bluuebunny/crossref_metadata_2025_split huggingface dataset:
253-LB: A Novel Membrane Binding Domain in Conjunction with Golga5 Recruits the Secretory Granule Biogenesis Factor HID-1 to the Golgi
Authors: ASENSIO CEDRIC S. 
Published: June 2020

Secretory granules (SGs) mediate the regulated release of neuropeptides and peptide hormones. HID-1 is a TGN localized peripheral membrane protein contributing to SG formation. Mice lacking HID-1 specifically in pancreatic β-cells are glucose intolerant and display impaired insulin secretion. However, there is no information about the structure or domain architecture of HID-1, and thus it remains unknown how HID-1 binds to the TGN and performs its function. We report that the N-terminus of HID-1 mediates membrane binding through a myristoyl group with a polybasic amino acid patch but lacks specificity for the TGN. Delineation of the minimal domain responsible for HID-1 targeting to the TGN reveals an interaction with the Golgi-localized protein Golga5. Finally, we identify the C-terminus as a novel membrane binding region and the functional domain of HID-1. This isolated domain, when tethered to the TGN, is also capable of rescuing the secretion and sorting defects observed in HID-1 KO cells. Finally, a point mutation within that domain, identified in patients with endocrine and neurological deficits, is not functional. We propose that HID-1 N-terminal and C-terminal domains, in cooperation with Golga5, ensure specific binding to Golgi membranes and functionality of HID-1.

Disclosure
C.S. Asensio: None.

Funding
American Diabetes Association (1-17-JDF-064); National Institutes of Health (GM124035, GM116096)
255-LB: Impaired Gsa/cAMP Signaling Exclusive to Pancreatic ß-Cells Exhibits a Unique Urinary Metabolome via Nontargeted Metabolomics in a Murine Model of Diabetes In Vivo
Authors: ILAIWY AMRO , CAPOZZI MEGAN , BROWN JENNIFER L. , D’ALESSIO DAVID , CAMPBELL JONATHAN 
Published: June 2020

Background: β-cell dysfunction is a hallmark feature of diabetes mellitus. G protein a-subunit (Gsa) mediates receptor-stimulated intracellular cAMP production In β cells in order to increase glucose-stimulated insulin secretion, cell proliferation and survival. Growing interest in urinary metabolome has emerged as many drugs aim to improve outcomes by targeting kidney function. Given clinical significance of the Gsa pathway, we aimed to study changes of urinary metabolome as a result of Gsa deficiency.
Methods: Mice with Gsα deficiency limited to β cells (Gsa βcell-/-) were generated by mating Gsα-floxed mice with MIPcreERT mice in order to directly examine Gsα/cAMP signaling role in β cells, in a similar method to Xie et.al. Urine was collected from (Gsa βcell-/-) mice and controls and stored at -80C until processed for non-targeted metabolomics using GCMS.
Results: In a small cohort, 17 metabolites were significantly altered between the two groups (P&lt;0.05). While pathway analysis somewhat echoed findings described in other models of diabetes (urea cycle, Malate-Aspartate shuttle, and amino acid metabolism), 4 metabolites were completely undetectable in (Gsa βcell-/-) urine including 3-Oxoglutaric acid and Methylglutarate. In addition, some changed in a different direction to what was previously described in other models of diabetes (e.g: Gsa βcell-/- mice exhibited decreased urinary adipic acid). Enrichment analysis of disease associated metabolite sets of the urine mimicked changes seen in enzymatic defects of 3-Hydroxy-3-Methylglutaryl-Coa Lyase, Kynureninase Deficiency, 2-Ketoglutarate Dehydrogenase and Wolcott-Rallison Syndrome (P&lt;0.05).
Conclusion: Gsa pathway deficiency in β cells produced a model of diabetes with unique metabolome. Studying changes of urine metabolome after treatment with antiglycemics in the future might highlight the drugs renal impact in the setting of Gsa deficiency.

Disclosure
A. Ilaiwy: None. M. Capozzi: None. J.L. Brown: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.
255-OR: ADA Presidents’ Select Abstract: Glucagon Receptor Antagonism Stimulates Beta-Cell Proliferation in Mouse and Human Islets
Authors: COATE KATIE C. , SPEARS ERICK , DAI CHUNHUA , WISNIEWSKI SCOTT , POFFENBERGER GREG , SHULTZ LEONARD D. , GREINER DALE L. , DRUCKER DANIEL J. , YAN HAI , SLOOP KYLE , POWERS ALVIN C. , DEAN DANIELLE 
Published: June 2020

