bluuebunny/crossref_metadata_2025_split huggingface dataset:
1679-P: Current State of Type 1 Diabetes in Adults: Data from the Canadian LMC Diabetes Registry
Authors: ARONSON RONNIE , BROWN RUTH E. , ABITBOL ALEXANDER , GOLDENBERG RONALD , AJALA OLUBUKOLA , YALE JEAN FRANCOIS , YARED ZEINA 
Published: June 2019

Population-based data regarding the current state of T1D care remains limited. This cross-sectional study describes adults with T1D in the LMC Diabetes Registry, comprised of the longitudinal health data of &gt;50 Endocrinology practices across 3 Canadian provinces. A cohort of 3386 adults under care ≥6 months were included: age 44.4 ± 15.3 years; age at diagnosis 22.6 ± 14.3 years; 54.8% male (Table). The majority use analogue insulin (98.4% basal and 99.8% bolus insulin use), 36.6% use an insulin pump and 12.8% use a CGM device. Mean A1C at referral was 8.6 ± 1.8%; current mean A1C was lower at 8.1 ± 1.5%. Although 23.5% were at target A1C ≤ 7.0%, a persistent A1C &gt; 9.0% was seen in 21.6%. Mean A1C was highest among young adults. Over half (56%) reported &gt;1 weekly episodes of hypoglycemia; 3.3% reported severe hypoglycemia in the prior year. In CGM users (n=352, mean A1C 7.7 ± 1.3%), mean glucose was 9.4 ± 2.0 mmol/L and mean CV was 38.5 ± 8.3%. Time in range was 54.4 ± 17.8% and time in hypoglycemia was 6.3 ± 6.1%. Common comorbidities included mental health (9.8%), microvascular (retinopathy 14.4%, CKD 8.2%, nephropathy 24.5%, clinically significant neuropathy 6.5%) and macrovascular (5.5%) disorders. Despite care from diabetes specialists, operating with advanced resources, and within a public health system, the majority of Canadian adults with T1D are not reaching glycemic targets and under-use available advanced technologies.

Disclosure
R. Aronson: Research Support; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Senseonics. R.E. Brown: None. A. Abitbol: Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc. Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., JDRF, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Senseonics, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker's Bureau; Self; AstraZeneca, Sanofi. R. Goldenberg: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. O. Ajala: None. J. Yale: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Bayer Canada, Mylan. Speaker's Bureau; Self; Abbott, AstraZeneca, Bayer Canada, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Takeda Canada. Z. Yared: None.

Funding
Sanofi Canada
168-OR: Autophagy Improves Insulin Sensitivity by Regulating Adiponectin Secretion
Authors: KURAMOTO KENTA , HE CONGCONG 
Published: June 2019

Autophagy is an essential lysosomal degradation pathway induced by stress. Although emerging evidence suggests that autophagy abnormality is implicated in metabolic dysfunction, the mechanism by which autophagy regulates insulin sensitivity is obscure. We recently identified a point mutation in the autophagy gene Becn1 (Becn1F121A) that leads to constitutive activation of autophagy, and generated Becn1F121A knockin mice of hyperactive autophagy. In response to high-fat diet feeding, the autophagy-hyperactive Becn1F121A mice show improved insulin sensitivity, and enhanced insulin-Akt signaling in tissues. We found that their metabolic tissues have higher activation of AMPK, which plays a central beneficial role in energy homeostasis. In addition, when added to cell culture media, serum from Becn1F121A mice can also enhance AMPK activation in the cells, suggesting a role of circulating factors in Becn1F121A-induced metabolic benefits. To further identify the autophagy-controlled circulating factor, we did a Luminex array on metabolic hormones in serum of WT and Becn1F121A mice, and detected a higher circulating level of adiponectin in Becn1F121A mice. Moreover, primary adipocytes isolated from Becn1F121A mice also secrete more adiponectin to medium, suggesting that Becn1F121A-induced adiponectin secretion is cell-autonomous. Adiponectin is an adipocyte-derived hormone that has antidiabetic effects via activating AMPK, and its blood level positively correlates with insulin sensitivity. Using biochemical approaches, we identified an interaction between Becn1 and exocyst components, and demonstrated that the Becn1F121A mutant shows higher affinity with the exocyst machinery. These data suggest that autophagy activation may improve insulin sensitivity by promoting exocyst function and adiponectin exocytosis. Our ongoing research will demonstrate for the first time how autophagy promotes adiponectin secretion, as a new mechanism by which autophagy improves metabolism.

