bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Maternal and Offspring Genetic Risk for Type 2 Diabetes with Offspring Birth Weight among African-Ancestry Populations
Authors: RAHMAN MOHAMMAD L. , SHRESTHA DEEPIKA , WORKALEMAHU TSEGASELASSIE , WU JING , ZHANG CUILIN , TEKOLA-AYELE FASIL 
Published: June 2018

Background: Mother’s genetic risk for type 2 diabetes (T2D) may influence intra-uterine glycemia leading to increased birth weight. However, the U-shaped relation between offspring birthweight and later-life T2D risk suggests that relations of offspring’s T2D genetic susceptibility with birthweight may be U-shaped.
Methods: We investigated the effects of maternal and offspring genetic risk for T2D on birthweight using genotype data from 949 mother-offspring pairs of African ancestry from the Hyperglycemia Adverse Pregnancy Outcome study. We generated a genetic risk score for T2D (dGRS) for mothers and offspring as the weighted sum of 90 T2D risk alleles. Offspring dGRS was separately calculated for birth weight-reducing and -increasing alleles based on the direction of correlation between a T2D-risk allele and birthweight in our data. We used linear regression adjusting for maternal and offspring covariates and the proportion of African ancestry to estimate the change in birthweight by quartiles of maternal and offspring dGRS.
Results: Changes in birthweight across increasing quartiles of mother’s dGRS were 0 (reference), 83.3g (95% CI: 6.7, 160.0), 102g (95% CI: 25.1, 179.5), and 92.9g (95% CI: 12.7, 173.1) (P-trend=0.042). In contrast, changes in birthweight across increasing quartiles of offspring dGRS based on birthweight-reducing alleles were 0, −105.7g (95% CI: −180.9, −30.5), −105.5g (95% CI: −180.4, −30.5), and −143.2g (95% CI: −218.6, −67.8) (P-trend=0.001), whereas those of dGRS based on birthweight-increasing alleles were 0, 15.3g (95% CI: −60.7, 91.3), 113.3g (95% CI: 38.1, 188.6), and 142.4g (95% CI: 66.8, 218.1) (P-trend=0.0002).
Conclusion: Maternal and offspring genetic risk for T2D exhibited a differential association with birth weight. Further characterization of individual alleles in a larger dataset will enhance our understanding of the causal roles of fetal and maternal genetic determinants of T2D on fetal growth.

Disclosure
M.L. Rahman: None. D. Shrestha: None. T. Workalemahu: None. J. Wu: None. C. Zhang: None. F. Tekola-Ayele: None.
The Burden of Uncontrolled Glycemia—A Systematic Literature Review
Authors: FERNANDES GAIL , IFF JOEL , OVCINNIKOVA OLGA , NASSIM MARIA , SUN LUCY , RICHARDS MARGARET S. , RAJPATHAK SWAPNIL 
Published: June 2018

The objective of this systematic literature review (SLR) was to understand the consequences of uncontrolled glycemia in patients with type 2 diabetes mellitus (T2DM) in terms of mortality, macro- or microvascular complications, as well as economic burden in terms of healthcare resource utilization (HCRU) and cost. A predefined search strategy was used in Medline, EMBASE, Cochrane CENTRAL, EconLit and NHS-EED, limited to the last five years, according to PRISMA guidelines. In terms of mortality and clinical data, twenty-two studies met our inclusion criteria. Five studies reported significantly increased risk of mortality for A1C greater than 7.5% (Hazard ratio (HR) ranged from 1.41-13.16). Three studies reported an increased risk of mortality for every 1% increase in A1C above 7% (HR from 1.10-1.40). In one landmark trial (ACCORD), however, comparing intensive (A1C target &lt;6.0%) to standard glycemic control (A1C target 7.0-7.9%), a higher risk of all-cause mortality in the intensive group was reported. Six studies showed that A1C higher than 7% was associated with an increased risk of macrovascular complications (HR / odds ratio (OR) from 1.13-2.26) and three studies reported that every 1% increase in A1C above 7% resulted in an increased risk of different macrovascular complications (HR / OR from 1.05-1.38). Three studies reported higher risk (HR / OR from 1.13-1.40) of microvascular events at A1C higher than 7%. For the economic data, 1 U.S. study reported increased healthcare cost (OR 1.73 (95% CI 1.00-3.01) for T2DM patients with A1C greater than 10%. In another U.S. study, 1% increase in A1C between 7-10.5% was associated with additional diabetes-related pharmacy/medical cost burden of $1586 ($133-$3537) per patient per year. Three non-U.S. studies also reported similar results on the association of A1C and economic burden. Our SLR showed an association between high A1C and increased risk of clinical outcomes, including mortality. Furthermore, poor glycemic control was also associated with increased HCRU and costs.

