bluuebunny/crossref_metadata_2025_split huggingface dataset:
1693-P: Rapamycin Reduces Maternal Diabetes-Induced Neural Tube Defects by Suppressing Premature Senescence
Authors: XU CHENG , YANG PEIXIN 
Published: June 2019

Maternal diabetes significantly increases the risk of structural birth defects. Senescence occurs after neural tube closure. We aimed to determine whether maternal diabetes induces premature senescence in the developing neuroepithelium. Maternal diabetes induced robust senescence associated β-galactosidase (SAβG) activity in the apical side of the developing neuroepithelium at embryonic day 8.5 (E8.5). The major senescence mediator p21 was induced preceding the SAβG signal at the same region. p21 gene deleted embryos of diabetic dams had a significantly lower neural tube defects (NTDs) incidence (3.6%) compared to wild type litter mates (25.9%). The transcriptional factor Forkhead transcription factor 3a (FoxO3a) is activated in diabetic embryopathy, and Foxo3a knockout reduces maternal diabetes-induced NTDs. Our data showed Foxo3a deletion diminished the signals of SAβG, and abrogated diabetes-increased abundance of p21 and DNA damage response proteins. MicroRNAs have been identified as novel inducers of cellular senescence. Two FoxO3a binding sites were found in the promote region of miR-200c. In vitro study confirmed both FoxO3a and high glucose stimulated miR-200 promoter activity. miR-200c null embryos had a lower NTD rate (4.3%) compared with that of WT embryos (29.2%) from diabetic dams. miR-200c repressed the expression of ZEB1 and ZEB2, which are transcription repressors for p21. In addition to the revelation of the gene regulation pathway in maternal diabetes-induced premature senescence, we found intraperitoneal injection of the senescence inhibitor Rapamycin in diabetic dams during E5.5-E9.5 diminished SAβG signal, and reduced the NTD rate from 24.0% to 4.5%) in diabetic pregnancy. Thus, our study revealed a novel FoxO3a-miR-200c-p21-mediated premature senescence pathway, and provided the mechanistic basis for targeting premature senescence in preventing diabetes-induced NTDs.

Disclosure
C. Xu: None. P. Yang: None.

Funding
American Diabetes Association (1-13-BS-220 to P.Y.); National Institutes of Health
1699-P: Identification of HNF1A Target Gene SNPs Associated with the Age of Onset of HNF1A MODY
Authors: LUDWIG-SLOMCZYNSKA AGNIESZKA , SEWERYN MICHAL , KAPUSTA PRZEMYSłAW , SKUPIEN JAN , KIEC-WILK BEATA M. , MACHLOWSKA JULITA , MALECKI MACIEJ , WOLKOW PAWEL P. , KLUPA TOMASZ ,   NEMO COLLABORATORS
Published: June 2019

HNF1A MODY is characterized by impaired insulin secretion but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. Here we focus on molecular targets of the transcription factor HNF1A and variants in these genes to identify variants associated with HNF1A-MODY age of onset. GWAS on age of onset in 837 HNF1AMODY patients was done and data were used for further analysis. Imputation was done on the Michigan Imputation Server. All modeling and statistics was done in R and python. Genetic association and relatedness structure estimation was done in package 'GENESIS.' The list of HNF1A target genes was based on the TRANSFAC database. For this analysis the HNF1A causal variants were binned according to the domain: DNA-binding, trans-acting, and dimerization. For each of the target gene, variants in the intergenic regions (500kb up- and down-stream) were selected for the analysis. Several common variants: rs12510870 in AFP, rs12441817 in CYP1A2, rs10841644 in SLCO1B3, rs12647527 in MTTP, rs12094103 in CRP and rs7525711 in CSRP1 were identified to be robustly associated with age of onset of MODY3. Moreover, the effect size (beta) of these SNPs were found to be dependent on the HNF1A functional variant. rs12441817 was found to be a significant eQTL for multiple genes in the locus across various tissues, rs10841644 was found to affect SLCO1B3 in the basal ganglia, and rs7525711 was found to be associated with the non-coding RNA in the CSRP1 locus (all in the GTEx eQTL analysis).
In conclusion, common variants in HNF1A target genes are associated with age of onset of MODY3 with the strength of association being dependent on the functional variant in HNF1A.

Disclosure
A. Ludwig-Slomczynska: None. M. Seweryn: None. P. Kapusta: None. J. Skupien: None. B.M. Kiec-Wilk: None. J. Machlowska: None. M. Malecki: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Bioton, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Merck & Co., Inc. P.P. Wolkow: None. T. Klupa: Advisory Panel; Self; Abbott, AstraZeneca, Bioton, Lilly Diabetes, Novo Nordisk A/S. Employee; Spouse/Partner; Ascensia Diabetes Care. Other Relationship; Self; Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic MiniMed, Inc.

