bluuebunny/crossref_metadata_2025 huggingface dataset:
1672-P: Identifying Type 1 Diabetes in Electronic Medical Records Data in Ontario: A Validation Study
Authors: WEISMAN ALANNA , YOUNG JACQUELINE , KUMAR MATTHEW , AUSTIN PETER , TU KAREN , JAAKKIMAINEN LIISA , LIPSCOMBE LORRAINE , BOOTH GILLIAN
Published: June 2019

Electronic Medical Record (EMR) data are an efficient method for constructing large type 1 diabetes (T1D) cohorts but are limited by availability of accurate diagnosis codes. We sought to derive an algorithm for identifying T1D using Electronic Medical Records - Primary Care (EMRPC) also known as EMRALD, a database including records from >300,000 primary care patients in Ontario, Canada. A 25% random sample of adults with diabetes and at least 1 year of records in EMRPC prior to September 30, 2015 formed the reference cohort. Charts of potential T1D cases (those on insulin±metformin) were abstracted; all others were classified as non-T1D. Algorithms were derived using variables from free-text searches (diagnosis terms in the Cumulative Patient Profile (CPP)) and standardized fields (medications, age, BMI) using 1)a priori combinations of variables; 2)classification and regression tree analysis (CART). Algorithms were evaluated for sensitivity, specificity, positive and negative predictive values (PPV and NPV) with adjustment for optimism for CART. Of 21,547 eligible patients with diabetes, the reference cohort was 5407: 4968 non-abstracted non-T1D, 240 abstracted non-T1D and 199 T1D. The prevalence of T1D was 3.7%. The optimal algorithm using a priori variable combinations was T1D diagnosis in the CPP + rapid-acting insulin (sensitivity 69.3% (95% CI 62.4-75.7%), specificity 99.8% (99.6-99.9), PPV 92.6% (87.2-96.3), NPV 98.8% (98.5-99.1)). CART partitioned on T1D diagnosis in the CPP, any insulin, and non-metformin oral hypoglycemic medications and improved performance with optimism-adjusted sensitivity of 77% (72.0-83.9), specificity 99.8% (99.8-100.0), PPV 96.8% (94.6-99.6), and NPV 99.1% (98.9-99.4). Simple algorithms using EMR variables yielded good diagnostic performance for identification of T1D and CART further improved performance. Pending additional validation these algorithms can be applied to study large T1D cohorts in EMR databases.

Disclosure

A. Weisman: None. J. Young: None. M. Kumar: None. P. Austin: None. K. Tu: None. L. Jaakkimainen: None. L. Lipscombe: None. G. Booth: None.

Funding

Diabetes Action Canada
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 >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 > 9.0% was seen in 21.6%. Mean A1C was highest among young adults. Over half (56%) reported >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<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<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 <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< 5x 10-8 and three suggestive loci at p<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 < 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>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<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<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.
1707-P: Maternal Smoking Around Birth, Offspring Genetic Susceptibility to Adiposity, and Risk of Type 2 Diabetes
Authors: SUN DIANJIANYI , ZHOU TAO , LI XIANG , HEIANZA YORIKO , QI LU
Published: June 2019

Prenatal exposure to maternal smoking (MS) and genetic predisposition to obesity have been related to an increased risk of developing type 2 diabetes (T2D), individually; however, little is known about whether these risk factors may interact with each other. This study included 394867 European participants in UK Biobank. Three types of adiposity polygenetic score (PGS) were created based on 97, 66, and 12 genetic loci associated with BMI, waist-to-hip ratio adjusted for BMI (WHRadjBMI), and percentage of body fat (PBF). The adjusted odds ratio (OR) of MS for T2D was 1.25 (95% CI: 1.21-1.28), and ORs for T2D were 1.09 (1.08-1.11), 1.07 (1.05-1.08), and 1.02 (1.01-1.04) per one SD increment of BMI-, WHRadjBMI-, and PBF- PGS. The joint associations of MS and a higher adiposity genetic susceptibility for T2D were 1.52 (1.45-1.60), 1.43 (1.36-1.50), and 1.35 (1.28-1.41), respectively. The estimated proportions of the joint association were 45.1% for MS alone, 28.4% for genetic susceptibility to obesity alone, and 26.5% for their additive interaction. Our results indicate that the increased risk of T2D due to the joint association of MS and adiposity genetic predisposition was greater than each factor. Our findings extend our knowledge on the synergistic contribution of prenatal factors and genetic make-up to adiposity on T2D risk, and re-emphasize the importance of smoking cessation around pregnancy in women.