Disclosure
G. Fernandes: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Janssen Research & Development. Stock/Shareholder; Self; Merck & Co., Inc.. Stock/Shareholder; Spouse/Partner; Janssen Research & Development. J. Iff: None. O. Ovcinnikova: None. M. Nassim: None. L. Sun: None. M.S. Richards: None. S. Rajpathak: Employee; Self; Merck & Co., Inc..
Accumulation of Endogenous Asymmetric Dimethylarginine Contributes to Diabetic Cardiomyopathy via Endoplasmic Reticulum Stress in Diabetic Rats
Authors: XIONG YAN , HE YULIAN , FANG WEI-JIN , LEI YANPING , LIN YUAN , HE ZHI-MIN 
Published: June 2018

Diabetic cardiomyopathy is a major cause of morbidity and mortality among diabetic patients. Endoplasmic reticulum (ER) stress has been involved in diabetic cardiomyopathy. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) is associated with diabetic cardiovascular complications. This study was to determine whether ADMA accumulation contributes to diabetic cardiomyopathy and whether its mechanism is related to ER stress in streptozotocin-induced diabetic rats and cultured rat cardiomyocytes. Cardiac function was measured by M-echocardiography. ER stress was reflected by transcription of glucose-regulated protein78, phosphorylation of eukaryotic initiation factor 2α kinase, splicing of X box-binding protein-1 mRNA and expression of C/EBP homologues protein. Changes of ADMA signal pathway were evaluated by ADMA and nitric oxide contents, NOS and dimethylarginine dimethylaminohydrolase activities, as well as their protein expression. The levels of ADMA in serum and myocardium were significantly elevated in diabetic rats compared to control rats. This elevation was associated with left ventricular diastolic and systolic dysfunction of diabetic rats in comparison with control rats. Furthermore, ADMA accumulation was not only coupled with the disorder of ADMA signal pathway, but also tied to ER stress and oxidative stress in myocardium of diabetic rats. Treatment of diabetic rats with antioxidant N-acetylcysteine could reduce oxidative stress and ER stress, but also ameliorate cardiac dysfunction of diabetic rats. Similar results to diabetic rats were observed in the exogenous NOS inhibitor-treated normal rats and ADMA-incubated cardiomyocytes. These results indicate that endogenous ADMA accumulation plays a pivotal role in the development of diabetic cardiomyopathy, and the underlying mechanism is close related to ER stress and oxidative stress.

Disclosure
Y. Xiong: None. Y. He: None. W. Fang: None. Y. Lei: None. Y. Lin: None. Z. He: None.
Diabetic Ketoacidosis Triggered by Pembrolizumab in a Patient with Bladder Cancer
Authors: SHAMY TANIA AL , AGUASVIVAS MARNIE , SERHAN MUSTAPHA , FOJAS MA.CONCHITINA M. 
Published: June 2018