Funding
European Foundation for the Study of Diabetes
170-LB: Efficacy and Safety of Technology in Type 1 Diabetes: A Systematic Review and Network Meta-analysis
Authors: PEASE ANTHONY J. , LO CLEMENT , EARNEST ARUL , KIRIAKOVA VELISLAVA , LIEW DANNY , ZOUNGAS SOPHIA 
Published: June 2019

Background: Comparisons of new technologies for type 1 diabetes through synthesis of randomized controlled trial (RCT) evidence are critical to guiding device selection. We thus conducted a systematic review and network meta-analysis to compare and rank the efficacy and safety of technologies for the treatment of type 1 diabetes.
Methods: We searched MEDLINE, MEDLINE In-Process and other non-indexed citations, EMBASE, PubMed, All Evidenced Based Medicine Reviews, Web of Science, PsycINFO, CINAHL and PROSPERO. We included RCTs ≥6 weeks duration comparing technologies among non-pregnant adults (≥18 years of age). We assessed risk of bias using a validated tool and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were HbA1c, rates of severe and non-severe hypoglycemia, and quality of life.
Findings: We identified 15,691 publications of which 50 eligible studies compared 12 technologies, with 3,885 participants. Integrated insulin pump and continuous glucose monitoring (CGM) systems resulted in HbA1c levels 0·95% (95% predictive interval 0·02-1·87) and 0·86% (0·10-1·61) lower than multiple daily injections (MDI) with either flash glucose monitoring or capillary glucose testing, respectively. Integrated systems also had the best overall ranking for HbA1c reduction. MDI with flash glucose monitoring was ranked as the best treatment for prevention of non-severe hypoglycemia with event rates significantly lower than any other intervention. The best treatment rankings for severe hypoglycemia and quality of life were MDI with flash glucose monitoring and CGM, respectively. The overall risk of bias rating was moderate-high for all outcomes. The certainty of evidence was very low.
Interpretation: Integrated insulin pump and CGM systems appeared superior for lowering HbA1c while glucose sensing devices appeared superior for preventing hypoglycaemia and improving quality of life.

Disclosure
A.J. Pease: None. C. Lo: None. A. Earnest: None. V. Kiriakova: None. D. Liew: Advisory Panel; Self; AstraZeneca, Bayer AG. Research Support; Self; AbbVie Inc., AstraZeneca, Bristol-Myers Squibb Company, CSL Behring, Pfizer Inc. S. Zoungas: None.
1713-P: ASB4 Regulates Glucose Homeostasis and Body Adiposity during Aging
Authors: VAGENA EIRINI , HE LI , ENGSTRÖM PAULINE , YULYANINGSIH ERNIE , OLSON DAVID , XU ALLISON 
Published: June 2019

Age is a major risk factor for the development of obesity and type 2 diabetes. However, how this process is regulated is poorly understood. Hypothalamic agouti-related peptide (AgRP) or the proopiomelanocortin (POMC), are important regulators of energy balance and glucose homeostasis. Notably, AgRP-deficient mice exhibit normal body weight as young adults but develop a lean phenotype as they age. We showed that AgRP neuronal innervation increases markedly with age onto specific neurons within the hypothalamus, and that this increased innervation exerts tonic inhibition onto these cells. Together these findings suggest that the age-associated increase in AgRP innervation is responsible for the increase in adiposity. However, the downstream components of this circuit are not well defined.
In a microarray screen, we identified ankyrin repeat and SOCS box-containing 4 (ASB4) as a potential downstream target of AgRP. We found that ASB4 protein is specifically expressed in brain areas innervated by AgRP. ASB4 expression in arcuate nucleus of the hypothalamus increases with age and ASB4 neurons are the prime targets of AgRP neuronal innervation that increases with age. As GWAS studies link ASB4 locus with human obesity we generated mice with germline deletion of ASB4. In direct contrast to the age-dependent leanness of AgRP-deficient mice, ASB4 knockout mice develop obesity with age. The loss of ASB4 also resulted in impaired glucose tolerance with age, independently of body adiposity. This weight-independent glucose intolerance phenotype was recapitulated when ASB4 was specifically removed from POMC neurons.
Together, we identified ASB4 as a key regulator of body weight and glucose homeostasis during aging. As ASB4 is known to be stimulated by leptin, our results suggest that the age-dependent increase of AgRP innervation onto ASB4 neurons may progressively inhibit ASB4 neuronal function with age, thereby attenuating the metabolic effects of anorexigenic hormones such as leptin whose levels increase with age.