Disclosure

D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. L. Qi: None.

Funding

National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46200); United States-Israel Binational Science Foundation (2011036)
1708-P: Enteroendocrine Lineage Enriched microRNAs Regulate Intestinal Progenitor Cell Dynamics
Authors: SETHUPATHY PRAVEEN
Published: June 2019

The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis and systemic energy balance. Notably, progenitors of EECs exhibit stem cell potential and contribute to intestinal epithelial proliferation and renewal; however, the molecular mechanisms are not well understood. In this study, we first report that miR-7 and miR-375 (previously thought to be specific to pancreatic beta cells) are very highly expressed along the EEC lineage trajectory and are among the most enriched miRNAs in Prox1+ EEC progenitors relative to Lgr5+ intestinal stem cells. Next, by studying intestinal stem/progenitor cell responses to microbiota, high-fat diet, and bariatric surgery, we show that miR-7 and miR-375 expression levels are inversely correlated with intestinal epithelial proliferative status. We then demonstrate by both loss- and gain-of function assays in ex vivo mouse enteroids that both miRNAs exert robust control of intestinal epithelial proliferation and enteroendocrine cell maturation. We also show by single cell RNA-sequencing, intestinal phenotyping, and metabolic phenotyping in a miR-375 knockout mouse model, that miR-375 controls intestinal stem/progenitor cell dynamics, especially with increasing age. Overall, this study demonstrates for the first time that two miRNAs highly enriched in the EEC lineage are critical regulators of intestinal epithelial proliferation and likely mediators of the effects of high-fat diet on the intestinal crypt. Ongoing studies are focused on the role of these two miRNAs in the rescue of intestinal crypt behavior after bariatric surgery.

Disclosure

P. Sethupathy: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-47)
1709-P: Assessing the Role of 211 “Established” Type 2 Diabetes Variants in American Indians
Authors: HANSON ROBERT L. , WEDEKIND LAUREN E. , HSUEH WEN-CHI , KOBES SAYUKO , BAIER LESLIE J. , BOGARDUS CLIFTON , KNOWLER WILLIAM C.
Published: June 2019

Genome-wide association studies (GWAS) have identified many variants associated with type 2 diabetes (T2D), but there is little information on their effects in high risk populations such as American Indians. We analyzed 211 primary variants, associated with T2D (P<5.0×10-8) in published GWAS, in 7659 American Indian participants in a population study (33.5% with T2D)- updating our previous study of 63 variants. Genotypes came from a custom Axiom array that captures common variation in American Indians; imputation was performed using whole genome sequence data from 266 Pima Indians. Variants were tested for association with T2D in a mixed model accounting for relatedness with adjustment for age, sex and the 1st 5 genetic principal components to account for population stratification. Heterogeneity was tested by comparing odds ratios (ORs) in American Indians with published ORs. A weighted polygenic risk score across all 211 variants was analyzed. Nominally significant (P<0.05) and directionally consistent replication was observed for 21 of the 211 variants. Notable associations were with rs2237895 in KCNQ1 (OR=1.29, P=2.5×10-8) and rs4929965 in INS/IGF2 (OR=1.28, P=9.8×10-8). Significant heterogeneity was seen for 23 variants- 21 had weaker effects in American Indians than in published values. A summary test over all variants showed effects were generally weaker in American Indians (P=4.0×10-11). The polygenic risk score was strongly associated with T2D (OR=1.38 per SD, P=2.8×10-22). The risk score was also associated with reduced insulin secretion measured by a 25 g intravenous glucose tolerance test (by 10% per SD, P=0.005, n=300 all with normal glucose tolerance), but not insulin sensitivity measured by a hyperinsulinemic-euglycemic “clamp” (P=0.78, n=557 all nondiabetic). These findings suggest that established T2D risk variants generally also affect T2D risk in American Indians (although effects tend to be weaker) and that they act predominantly through diminished insulin secretion.