Disclosure
K. Kuramoto: None. C. He: None.
1687-P: An Examination of Clinical Outcomes in People with T1D and Obesity
Authors: STEWART EMMA R. , MONIE ALLISON M. , BILLINGS LIANA K. 
Published: June 2019

A lack of knowledge exists concerning how best to treat type 1 diabetes (T1D) and obesity simultaneously. This cross-sectional study examined whether people with T1D and obesity have differences in the prevalence of outcomes, treatment methods, and healthcare utilization. The data were pulled from the electronic medical record for 1546 patients with T1D (≥ 18 years) seen at NorthShore University HealthSystem during 2017. The study population was 53% female; mean age was 46.4 ± 18.0 years. About 32% of patients had a normal weight (BMI 20-24.99) and 28% of patients had obesity (BMI ≥ 30). The patients with obesity were compared to the patients with normal weight (NW).There was a significantly higher prevalence of hypertension (p&lt;0.001) and depression (p=0.038) among patients with obesity compared to patients with NW. No significant difference in the prevalence of other comorbidities (heart failure, myocardial infarction, cancer, dementia, peripheral vascular disease, chronic kidney disease, stroke) were observed. Patients with obesity had a significantly higher rate of retinopathy, neuropathy, and microalbuminuria (p&lt;0.0001, p=0.005, p=0.005, respectively) compared to patients with NW. Adjusted for age, sex, and years of T1D duration, patients with obesity were 57%, 92%, and 60% more likely to have neuropathy, retinopathy, and microalbuminuria, respectively, than NW patients. There were no difference in mean HbA1C or total cholesterol level between the groups. Adjusted for age, sex, and years of T1D duration, the use of an insulin pump was not associated with BMI. Patients with obesity attended more outpatient visits in 2017 than NW patients (p=0.001), but did not differ in ER or inpatient visits. The higher rate of diabetes-related outcomes, hypertension, depression and healthcare utilization among T1D patients with obesity, compared to those of NW provide the impetus for further investigation into how best to treat patients with T1D and obesity to prevent the disparities in outcomes elucidated by this study.

Disclosure
E.R. Stewart: None. A.M. Monie: None. L.K. Billings: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S.
1688-P: Component Causes of HbA1c Trajectories among Adolescents/Young Adults with Type 1 Diabetes
Authors: WISK LAUREN E. 
Published: June 2019

We sought to examine trajectories in glycemic control across the transition from adolescence into early adulthood and identify component causes related to co-occurring psychosocial and behavioral changes. The cohort included 48,137 HbA1c values for 10,174 participants (ages 13-25) with T1D (49% female; 51% pump users) enrolled in the T1D Exchange registry. Multivariate mixed effects models were used to identify HbA1c trajectories; interactions between age and predictors were used to quantify how each predictor moderated trajectory shape. Mean HbA1c for the cohort was high (8.66), with only 14.0% meeting the adult target of &lt;7.0%. Key indicators of self-management, including frequency of daily testing and testing before administering insulin, declined steadily into early adulthood while diabetes distress peaked in early 20s; in adjusted analyses, these strongly influenced the shape of HbA1c trajectories (see Figure) whereby increases in HbA1c were exacerbated with suboptimal self-management/distress. These psychosocial and self-management indicators were more influential than treatment regimen for predicting glycemic control. Late adolescence/early adulthood are periods of distinct vulnerability that warrant additional efforts to improve disease control via affecting self-management and distress.