Disclosure
E. Vagena: None. L. He: None. P. Engström: None. E. Yulyaningsih: None. D. Olson: Research Support; Self; MedImmune, Novo Nordisk A/S. A. Xu: None.

Funding
American Diabetes Association (1-18-PDF-023 to E.V.); Larry L. Hillblom Foundation
1718-P: Type 2 Diabetes Is Associated with Higher Serum Levels of Circulating Adenylyl Cyclase 8: A Novel Biomarker of the Disease
Authors: MADHOUN ASHRAF AL , AL-MULLA FAHD 
Published: June 2019

Aim: A prospective study to evaluate the functional relevance of circulating adenylyl cyclase’s (ADCY), specifically ADCY1, 3 and 8 in patients with type 2 diabetes (T2D) vs. controls.
Method: A total of 188 individuals, 92 T2D and 96 nondiabetic (ND) were recruited. Specific enzyme-linked immunosorbent assay kits were used to quantify the levels of circulating plasma ADCY and its end product cyclic AMP (cAMP) in our study population.
Results: Plasma levels of ADCY1, 3 and 8 were measured. We observed significantly increased measures of plasma levels of ADCY8 in T2D compared to ND (mean ± SEM: 12.645 ± 0.179 vs. 12.056 ± 0.167 ng/mL, p= 0.017). Increased ADCY-8 levels exhibited a positive correlation with the prevailing Hb1Ac levels (r = 0.188, p= 0.012). T2D patients who are obese (12.941 ± 0.207) showed increased levels of ADCY8 relative to non-obese (12.142 ± 0.317, p= 0.039). No significant differences were observed between the plasma concentrations of ADCY -1 or -3 relative to T2D or obesity. The functional relevance of this increased circulating ADCY levels were investigated. Hence, significantly higher levels of plasma cAMP were observed in T2D compared to ND (p&lt; 0.001); irrespective of their obesity status. Higher levels of cAMP positively correlated with fasting plasma glucose levels (r= 0.266, p= 0.026).
Conclusion: Heightened state of ADCY8 and cAMP possibly reflects its potential as a biomarker for disease progression and development of complications in T2D.

Disclosure
A. Al Madhoun: None. F. Al-Mulla: None.

Funding
Kuwait Foundation for the Advancement of Science; Dasman Diabetes Institute
1724-P: Interaction between Genetic Variants and Hemoglobin A1c Level on the Risk of Sight-Threatening Diabetic Retinopathy in Patients with Type 2 Diabetes
Authors: KI NG KELVIN KA , LEE CHI HO , WOO YU CHO , FONG HO YI , WONG RACHEL , LAM KAREN S. , YAN CHEUNG CHLOE YU 
Published: June 2019

Objectives: While hemoglobin A1c (HbA1c) is a well-established risk factor of diabetic retinopathy (DR), it only accounts for limited variation in DR risk. Recent genome-wide association studies (GWAS) have identified some susceptibility single nucleotide polymorphisms (SNPs) for DR. This study aimed to evaluate the possible SNPxHbA1c interaction for the risk of sight-threatening DR (STDR) among patients with type 2 diabetes (T2DM).
Methods: Sixty-nine SNPs that showed top association signals (P&lt;5x10-4; r2&lt;0.9) in previous GWAS of DR were genotyped in 1106 STDR cases and 2069 non-DR controls. The associations between the SNPs and STDR were examined by multiple logistic regression analyses with adjustment for the traditional risk factors. HbA1c level was dichotomized according to a cut-off of 7% as suggested for an optimal glycemic control of diabetes. Interaction with HbA1c was examined by implementing an interaction term of SNP x dichotomized HbA1c in the logistic regression model.
Results: COL5A1 rs59126004 (P=0.016;OR=0.82), IGSF21-KLHDC7A rs3007729 (P=0.022;OR=0.86), LOC728275-LOC728316 rs227455 (P=0.031;OR=0.88), C6orf170 rs17083119 (P=0.035;OR=0.82) and SLC25A32 rs3098241 (P=0.046;OR=0.88) showed significant associations with STDR. Among these, COL5A1 rs59126004 also showed a significant interaction with HbA1c for the risk of STDR (Pinteraction=0.002). Stratified analysis showed that the minor allele of this SNP was associated with a reduced risk of STDR only in the patients with HbA1c &lt;7% (P=1.79x10-4; OR=0.58), but not in patients with HbA1c ≥7%.
Conclusions: We have demonstrated a potential interaction between the COL5A1 rs59126004 and HbA1c for the susceptibility to STDR. Further studies to validate our findings are warranted.