This is a 71-year-old male with history of Hypertension, well controlled type 2 DM on metformin (HbA1c 6.6%), and high grade urothelial bladder cancer treated with transurethral resection of the bladder. Due to cancer progression, he required neoadjuvant chemotherapy followed by Pembrolizumab in July 2017. He presented with fatigue, polyuria and polydipsia in August 2017. He was diagnosed with DKA and managed in the ICU. Workup revealed HbA1c 9%, high GAD-65 antibody (&gt;250 IU/ML), and low C-peptide (0.26 ng/ml). He was stabilized and discharged on insulin. T cell activity is regulated by programmed death ligand-1(PD-L1)/programmed death-1 (PD-1). Tumor cells select specific immune-checkpoint pathways as a mechanism of immune resistance against T cells and evade the antitumor immune response by overexpressing PD-L1. Pembrolizumab is a humanized monoclonal antibody against PD-1 acting as an immune checkpoint inhibitor (ICI). Pembrolizumab is approved for treating metastatic urothelial carcinoma, cisplatin-ineligible cancer or disease progression after cisplatin therapy. ICIs are associated with multi-system immune related adverse events (irAEs) due to the disinhibition of the host immune homeostasis. Most of the irAEs are reversible with supportive treatment, however life-threatening irAEs can occur including severe skin reaction, type 1 DM, hypophysitis, and rhabdomyolysis. In our patient, we suspected pembrolizumab was related to new onset type 1 DM. type 1 DM and DKA were reported in 6 (0.2%) of 2,799 patients on Pembrolizumab in 3 randomized, open-label, and active-controlled clinical trials. There are 12 reported cases of PD-1/PD-L1-associated type 1 DM. The onset of disease from use varied from 1 week to 12 months, with most patients presenting with type 1 DM with DKA. ICIs are breakthroughs in cancer treatment. Clinicians should be aware of their possible irAEs. The development of autoimmune diabetes is rare, but its complications are life threatening if not attended to immediately.

Disclosure
T. Al Shamy: None. M. Aguasvivas: None. M. Serhan: None. M.M. Fojas: None.
IGFBP-2 Ameliorates Vascular Insulin Resistance and Contributes to Cardiometabolism
Authors: LI ZHUO , LV YOU , GUO WEIYING , WANG GUIXIA 
Published: June 2018

Insulin-like growth factor binding protein-2 (IGFBP-2) has been implicated in the etiology of insulin resistance. And previous studies have pointed that IGFBP-2 overexpression could prevent age-related hypertension. The present study was aimed to document the modulation of dual vascular actions of IGFBP-2 in human umbilical vein endothelial cells (HUVECs). HUVECs at passage 4-6 were cultured with either 20 μM hydrogen peroxide (H2O2) or 2mM glucosamine (GLU) to induce insulin resistance, which declined the expression of IGFBP-2 in HUVECs and resulted in endothelial nitric oxide (NO) and endothelin-1 (ET-1) production were reduced significantly compare to those control cells (p&lt;0.01), the suppression of NO production was more notable. The insulin-induced phosphorylation of Akt at The3and endothelial NO synthase (eNOS) at Ser1177 were also slightly decreased in IGFBP-2 down-regulated HUVECS. Coherently, insulin-induced phosphorylated eNOS and extracellular signal-related kinase 1/2 (ERK1/2) were 3.5 (p&lt;0.01) and 1.5 (p&lt;0.05) folds increased by an overnight IGFBP-2 treatment, respectively. As the production of ET-1 was mediated by ERK1/2 and the secretion of NO was regulated by eNOS, we suspected that IGFBP-2 played an important role on endothelial diastolic and systolic function, may robustly improved vasodilation more than vasoconstriction in insulin resistant HUVECs.