Disclosure
L.E. Wisk: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK116932-01)
1689-P: Assessments of Alternative C-Peptide (C-P) Endpoints for New-Onset Type 1 Diabetes (T1D) Clinical Trials
Authors: ISMAIL HEBA M. , BUNDY BRIAN N. , ATKINSON MARK A. , MOORE WAYNE V. , HALLER MICHAEL J. , RUSSELL WILLIAM E. , GITELMAN STEPHEN E. , HEROLD KEVAN C. , REDONDO MARIA JOSE , SOSENKO JAY M. 
Published: June 2019

The mean 2-hour MMTT AUC C-P at 12 months of follow-up has been the primary endpoint for all TrialNet clinical trials of individuals newly diagnosed with T1D. However, it is possible that other measures of C-P responsiveness from MMTTs could provide useful efficacy information for such trials. Thus, we assessed other C-P measures as potential endpoints by substituting them in place of the AUC C-P in completed trials that showed effects of interventions (Rituximab, Abatacept, ATG and ATG+GCSF). These measures included the 30-0 min C-P, AUC C-P partitioned for a response during the first and second hours, peak C-P, as well as AUC C-P/AUC glucose. Estimates for the differences between the treatment and placebo arms were expressed in standard deviation units. The Table below shows differences between treatment and placebo arms along with the significance of the AUC C-P and the substituted endpoint measures for the trials. We found that the differences and their statistical significance were similar to the 2-hour AUC C-P. However, the peak C-P tended to show a wider divergence between the treatment and placebo arms for ATG+GCSF. Our findings show that additional measures of C-P responses could serve as clinical trial endpoints. Other measures of the C-P response besides the AUC could be helpful in assessing the effects of interventions and has potential implications for trials previously considered negative.

Disclosure
H.M. Ismail: None. B.N. Bundy: None. M.A. Atkinson: None. W.V. Moore: None. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. W.E. Russell: None. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. K.C. Herold: Consultant; Self; Provention Bio, Roche Pharma. M.J. Redondo: None. J.M. Sosenko: None.

Funding
National Institutes of Health
169-OR: MondoA Mediates Myocyte Lipid Accumulation and Insulin Resistance Driven by Chronic Nutrient Excess
Authors: AHN BYUNGYONG 
Published: June 2019

Obesity-related insulin resistance is strongly associated with accumulation of neutral lipid in extra-adipose tissues. This phenomenon is particularly well-documented in skeletal muscle. The mechanistic underpinnings of this linkage are not fully understood. We hypothesized that fundamental homeostatic mechanisms exist to coordinately control cellular lipid stores and insulin-mediated glucose uptake. Previously, we found that the muscle-enriched transcription factor MondoA inhibits myocyte insulin signaling via induction of TXNIP and increases myocyte neutral lipid stores through an unknown mechanism. Current studies demonstrated that the activity of MondoA (a muscle-enriched relative of ChREBP) is regulated by nutrient (glucose and fructose) availability in human skeletal myocytes. Whole genome RNA-seq and ChIP-seq studies defined an array of MondoA target genes involved in insulin signaling, cellular nutrient storage pathways (triacylglyceride and glycogen synthesis), and hexosamine biosynthesis. In addition, MondoA regulates KLF10 and KLF11, known regulators of glucose homeostasis. Mice with muscle-specific genetic deletion of MondoA (msMondoA-/- mice) exhibited improved glucose tolerance and reduced muscle lipid accumulation in the context of diet-induced obesity (DIO). Insulin-stimulated glucose uptake was increased in muscles isolated from DIO msMondoA-/- mice vs. wild type controls. We conclude that MondoA serves to balance nutrient storage and catabolism by suppressing insulin signaling and shuttling fatty acids into triglyceride stores during conditions of “plenty.” However, with chronic nutrient excess, chronic activation of MondoA drives a vicious cycle of myocyte lipid accumulation and insulin resistance. Accordingly, MondoA signaling is a candidate target for new therapeutic strategies aimed at reducing insulin resistance and cellular lipotoxicity.

Disclosure
B. Ahn: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1690-P: Predicting Onset of Type 1 Diabetes Using a Novel Interaction Model
Authors: LIU BIN , ANAND VIBHA , GHALWASH MOHAMED , NG KENNEY , DUNNE JESSICA L. , VEIJOLA RIITTA , REWERS MARIAN , LUNDGREN MARKUS ,   T1DI STUDY GROUP
Published: June 2019