Disclosure
K. Ng: None. C. Lee: None. Y. Woo: None. H. Fong: None. R. Wong: None. K.S. Lam: None. C.Y. Cheung: None.

Funding
Hong Kong Health and Medical Research Fund; Hong Kong Special Administrative Region
173-OR: Effects of Mild Acute Hypertriglyceridemia on Fasting and Post-Load Glucose Homeostasis
Authors: TRICO DOMENICO , MENGOZZI ALESSANDRO , SEGHIERI MARTA , MARI ANDREA , NATALI ANDREA 
Published: June 2019

Background: Mild hypertriglyceridemia is associated with reduced glucose tolerance and increased risk of type 2 diabetes, independent of obesity and insulin sensitivity, in cross-sectional and prospective studies. To what extent these effects are directly produced by triglycerides and which are the major glucose homeostatic mechanisms involved is unclear.
Methods: We examined the effects of acute triglyceride elevation on tracer-derived glucose metabolic fluxes, model-derived β-cell function, insulin sensitivity, and insulin clearance during two 3-h oral glucose tolerance tests with infusion of either normal saline or 20% Intralipid (25 ml/min/m2, without heparin) in 8 healthy lean volunteers.
Results: A 2-h Intralipid infusion increased plasma TG by 2.7-fold (from 52±7 to 192±29 mg/dl; p=0.0003) without affecting plasma FFA, glucose, or insulin levels. After glucose ingestion, the lipid infusion elicited a marked increase in plasma glucose (iAUC +60%, p=0.01) and insulin (iAUC +52%, p=0.02) levels, while FFA were similarly suppressed. The deterioration in glucose tolerance was associated with reduced insulin sensitivity (Matsuda index -22%, p=0.04) and glucose clearance (-16%, p&lt;0.05), and occurred despite a mild inhibition of the endogenous glucose production (-17%, p&lt;0.05). Hyperinsulinemia was produced by reduced insulin clearance (-15%, p=0.04) and enhanced insulin secretion (assessed by C-peptide deconvolution; +29%, p=0.02) due to higher glucose levels and increased β-cell potentiation (+53%; p=0.04).
Conclusions: Mild acute hypertriglyceridemia, independent of FFA, impairs glucose tolerance in healthy subjects by reducing insulin sensitivity and glucose clearance. The magnitude of these effects on glucose tolerance exceeds that of hyperinsulinemia resulting from enhanced β-cell potentiation and reduced insulin clearance.

Disclosure
D. Trico: None. A. Mengozzi: None. M. Seghieri: None. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. A. Natali: None.

Funding
Italian Society of Diabetology; European Foundation for the Study of Diabetes
1738-P: Immune Checkpoint Inhibitor Therapy Precipitates the Rapid Development of Type 1 Diabetes
Authors: AKTURK HALIS K. , KAHRAMANGIL DOGA , SARWAL ASHWIN , MURAD M. HASSAN , MICHELS AARON 
Published: June 2019

Immune checkpoint inhibitors (ICI) that target programmed cell death protein-1 (PD-1) and its ligand (PD-L1) are beneficial cancer immunotherapies but infrequently cause type 1 diabetes (T1D), which can present with life-threatening diabetic ketoacidosis (DKA). We conducted a systematic review and meta-analysis to understand the timing and factors associated with ICI-induced T1D. We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on ICI and identified 71 cases in 55 publications. Comparisons were made using Fisher’s exact and Student t-tests. Mean age at T1D presentation was 61.7±12.2 years, 55% were male, and melanoma (53.5%) was the most frequent cancer. Mean duration to T1D onset was only 83.5±88.5 days with DKA in 76% of cases. Average HbA1c was 7.84±1.0% at presentation. All cases had insulin deficiency and required permanent insulin treatment. The majority of patients developed T1D within just 3-months of initial ICI exposure (Figure). Half of the cases reported T1D associated antibodies at diabetes presentation, and those with antibodies had a more rapid onset (p=0.005) and higher incidence of DKA (p=0.02) compared to patients without antibodies. This study provides a framework for prospective clinical studies to screen patients receiving these state-of-the-art therapies for risk factors associated with T1D onset to prevent life-threatening DKA.

Disclosure
H.K. Akturk: Advisory Panel; Self; Sanofi. Research Support; Self; Eli Lilly and Company, MannKind Corporation, REMD Biotherapeutics. Speaker's Bureau; Self; MannKind Corporation. D. Kahramangil: None. A. sarwal: None. M. Murad: None. A. Michels: Stock/Shareholder; Self; IM Therapeutics.