Disclosure

R.L. Hanson: None. L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. L.J. Baier: None. C. Bogardus: None. W.C. Knowler: None.
171-LB: A Pilot Study to Evaluate the Utility of an Interconnected Diabetes Management Solution in People with T2D
Authors: KLAFF LESLIE J. , MAIER THOMAS , RICHARDSON JAMES M. , PARDO SCOTT
Published: June 2019

Use of remote monitoring/smartphones can lower HbA1c in T2D. This 12-week (W) single-arm pilot evaluated the utility of an investigational Interconnected Diabetes Management Solution (IDMS) using remote behavioral coaching from a certified diabetes educator (guide) and a mobile application (app). The app and call(s) allowed user (service member)-guide communication and monitoring of guide-directed tasks (short, time-limited behavioral interventions to improve testing, food choice, activity, stress and sleep). Members (adults: confirmed T2D; HbA1c 7-11%) provided quantitative and qualitative data. Members used a wireless enabled Contour® Next ONE blood glucose smart meter linked to the app on their mobile device. ∆HbA1c (0-12W) was evaluated. Baseline characteristics, n=58 (% or mean): male, 62%; age, 62 years; Caucasian, 88%; hypertension, 50%; BMI ≥30 kg/m2, 60%; hyperlipidemia, 48%; neuropathy, 28%; retinopathy, 12%; CVD, 10%; T2D for >10 years, 71%. Mean %-HbA1c (±SEM) significantly decreased from 8.44 (0.08) to 8.01 (0.08) at W12: -0.43%, p<0.0007 (Figure). A significant decrease in HbA1c was present in individuals with no change to diabetes medication(s). The investigator deemed all adverse events (n=59) unrelated to the IDMS. Conclusion: mean HbA1c significantly decreased independent of changes to medication(s), suggesting improved self-care and glycemic control. Figure.

Disclosure

L.J. Klaff: Research Support; Self; Abbott, Ascensia Diabetes Care, Cnoga Medical, Gan & Lee Pharmaceuticals, Lilly Diabetes, Medtronic MiniMed, Inc., Novo Nordisk Inc., REMD Biotherapeutics, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. T. Maier: Employee; Self; Ascensia Diabetes Care. J.M. Richardson: Employee; Self; Ascensia Diabetes Care. Employee; Spouse/Partner; Ascensia Diabetes Care. S. Pardo: Employee; Self; Ascensia Diabetes Care.
171-OR: Metformin Prevents Microvascular Insulin Resistance and Preserves Endothelial Function in High-Fat Diet-Fed Rats
Authors: LIU JIA , CHAI WEIDONG , GONG LIYING , AYLOR KEVIN W. , LIU ZHENQI
Published: June 2019

Endothelial dysfunction and vascular insulin resistance coexist and both contribute to the development of type 2 diabetes mellitus (T2DM) and increased cardiovascular risks. Insulin relaxes precapillary arterioles to increase insulin delivery to and action in muscle via recruiting muscle microvasculature and this action is impaired in the insulin resistant states. Metformin is the first line therapy for T2DM and has been shown to improve endothelial function beyond its hypoglycemic effects. Here we aim to examine whether metformin could restore vascular insulin responses in the setting of insulin resistance induced by high fat diet (HFD) feeding via the modulation of endothelial function. Adult, male Sprague-Dawley rats were fed on HFD with or without metformin treatment for 2 weeks. A chow fed group served as control. After dietary intervention, rats were fasted overnight and received a euglycemic-hyperinsulinemic clamp for 120 min. Insulin-mediated muscle microvascular recruitment was assessed before and during insulin infusion using contrast-enhanced ultrasound. Distal saphenous artery was isolated and used for determination of endothelial function and vascular insulin responses. Compared with controls, HFD feeding abolished insulin-induced muscle microvascular recruitment in muscle, decreased insulin-mediated whole body glucose disposal and blunted the vasodilatory response to insulin in small resistance vessel. Metformin treatment significantly enhanced insulin’s microvascular action, effectively rescued small arteriole endothelial function, but did not improve insulin-stimulated whole body glucose disposal in HFD rats. We conclude that metformin could reverse microvascular insulin resistance and attenuate endothelial dysfunction induced by HFD feeding. There findings may provide a novel mechanistic insight into metformin’s cardiovascular protective effect in patients with diabetes.