Progression to type 1 diabetes (T1D) is strongly predicted by multiple risk factors including genetic and non-genetic variables such as islet autoantibodies (AAb). Little is known, however, about the impact of interactions among the known risk factors on T1D risk prediction.
Through consideration of interactions among risk factors, we aimed to evaluate time-to-diagnosis for T1D from seroconversion for AAb using a novel time-to-event model (RankSvx). RankSvx simultaneously predicts subject-level event times and risk scores as measured by Mean Absolute Error (MAE) and Concordance Index (CI), respectively. We control for subject-level characteristics (4 HLA groups, sex, and their interactions with AAb, age at seroconversion and visit-level AAb count) and use LASSO for feature selection. We also explored up to 12 months of AAb dynamics (i.e., appearance or disappearance of AAb in 3-month intervals) post seroconversion using an interaction model and compared it to a non-interaction (baseline model at seroconversion) and a traditional Cox model.
We used a harmonized dataset of the DAISY, DiPiS, and DIPP studies with 1,880 AAb positive subjects of whom 512 (27%) progressed to T1D. First, we found the interaction model was superior to the baseline model without interactions (Wilcoxon Rank test p-value: 0.016). Second, incorporating AAb dynamics further improved T1D onset time prediction. When including post seroconversion AAb dynamics at 12 months, the interaction model performed 15% better than the baseline model (CI: 0.83 vs. 0.68, MAE: 2.5 years). Finally, the top identified interactions included: 1) young age at seroconversion interaction with IA-2A, and 2) HLA Group that includes at least one DR3-DQ2.5 haplotype interaction with ZnT8A or GADA.
Our results are consistent with recent findings in the TEDDY dataset of patterns of AAb appearance and genetic association and age-related T1D incidence. Further investigations on seroconversion and post seroconversion endotypes are necessary.

Disclosure
B. Liu: None. V. Anand: None. M. Ghalwash: None. K. Ng: None. J.L. Dunne: None. R. Veijola: None. M. Rewers: None. M. Lundgren: None.

Funding
JDRF
1695-P: Genetic Determinants of Estimated Glomerular Filtration Rate (eGFR) in Type 1 Diabetes
Authors: MCGURNAGHAN STUART , SPILIOPOULOU ATHINA , COLHOUN HELEN M. , MCKEIGUE PAUL M. 
Published: June 2019

Background and Aims: Diabetic kidney disease (DKD) is known to be heritable but few genetic determinants have been found. We performed a GWAS of eGFR in a large nationally representative cohort of people with type 1 diabetes (T1D): the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO).
Materials and Methods: The study included 5368 unrelated people with T1D. Samples were genotyped using the Illumina Human CoreExome array and imputed using the online service of the Sanger Institute. eGFR was calculated using the CKD-EPI equation. We modelled the most recent eGFR adjusted for age, sex and duration of diabetes. GWAS was performed with SNPTEST, adjusting for and first three principal components. The FUMA and GENOSCORES platforms were used to annotate GWAS findings.
Results: We identified two novel loci with GWAS significance for eGFR at p&lt; 5x 10-8 and three suggestive loci at p&lt;1x10-6. The GRM7 locus (lead SNP rs342036, p=1.2x10-9) has previously been reported as a susceptibility locus for acute kidney injury in a GWAS of 1253 individuals of European ancestry. Multiple suggestive SNPs in this locus are QTL’s for EMILIN-3 protein and IGP63 IgG Glycan. The XRCC4 locus (SNP rs72767159, p=4.2x10-8), involved in DNA repair, has not been reported associated with eGFR. The three suggestive loci were at the RBP7 (rs112409036, p=5.2x10-7), PIP5K1B (rs10117043, p=4.4x10-7) and LINC00871 (rs74891506, p=4.6x10-7) genes. The lead SNP at RBP7 is a methylation QTL for RBP7. PIP5K1B was previously reported as a locus for diabetic nephropathy and the lead SNP is a QTL for the succinylcarnitine metabolite, previously associated with glycaemic control.
Conclusion: We identified two genome wide significant and three suggestive eGFR loci. Further functional analyses will including testing the utility of potential biomarkers in these pathways, such as EMILIN-3, IGP63 and succinylcarnitine, for DKD.

Disclosure
S. McGurnaghan: None. A. Spiliopoulou: None. H.M. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. P.M. McKeigue: Advisory Panel; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Stock/Shareholder; Spouse/Partner; Bayer AG, Roche Pharma.