Disclosure
Z. Li: None. Y. Lv: None. W. Guo: None. G. Wang: None.
Development of DQ-MHC Class II Monoclonal Antibodies—A New, Targeted Therapeutic Approach in Type 1 Diabetes
Authors: LOMBARDI ANGELA , ZHU MING , MORAN THOMAS , KRAUS THOMAS A. , HSIEH MICHAEL , STEVENS CHAD , MURPHY DENISE , DONOVAN CAROL B. , ATKURI KONDALA , MESSING DEAN M. , CHAMOUN JEAN , BROWN THOMAS P. , GUNTAS GURKAN , BENNETT DONALD V. , CONCEPCION ERLINDA , JOHNSON KRISTEN , TOMER YARON 
Published: June 2018

Purpose: Type 1 diabetes (T1D) is a disease affecting almost three million Americans; every year 30,000 new cases are diagnosed, 50% of whom are children. There is currently no curative therapy for T1D and the only available treatment is insulin replacement. Substantial recent data demonstrate a strong association between the MHC Class II molecule DQ8 and the development of T1D. Indeed, DQ8 has been shown to present antigenic peptides (such as InsB:9-23 and GAD65) driving activation of CD4+ T cells in T1D patients. The goal of this study was to identify and optimize a monoclonal antibody that binds to DQ8 molecule and blocks the continued activation of DQ8 restricted T cells.
Methods: Hybridoma clones were generated from spleens of BALB/c mice immunized with DQ8 molecule bound with the InsB:9-23 peptide and screened by high throughput flow cytometry using human B-cells expressing DQ8. 28 clones found positive by flow cytometry were functionally tested in a mixed lymphocyte reaction containing a murine T cell line expressing a human TCR specific for the InsB: 9-23 - DQ8 complex. DQ8-103, a murine version of our best candidate antibody (DQ8-27), was tested in transgenic DQ8 mice immunized with GAD65 peptide; Cytokine production from the recall response ex vivo and in vivo was evaluated using a Luminex assay. Immunophenotyping of blood, spleens and draining lymph nodes isolated from immunized DQ8 mice was done by mass cytometry (CyTOF).
Results: We generated a monoclonal antibody against DQ8 (DQ8-27), that was able to bind human DQ8 molecule expressed on human B-cells and on murine splenocytes isolated from transgenic DQ8 mice. The murine version of DQ8-27 (DQ8-103) was able to significantly inhibit T cell activation in DQ8 mice immunized with GAD65 both ex vivo and in vivo, by decreasing the production of pro inflammatory cytokines IL-2 and IFN-γ. Of note, DQ8-103 caused a significant depletion of DQ8+ B-cells in treated mice compared to mice injected with a control antibody.

Disclosure
A. Lombardi: None. M. Zhu: None. T. Moran: None. T.A. Kraus: None. M. Hsieh: None. C. Stevens: None. D. Murphy: None. C.B. Donovan: Employee; Self; Pfizer Inc.. K. Atkuri: None. D.M. Messing: None. J. Chamoun: None. T.P. Brown: None. G. Guntas: None. D.V. Bennett: None. E. Concepcion: None. K. Johnson: None. Y. Tomer: None.
Associations between Executive Dysfunction and Disordered Eating Behavior (DEB) Risk in Teens with Type 1 Diabetes (T1D)
Authors: CECILIA-COSTA RAQUEL , HANSMANN MEREL , HARRINGTON KARA R. , VOLKENING LISA , LAFFEL LORI M. 
Published: June 2018

Background: The adolescent brain remains immature with ongoing development in areas such as executive function (EF). DEBs also commonly emerge during adolescence. We explored associations between EF and risk of DEBs in teens, ages 13-17, with T1D.
Methods: EF was assessed by the Behavior Rating Inventory of Executive Function (BRIEF), both teen self-report and parent proxy-report versions. Scores ≥60, as total (Global Executive Composite [GEC]) score or on 2 indices (Behavioral Regulation [BRI] and Metacognition [MI]) or 8 subscales, indicate EF problems. DEB risk was assessed by the Diabetes Eating Problem Survey Revised (DEPS-R). DEB risk was categorized by DEPS-R scores: low risk &lt;10; moderate risk 10-19; high risk ≥20.
Results: Teens (N=169, 46% female) were aged 15.9±1.3 (M±SD) years and had T1D for 8.4±3.7 years; A1c was 8.5±1.2% and 44% were overweight/obese. Based on teen self-reported DEPS-R score, 59% had low DEB risk, 29% moderate risk, and 12% high risk. Higher DEB risk was significantly associated with EF problems by teen self-report on GEC, BRI, and MI and by parent report on BRI (Figure). EF subscales associated with DEB risk included emotional control, organization, task completion, goal setting, and problem-solving.
Conclusion: In teens with T1D, executive dysfunction was associated with DEB risk, suggesting need for future study of the relationship between EF and DEBs.