Disclosure

J. Liu: None. W. Chai: None. L. Gong: None. K.W. Aylor: None. Z. Liu: None.

Funding

American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)
1711-P: Pancreas Single-Cell Patch-Seq Links Physiologic Dysfunction in Diabetes to Transcriptomic Phenotypes
Authors: SOLER JOAN CAMUNAS , DAI XIAOQING , HANG YAN , KIM SEUNG , MACDONALD PATRICK
Published: June 2019

Pancreatic islet-cells regulate glucose levels in the body through insulin and glucagon secretion; dysfunction of these cells leads to severe disease such as diabetes. Several single-cell transcriptome studies have shown heterogeneous gene expression in major islet cell-types such as beta and alpha cells. However, it has remained an open challenge to reconcile the heterogeneity in transcriptomic signatures with physiological observations of functional heterogeneity. Here we combined electrophysiological profiling and single-cell RNA sequencing of the same cells (pancreas patch-seq) to link transcriptomic phenotypes of islet cells to their physiologic properties. We collected 1,369 pancreas patch-seq cells from fresh and cryopreserved tissue and assessed function-gene expression networks in nondiabetic, type 1 diabetic (T1D) and type 2 diabetic (T2D) humans. We discovered that ‘hub’ genes and pathways drive functional heterogeneity in nondiabetic beta-cells and show that specific transcriptional programs correlate with physiologic dysfunction early in T2D. We have also found evidence that alpha-cell transcriptional plasticity acts as a driver of dysfunction in T1D.

Disclosure

J. Camunas Soler: None. X. Dai: None. Y. Hang: None. S. Kim: None. P. MacDonald: None.

Funding

Chan Zuckerberg Biohub; California Institute for Regenerative Medicine; National Institutes of Health
1716-P: MODY5 and Serous Ovarian Carcinoma in 17q12 Recurrent Deletion Syndrome
Authors: HOLLAR LAURA , SALAM MAAMOUN , THAKER PREMAL H. , MCGILL JANET B.
Published: June 2019

Background: Maturity onset diabetes of the young type 5 (MODY5) is due to a mutation in the hepatocyte nuclear factor 1b (HNF1b) gene on chromosome 17q12. HNF1b mutations have been found in clear cell ovarian carcinomas (CCOC) while non-CCOC express this mutation rarely. 17q12 recurrent deletion syndrome presents with urogenital anomalies, MODY5, neurodevelopmental and psychiatric disorders. We report a patient with 17q12 recurrent deletion syndrome with MODY5, uterine abnormalities and low grade serous ovarian cancer.

Clinical Case: The female proband was diagnosed with diabetes at age 12. GAD65, islet cell and insulin auto-antibodies were negative, C-peptide was 2.7 ng/mL. Childhood history included strabismus, depression and chronic transaminitis with unremarkable liver biopsy. Mother’s medical history was notable for single kidney, partially-septated uterus, and diabetes. At age 25, the patient presented with abdominal pain. CT showed pancreatic atrophy, ascites, omental and peritoneal nodularity and calcifications. Tumor markers were normal except an elevated CA-125 of 240 U/mL. Short stature was noted, height 147 cm, BMI 27 kg/m2. Laparoscopy revealed bicornuate uterus, 2 cervices and vaginal septum. She underwent TAH-BSO, lymph node dissection and omentectomy for a stage IIIC low grade serous ovarian carcinoma. Chromosomal microarray analysis of the tumor revealed a pathogenic ∼1.8 Mb loss of 17q12, denoted arr[hg19] 17q12(34477479_36283807)x1.