Funding
Diabetes UK; JDRF
1697-P: Functional Impact of Type 1 Diabetes Risk Variants Identified in African- and European-Ancestry Populations
Authors: ONENGUT SUNA , YANG HANZHI , PICKIN REBECCA R. , RICH STEPHEN S. 
Published: June 2019

Genetic risk is the earliest measurable contributor to diseases such as type 1 diabetes (T1D). Multiple groups have demonstrated that genetic (or polygenic) risk scores can quantify individual disease risks in a clinically significant way for complex diseases such as T1D. To date, genetic studies of T1D have been conducted primarily in European-ancestry populations and have identified over 40 susceptibility regions. Genetic risk estimates for T1D have been predominantly calculated from these findings. At the same time, there is also strong evidence that there are limitations in transferability of risk estimates from European-ancestry populations to African ancestry populations. Thus, establishing a better understanding of the genetic architecture of T1D in different populations is critical for appropriate applications of risk scores and eliminating health disparities. Aiming to close this gap in knowledge, we conducted the largest T1D association study in African-ancestry participants to date. Single nucleotide polymorphisms (SNPs) in the 12q13.2 region were associated with T1D in European- and African-ancestry populations. We used comparative mapping in the 12q13.2 region to fine-map this physically large and gene-rich T1D risk locus coupled with functional studies. Twelve SNPs (of 22 previously identified European credible SNPs) were nominally (P &lt; 10-4) associated with T1D in African-ancestry populations. Using bioinformatics and ENCODE data, we identified four putative candidate causal SNPs. Using functional assays, we confirmed allele-specific protein binding for two of the 12q13.2 SNPs near RPS26 and IKZF4. While biological influence and detailed functional role of each risk variant will need to be characterized in future functional studies, incorporation of SNPs that capture genetic risk in genetically diverse populations provides insights into causality.

Disclosure
S. Onengut: None. H. Yang: None. R.R. Pickin: None. S.S. Rich: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1701-P: Genome-Wide Association Study Identifies Novel Potential Associations with Birth Weight in a Southwestern American Indian Population
Authors: WEDEKIND LAUREN E. , HSUEH WEN-CHI , KOBES SAYUKO , OLAIYA MUIDEEN T. , KNOWLER WILLIAM C. , BAIER LESLIE J. , HANSON ROBERT L. 
Published: June 2019

Epidemiologic studies in many populations have shown that birth weight is associated with risk of type 2 diabetes (T2D) in adulthood. In a Southwestern American Indian population, lower and higher birth weight groups are at higher risk for T2D than those with normal birth weight. We performed a genome-wide association study (GWAS) of birth weight in 3700 Southwestern American Indians (2037 female; 1663 male).
496,190 SNPs (allele frequency&gt;1%) were directly genotyped using an Axiom array designed to capture common variation in this community (Affymetrix; Santa Clara, CA). Birth weight was ascertained from Arizona state and medical records. T2D was determined according to American Diabetes Association criteria at a research exam or during clinical care. Birth weight data were normalized separately by sex and analyzed for genetic associations using a mixed model (SOLAR-Eclipse; Catonsville, MD) accounting for genetic relationships (based on genetic markers among all pairs of individuals) and adjusted for birth year and the 1st 5 genetic principal components.
We identified 41 variants suggestively associated (p&lt;0.0001) with birth weight. The strongest associations are with rs4799141 in PARD6G (β=-0.14 SD per T allele; p=7.5E-6), rs17333221 in MEOX2 (β=-0.15 SD per C allele; p=1.0E-5), rs11704996 in TRIOBP (β=0.15 SD per A allele; p=1.0E-5) and a missense variant in ABCC8, R1420H (β=0.41 SD per H allele; p=1.5E-5).
5 of the 41 variants are also nominally associated with T2D (p&lt;0.05) in 7659 individuals from this population; the most notable was the R1420H variant in ABCC8, which we previously reported as associated with T2D (OR=2.2, p=3.0E-5) and for which activating mutations cause hyperinsulinemic hypoglycemia of infancy. In sum, we identified novel suggestive genetic associations with birth weight, which require confirmation in additional studies, and show that R1420H in ABCC8 is a strong genetic determinant of birth weight in this population.

Disclosure
L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. M.T. Olaiya: None. W.C. Knowler: None. L.J. Baier: None. R.L. Hanson: None.