetes
Authors: CZUPRYNIAK LESZEK , SIELSKA-BADUREK EWELINA , NIEBISZ AGNIESZKA , SOBOL MARIA , KMIECIK MAGDALENA , JEDRA KATARZYNA , SZYMANSKA-GARBACZ ELEKTRA , NIEMCZYK KAZIMIERZ 
Published: June 2019

Anecdotal evidence suggests that high pitched voice may be a clinical symptom of hypoglycemia. We conducted a pioneer study aiming at assessing voice variables during hypoglycemia and hyperglycemia. We recruited 10 non-smoking individuals with type 1 diabetes (4 women, 6 men; mean [±SD] age 40.2±10.4 years, diabetes duration 21.4±9.9 years, HbA1c 8.0±1.8%) who were using real time continuous glucose monitoring system (rt-CGM, Guardian Connect, Medtronic) for mean 5.2±0.6 days in controlled hospital setting. At regular intervals during normoglycemia and additionally at blood glucose &lt;70 mg/dl or &gt;200 mg/dl each patient was instructed to record with a professional voice recorder (LS-14, Olympus) a standardized sentence and the sound of vowel ‘a’ for 3 seconds. The voice samples (n=177) were analyzed against CGMS data with the DiagnoScope software (DiagNova, Wroclaw, Poland). Number of fundamental PERiods (PER), time of fundamental PERiods (PERTime), fundamental frequency (F0), energy (E), amplitude of fundamental frequency (AF0), indicator of voiced/phonation probability (Voiced), simple voice quality (SimpleQ), relative average perturbation (RAP), shimmer (Shimm), amplitude perturbation quotient (APQ), four formant frequencies (F1-F4), harmonic perturbation quotients (HPQ), residual to harmonic ratio (R2H), unharmonic to harmonic ratios (U2H), subharmonic to harmonic ratio (S2H), noise to harmonics ratio (NHR), 1st to 4th harmonic to all energy ratio (Fx1-Fx4) were analyzed. In women during hypoglycemia E, AF0, Voiced, F1, F4, R2H, Fx3, Fx4, while in hyperglycemia - RAP and F2 were significantly altered when compared to normoglycemia. In men in hypoglycemia the differences were found in PER, PERTime, Voiced, SimpleQ, Shimm, APQ, F2, U2H, S2H, Fx2, NHR, while in hyperglycemia - PERTime, F1, HPQ, U2H, Fx2 (all p&lt;0.05). We report for the first time that hypoglycemia and hyperglycemia modulate human voice. This phenomenon may offer potential for early detection and prevention of hypoglycemia.

Disclosure
L. Czupryniak: None. E. Sielska-Badurek: None. A. Niebisz: None. M. Sobol: None. M. Kmiecik: None. K. Jedra: None. E. Szymanska-Garbacz: None. K. Niemczyk: None.

Funding
Polish Ministry of Science and Higher Education
38-LB: Discovery Analysis of MicroRNAs (miRs) Associated with Microvascular Complications in Adults with Type 1 Diabetes
Authors: JANUSZEWSKI ANDRZEJ S. , SCOTT EMMA S. , JOGLEKAR MUGDHA , CARROLL LUKE , FARR RYAN , WONG WILSON , O’NEAL DAVID N. , KARSCHIMKUS CONNIE , FULCHER GREG , HARDIKAR ANAND , JENKINS ALICIA J. 
Published: June 2019

Objective: Despite therapeutic advances, type 1 diabetes (T1D) is associated with a risk of development of micro- and macrovascular complications. Early treatment of complications is associated with a more favorable prognosis, hence biomarkers to enable early detection and to monitor treatments may be useful.
Methods: Plasma (EDTA) samples were obtained from 30 adult (M/F = 20/10) individuals with T1D, age 42±16 years, T1D duration 24±11 years, HbA1c 7.5±1.2% and BMI 26.5±4.0 kg/m2 (15 with microvascular complications (retinopathy or nephropathy) - CX+, and 15 without complications - CX-) and compared with 15 nondiabetic controls (CON, matched age, gender, smoking and BMI). T1D CX+ and CX- individuals were matched for age, gender, diabetes duration, smoking, BMI, HbA1c and insulin therapy modality (CSII/MDI). In these discovery cohort samples, profiling of 754 miRs was done using a high throughput probe based quantitative PCR on nanofluidics Open Array platform . Results were analyzed using independent T test, Mann-Whitney test and classification trees. Statistical analysis was undertaken using R (ver. 3.5.1) and XLStat (ver. 2018.6).
Results: Of 754 available miRs on the array, 186 miRs were detectable in plasma. Using an unbiased approach expression of 32 miRs differed significantly in CON vs. T1D and 16 miRs were differentially expressed between CX+ and CX- T1D subjects. Using a Random Forest wrapper algorithm 5 miRs were identified with importance for segregating CX+ vs. CX- status: miR-483-5p, miR-328, miR-1274B, miR-7 and miR-30a-5p. In logistic regression those 5 miRs provided a ROC curve with AUC=0.90 for the CX+ vs. CX- discrimination.
Conclusion: In a discovery analysis of well- matched CX+ and CX- selected miRs provided good discrimination between T1D CX status. Validation studies in a larger cohort of cross-sectional and longitudinal samples are in progress.

Disclosure
A.S. Januszewski: None. E.S. Scott: None. M. Joglekar: None. L. Carroll: None. R. Farr: None. W. Wong: None. D.N. O’Neal: None. C. Karschimkus: None. G. Fulcher: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Research & Development, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Research & Development, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. A. Hardikar: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.

Funding
Sydney Medical School Foundation; National Health and Medical Research Council of Australia