Funding
National Institutes of Health (DK108868, DK110845, DK032083)
1739-P: Checking the Checkpoints: A Case of Type 1 Diabetes following PD-1 Inhibition in a Patient with HIV
Authors: HUGHES MICHAEL S. , BEDROSE SARA , VASUDEVAN MADHURI , MARCELLI MARCO 
Published: June 2019

Introduction: Type 1 diabetes mellitus (T1DM) is a known immune related adverse event (irAE) following treatment with Programmed Death 1 (PD-1) immune checkpoint inhibitors with reported 0.9% incidence. Little is known about such irAEs in individuals with HIV treated with PD-1 inhibitors.
Case: A 48-year-old man with HIV on HAART, diagnosed with Hodgkin’s lymphoma, initiated PD-1 inhibitor nivolumab. After 6 months, he reported polydipsia and polyuria. Labs revealed glucose 764 mg/dl and A1c 7.1%. Low C-peptide and elevated GAD-65 antibody levels confirmed T1DM, and he started insulin therapy. Nivolumab continued for 12 more months. Despite discontinuation of nivolumab, he remains on insulin therapy.
Discussion: While A1c may reflect average glycemia, it alone cannot distinguish T2DM from T1DM progression. C-peptide and autoantibodies for T1DM must be included when screening patients on PD-1 inhibitors.
Patients with HIV have higher autoantibody titers in active disease states or following HAART initiation, as seen in immune reconstitution. Moreover, in vitro PD-1 inhibition elevates HIV cell proliferation and immune hyperactivity. The challenge in patients with HIV on HAART and PD-1 inhibitors is unraveling whether autoantibody generation resulting in T1DM is potentiated by pre-existing HIV on HAART and/or provoked by immune response to PD-1 inhibition.
Conclusion: Clinicians treating patients with immune checkpoint inhibitors should maintain a high index of suspicion for development of autoimmune disorders. Literature on the use of PD-1 inhibitors in HIV patients is limited and warrants further investigation. To our knowledge, this is the first reported case of T1DM following PD-1 inhibition in a patient with HIV on HAART therapy. Such patients are predisposed to immune reconstitution, and response to PD-1 inhibition may potentiate risk for autoimmune complications. Therefore, higher clinical suspicion for irAEs is merited in patients with HIV on PD-1 inhibitors.

Disclosure
M.S. Hughes: None. S. Bedrose: None. M. Vasudevan: None. M. Marcelli: None.
1747-P: 3D Imaging and Quantification of Pancreatic Immune Cell Infiltration during Emergence and Progression of Spontaneous Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice
Authors: BOLAND BRANDON B. , MANRESA-ARRAUT ALBA , GRÔNLUND RIKKE V. , ROOSTALU URMAS , HECKSHER-SØRENSEN JACOB , VRANG NIELS , JELSING JACOB , FINK LISBETH N. 
Published: June 2019

The non-obese diabetic (NOD) mouse develops diabetes as the result of spontaneous autoimmune insulitis and is widely used as a translational polygenic model of type 1 diabetes. Disease progression in the NOD mouse model is slow, involving a long prodromal phase of pancreatic islet infiltration before autoimmune β-cell destruction and manifestation of diabetic hyperglycemia, making the NOD mouse ideal for probing the effectiveness of potential disease prevention therapies. Improved understanding of the spatial dynamics of immune cell infiltration of the pancreas during the emergence and natural progression of autoimmune diabetes would permit further resolution of drug treatment effects in this model. The present study therefore aimed to image the spontaneous development and progression of autoimmune diabetes dynamically and at 3-dimensional cellular resolution in the NOD mouse. Female NOD mice were terminated before diabetes onset, at 14 and 18 weeks of age, and pancreata were isolated and divided into two alternating samples consisting of either the head and tail. One half was stained for insulin and CD45 using iDISCO whole-mount immunohistochemistry and subsequently scanned using a light sheet microscope. Islet infiltration was quantified using an in-house developed algorithm. The other half of each pancreas was simultaneously evaluated by flow cytometry to discriminate and quantify immune cells of lymphoid and myeloid lineage. Infiltrating CD45-positive leukocytes progressively increased in abundance over time, however, with highly variable distribution in the pancreas. Flow cytometry confirmed extensive leukocyte infiltration and revealed predominant changes in T-cell profiles.
In conclusion, 3D imaging allows for visualization and unbiased quantitative analysis of the unsynchronized spreading of insulitis into different parts of the pancreas in NOD mice.

Disclosure
B.B. Boland: Employee; Self; Gubra, MedImmune. A. Manresa-Arraut: None. R.V. Grônlund: None. U. Roostalu: Employee; Self; Gubra. J. Hecksher-Sørensen: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S.