Conclusion: While 17q12 has been described as a susceptibility locus in some ovarian cancers, ovarian cancer predisposition is not a reported feature of MODY5 or 17q12 recurrent deletion syndrome. The disease association reported here suggests that women with MODY5 should have periodic evaluation for ovarian cancer in addition to screening for gut and urogenital tract abnormalities. Patients with diabetes plus urogenital tract abnormalities or 17q12 deletion in an ovarian tumor should have genetic evaluation for MODY5.

Disclosure

L. Hollar: None. M. Salam: None. P.H. Thaker: Advisory Panel; Self; Clovis. Consultant; Self; AbbVie Inc., Celsion, Tesaro, UpToDate. Research Support; Self; Celsion, Merck & Co., Inc. Speaker’s Bureau; Self; Merck & Co., Inc., Tesaro. J.B. McGill: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk Inc., Sanofi US. Research Support; Self; Dexcom, Inc., Medtronic, Novartis AG, Sanofi US. Speaker's Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation.
173-LB: Using a Diabetes Kidney Disease (DKD) Registry to Treat to Multiple Targets (TMT)—A JADE Technology-Based RCT
Authors: CHAN JULIANA C.N. , NGUYEN KHUE THY , TAN ALEXANDER , CHIA YOOK C. , HWU CHII-MIN , HONG EUN-GYOUNG , THEWJITCHAROEN YOTSAPON , DU JIAN , YOO SOON JIB , MIRASOL ROBERTO C. , LAU ERIC S. , LAU VANESSA , FU AMY W.C. , MOHAMED MAFAUZY , YOON KUN-HO , TSANG CHIU CHI , LUK ANDREA
Published: June 2019

DKD causes co-morbidities made preventable by attaining multiple targets. Patient empowerment, regular feedback and team-based care assisted by JADE Technology with risk stratification and decision support may improve targets attainment and clinical outcomes. In 2014-2018, 2435 patients1 with DKD2 (age:67.6±9.9 years, DM duration:16.5±9.7 years; BMI:26.9±4.7 kg/m2; A1c:7.9±1.6%; SBP:139±18 mmHg; LDL-C:2.35±1.05 mmol/L; TG:1.92±1.29 mmol/L; RASi:70.0%; statin:74.8%; CVD:32.0%, cancer:5.0%, heart failure:3.9%, ≥3 targets3:33.6%), were randomized to usual care (UC=809), empowered care (EC=819) and team-based empowered care (TEC=807) for 1 year with endpoints defined at year 1 and when study ends. After structured assessment, EC and TEC received JADE report, with EC receiving 3-monthly phone calls by nurses and TEC, additional 3-monthly review by a doctor-nurse team with JADE follow-up reports. Amongst 1837 returnees at 1 year, TEC had the lowest HbA1c and LDL-C and highest proportion with ≥3 targets (TMT)4. Non-returnees had worse risk profiles and were less likely to have familial DM and received prior DM education. At study end (2019)5, TMT group (27/408) had fewer CV-renal-cancer endpoints than non-TMT group (66/676) with RR of 0.678 (95% CI: 0.668-0.687). Empowerment, information support and continuing team-based care improve risk factor control and clinical outcomes in DKD.

Disclosure

J.C.N. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp & Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare. K.T. Nguyen: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novo Nordisk A/S, Sanofi-Aventis. A. Tan: None. Y.C. Chia: None. C. Hwu: None. E. Hong: None. Y. Thewjitcharoen: None. J. Du: None. S. Yoo: None. R.C. Mirasol: None. E.S. Lau: None. V. Lau: None. A.W.C. Fu: None. M. Mohamed: None. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. C. Tsang: None. A. Luk: None.

Funding

Asia Diabetes Foundation
1731-P: The Involvement of Glutaminolysis in ß-Cell Differentiation and Its Clinical Application for Type 1 Diabetes
Authors: HAJIME MAIKO , IWATA SHIGERU , ZHANG MINGZENG , NAKAYAMADA SHINGO , OKADA YOSUKE , TANAKA YOSHIYA
Published: June 2019

Objective: B cells play a crucial role in type 1 diabetes (1DM). Recently, “Immunometabolism” attract much attention. In this study, we examined the role of mitochondrial function and glutaminolysis in B cell differentiation and its relevance to 1DM.