Disclosure
R. Cecilia-Costa: None. M. Hansmann: None. K.R. Harrington: None. L. Volkening: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC..
The Metabolic Drivers of Neuropathy in India
Authors: CALLAGHAN BRIAN C. , VISWANATHAN VIJAY , REYNOLDS EVAN L. , FELDMAN EVA L. 
Published: June 2018

Recent studies demonstrate that diabetes, prediabetes, and obesity are the main metabolic components associated with neuropathy. However, none of these studies were performed in India, where different waist circumference cutoffs exist. As part of an ongoing study, we are enrolling new patients from the M.V. Hospital for Diabetes in Chennai, India. Neuropathy was defined as a score of 2.5 or greater on the Michigan Neuropathy Screening Instrument (MNSI) Examination. Secondary neuropathy outcomes included the MNSI questionnaire, monofilament, biothesiometer, and sural device. Metabolic syndrome (MetS) components were defined using the International Diabetes Federation definition with South Asian waist circumference cutoffs. We determined the prevalence of neuropathy stratified by glycemic (ADA definition based on the glucose tolerance test). Multivariable logistic regression models were used to assess the association of metabolic components with neuropathy. To date, 264 patients have been recruited. Neuropathy was present in 8.7% of those with normoglycemia, 10.3% with prediabetes, and 23.7% with diabetes (p=&lt;0.01) (Table). Diabetes (OR=3.87, 95% CI 1.05-14.28) was the only metabolic component associated with neuropathy. The prevalence of neuropathy increases with worsening glycemic status, but larger numbers are needed to determine which specific MetS components, other than diabetes, are the main drivers of neuropathy in India.Neuropathy status stratified by glycemic statusNeuropathy outcomeNormoglycemiaN (%)Pre-diabetesN (%)DiabetesN (%)MNSI exam4 (8.7%)9 (10.3%)31 (23.7%)MNSI questionnaire2 (4.4%)3 (3.5%)26 (20.3%)Monofilament0 (0.0%)3 (3.5%)6 (4.6%)Biothesiometer0 (0.0%)5 (6.1%)28 (22.6%)Sural device5 (17.9%)16 (23.5%)45 (43.3%)

Disclosure
B.C. Callaghan: Research Support; Self; Impeto Medical. Other Relationship; Self; American Academy of Neurology. Consultant; Self; Immune Tolerance Network. V. Viswanathan: None. E.L. Reynolds: None. E.L. Feldman: None.
HBsAg-1018, a Two-Dose Hepatitis B Vaccine, Is Well Tolerated and Effective in Diabetic Patients Aged 60 Years or Older
Authors: HYER RANDALL N. , JANSSEN ROBERT S. 
Published: June 2018