Methods: Peripheral blood mononuclear cells were obtained from healthy controls (HCs) and 1DM patients and assessed by FACS. In addition, CD19+ cells were isolated from HCs and change of mitochondrial function and glutaminolysis were assessed in the absence of glucose or glutamine, by metformin in vitro.

Results: Initially, mitochondrial function in B cells from 1DM patients was assessed using DiOc6 as a marker of depolarization-activated mitochondrial membrane. CD24-DiOc6+ cells in IgD-CD27- memory B cell from 1DM patients were significantly higher than those of HCs. Next, we assessed the role of mitochondrial function and glutaminolysis in human B cell differentiation in vitro. Stimulation with CpG (TLR9 ligand) and IFN-α, 1) increased the area of cytoplasm including many expanded mitochondrial cristae with slightly wider and loosely organized intermembrane space in electric microscopy, accompanied with ROS production and DiOc6 up-regulation, 2) induced CD27hiCD38hi plasmablasts differentiation and immunoglobulin production. Interestingly, ROS production and DiOc6 expression were significantly decreased in the absence of glutamine, leading to inhibition of plasmablasts differentiation and immunoglobulin production. This tendency was not shown in the absence of glucose. Metformin, which is known as AMPK activator, abrogated glutamine uptake, resulting in suppression of ROS production, DiOc6 expression, plasmablast differentiation and immunoglobulin production.

Conclusion: These results suggest that mitochondrial activation via glutaminolysis may play an important role in the differentiation from IgD-CD27- double negative B cells to plasmablasts and production of immunoglobulins in 1DM patients.

Disclosure

M. Hajime: None. S. Iwata: None. M. Zhang: None. S. Nakayamada: None. Y. Okada: None. Y. Tanaka: None.
1736-P: Significance of Anti-insulin Immune Responses in Autoimmune Diabetes with HLA DR9
Authors: SHIMADA AKIRA , SATOMURA ATSUSHI , HAISA AKIFUMI , OIKAWA YOICHI
Published: June 2019

Previously we reported that CXCL10 in type 1 diabetes (T1D) is higher than controls, and the level reflects islet associated antigen specific T cell responses and disease activity in T1D (Diabetes Care, 2001). However, little is known regarding the relationship between CXCL10 level and autoantibody levels in T1D. Therefore, we investigated relationship between the marker of cellular immunity including CXCL10 levels and islet associated autoantibody levels in T1D. We obtained informed consent and blood samples from 101 T1D patients, and examined HLA (DRB1*04:05, *09:01; susceptible HLA types in Japanese), serum CXCL10, insulin peptide (B9-23, 10-24, 11-25, 12-26) and PPD reactive T cell responses by using ELISPOT (IFNg), GAD, IA-2, ZnT8 Abs and insulin antibody. Because it has been reported that BCG administration might affect the autoimmune responses in T1D, we assessed the PPD responses in these patients as well. Among them, we focused to GAD Ab positive T1D including acute onset (n=28, 13 male and 15 female, mean age 43.1 years, disease duration 5.9 years), and slowly progressive type (n=17, 9 male and 8 female, mean age 56.9 years, disease duration 9.1 years); i.e., autoimmune diabetes subjects. We found significant positive correlation between serum CXCL10 and insulin antibody levels in the autoimmune diabetes with DRB1*09:01 (p<0.05), but it was not the case in those with DRB1*04:05. Interestingly, there was significant positive correlation between insulin peptide reactive T cells and PPD responses in the autoimmune diabetes with DRB1 09:01 (p<0.05), but it was not the case in those with DRB1 04:05. The observation was still true when we focused to acute onset subjects. These results suggest that insulin antibody levels seem to reflect higher disease activity in the autoimmune diabetes with DR9, and modulation of PPD responses may affect insulin peptide T cell responses in those patients.

Disclosure

A. Shimada: Advisory Panel; Self; Terumo Medical Corporation. Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. A. Satomura: None. A. Haisa: None. Y. Oikawa: None.