Background: Adult patients with diabetes mellitus (DM) have a greater risk of contracting hepatitis B virus (HBV) than the general population, including those ≥ 60 years of age. When infected, patients with DM have more severe HBV-related morbidity and accelerated progression. The CDC recommends HBV vaccination of all adults with DM who are ≥ 60 years of age at the discretion of the treating physician. Due to persistent challenges, including hyporesponsiveness with current 3-dose vaccines, 87% of individuals with DM who are ≥ 60 years of age remain unvaccinated. HBsAg-1018 (Heplisav-BTM) is a 2-dose HBV vaccine with demonstrated higher protection rates than a 3-dose vaccine, particularly in populations known to be hyporesponsive. In this post-hoc analysis of a phase 3 trial, we assessed the safety and efficacy of HBsAg-1018 in patients with type 2 DM (T2DM) who were ≥ 60 years of age.
Methods: Patients with T2DM and who were 60-70 years old received either 2-dose HBsAg-1018 at 0 and 4 weeks and placebo at 24 weeks or 3-dose HBsAg-Eng (Engerix-B®) at 0, 4, and 24 weeks. Peak (week 24, HBsAg-1018 vs. week 28, HBsAg-Eng) seroprotection rates (SPRs) and safety were assessed by subgroups (sex, body mass index [BMI], and smoking status).
Results: A total of 480 patients (HBsAg-1018, n=327; HBsAg-Eng, n=153) were included in this analysis. Among patients who received all study injections, the peak SPR was significantly higher with HBsAg-1018 at week 24 (88.2% [231/262]) than with HBsAg-Eng at week 28, giving an overall difference of 29.7% (95% CI: 20.5, 39.1; P&lt;.0001). SPRs with HBsAg-1018 were significantly higher compared with HBsAg-Eng regardless of sex, BMI, or smoking status (P ≤ .01). Adverse events, serious adverse events, and deaths were comparable between HBsAg-1018 and HBsAg-Eng.
Conclusion: Two-dose HBsAg-1018 provides better protection against HBV than a 3-dose vaccine (HBsAg-Eng) with a similar safety profile in patients ≥ 60 years of age with T2DM regardless of subgroup.

Disclosure
R.N. Hyer: Employee; Self; Dynavax Technologies. R.S. Janssen: Employee; Self; Dynavax Technologies.
High Level of Gingival Inflammation in Subjects with Type 1 Diabetes Despite Regular Dental Visits and Limited Microvascular Complications
Authors: ROY MARGAUX , GASTALDI GIACOMO , MOMBELI ANDREA , GIANNOPOULOU CATHERINE 
Published: June 2018

The aim of the study was to evaluate small fiber neuropathy and periodontal health conditions on a cohort of patients with type 1 diabetes. The study participants were 18 females and 23 males with a mean age of 37.9 years (age range: 18-83 years). First, a routine medical examination was conducted at the Diabetology Clinics of the Geneva Universtity Hospital. Electrochemical skin conductance (ESC) was measured by Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy. Participants were further examined for presence of periodontal disease by means of Plaque and Gingival indices (PI and GI respectively), probing depth (PD) and bleeding on probing. Self-reported attitudes and behavior regarding dental care was also collected during the visit. The mean duration of affliction with diabetes was 14.6 ±11.9 years, with a mean glycosylated heamoglobin (HbA1c) of 7.96±1.68%. The Sudoscan measurements showed an average ESC value between right and left sides for the hands of 68.2±13.4 microSiemenns (µS) and for the feet an ESC value of 79±6.9 µS. Seven percent of the subjects presented moderate dysfunction (ESC values 60-40 µS) whereas only one subject presented severe dysnfunction (&lt; 40 µS). The periodontal examination revealed that all patients (except from 2) had signs of gingivitis, defined as presence of at least 2 sites with a GI&gt;1. Gingival inflammation and bleeding on probing was present in 66% of the participants in more than 20% of sites independently of the presence of small fiber neuropathy. Periodontitis was observed in 15% of the subjets with a mean of 13 sites with PD&gt;4mm and bleeding on probing. The majority of subjects (70%) reported having regular dental visits at least once per year. In the present cohort of patients with type 1 diabetes the main finding was the occurrence of pronounced gingival inflammation in the majority of subjects independently of small fiber neuropathy and despite regular dental visits.

Disclosure
M. Roy: None. G. Gastaldi: Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk A/S, Medtronic, Dexcom, Inc., Sanofi, Roche Diabetes Care Health and Digital Solutions, Boehringer Ingelheim GmbH. A. Mombeli: None. C. Giannopoulou: None.