Interrupting glucagon signaling (IGS) elicits robust alpha cell proliferation in an amino acid-dependent manner in mouse and human pancreatic islets. To determine whether IGS triggers beta cell proliferation in mouse and human islets in vivo, we quantified the percentage of Ki67-positive beta cells in adult mouse and human islets after IGS. Wild type (WT) mouse islets transplanted into liver-specific glucagon receptor (GCGR) knockout (LKO) mice exhibited a 4.1-fold increase in beta cell proliferation (WT to LKO: 0.98±0.34%, WT to WT: 0.24±0.19%, P=0.008, n=8). Likewise, treatment of C57BL6 mice with an anti-GCGR monoclonal antibody (GCGR-Ab) elicited a 3.6-fold increase in beta cell proliferation (GCGR-Ab: 1.09±0.21%, control (CTR): 0.30±0.14%, P=0.004, n=10). Given that the cationic amino acid transporter, Slc7a2, is one of the most highly expressed amino acid transporters in pancreatic islets and required for IGS-induced alpha cell proliferation, we assessed GCGR-Ab-induced beta cell proliferation in adult mice with inactivation of Slc7a2. There was a 3.2-fold increase in beta cell proliferation in WT mice treated with GCGR-Ab (GCGR-Ab: 1.45±0.46%, CTR: 0.46±0.15%, P=0.001, n=10). Notably, this effect was absent in Slc7a2 knockout mice (GCGR-Ab: 0.35±0.35%, CTR: 0.41±0.28%, n=10), suggesting that GCGR antagonism induces beta cell proliferation in an amino acid-dependent manner in mice. Furthermore, transplanted human islets from normal donors (ages 10-55, n=8) into immunodeficient mice exhibited a 2.8-fold increase in beta cell proliferation (GCGR-Ab: 0.61±0.60%, CTR: 0.22±0.21%, P=0.05, n=8) following GCGR-Ab treatment. These data indicate that IGS stimulates beta cell proliferation in mouse and human islets and that in mouse islets, this is Slc7a2-dependent.

Disclosure
K.C. Coate: None. E. Spears: None. C. Dai: None. S. Wisniewski: None. G. Poffenberger: None. L.D. Shultz: None. D.L. Greiner: None. D.J. Drucker: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics. Research Support; Self; Novo Nordisk Inc. H. Yan: Stock/Shareholder; Self; REMD Biotherapeutics Inc. K. Sloop: None. A.C. Powers: None. D. Dean: None.

Funding
National Institutes of Health (DK117147)
258-OR: DNA Methylation Regulates the Identity of Pancreatic Beta Cells
Authors: PARVEEN NAZIA , WANG JEAN K. , DHAWAN SANGEETA 
Published: June 2020

Diabetes is associated with the loss of beta-cell identity and function. Thus, understanding the mechanisms that simultaneously regulate beta-cell function and identity is critical for developing beta-cell replacement therapies. In this study, we show that the de novo DNA methyltransferase, Dnmt3a, orchestrates beta-cell identity and function. Previously, we have shown that loss of Dnmt3a in pancreatic beta-cells prevents the developmental metabolic reprogramming, resulting in loss of glucose stimulated insulin secretion (GSIS). To gain insights into the role of new DNA methylation patterns established in early pancreas development, we deleted Dnmt3a in the embryonic pancreatic progenitors in mice. RNA sequencing of Dnmt3aKO and control islets in adult life revealed that loss of Dnmt3a in progenitors leads to dysregulation of key genes involved in the maintenance of beta-cell identity and function. Notably, loss of Dnmt3a led to the upregulation of Tyrosine Hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, along with dysregulation of several genes involved in Dopamine signaling. Specifically, a large proportion of beta-cells in KO was marked by TH expression, compared to controls. Bisulfite sequencing analysis revealed that TH expression is repressed in beta-cells due to DNA methylation during differentiation of endocrine progenitors. In addition, the TH positive beta-cells displayed G2/M cell cycle arrest, along with elevated ER-stress markers. This alteration of cell identity was accompanied by impaired glucose tolerance and a GSIS profile resembling functionally immature beta-cells in the KO mice. The Dnmt3aKO mice did not show any significant change in beta-cell mass, while delta- and alpha- cell masses were increased at 7 month. Taken together, our results show that de novo methylation during early pancreatic development is critical for the establishment of beta-cell identity and function.

Disclosure
N. Parveen: None. J.K. Wang: None. S. Dhawan: None.

Funding
National Institutes of Health (R01DK120523)
275-OR: The Association between the Biological Disease-Modifying Antirheumatic Drugs and Incidence of Diabetes
Authors: LIN CHU , JI HONGYU , CAI XIAOLING , YANG WENJIA , JI LINONG 
Published: June 2020

Purpose: To evaluate the association between the biological disease-modifying anti-rheumatic drugs (bio-DMARDs) and the incidence of diabetes.
Methods: Studies recording the incidence of new-onset diabetes in subjects treated with bio-DMARDs were included.
Results: In total, 23 relevant studies were included. The pooled analysis suggested that bio-DMARDs treatment did not reduce the incidence of diabetes (RR= 0.87, 95% CI, 0.69 to 1.08, P = 0. 21) compared with non-bioDMARDs. However, subgroup analyses revealed incidence of new-onset diabetes was significantly reduced in patients with abatacept treatment (RR = 0.61, 95% CI, 0.38 to 0.99, P = 0.04).
Conclusions: The utilization of bio-DMARDs in general was not associated with the incidence of diabetes while the abatacept treatment may reduce the risk of diabetes.

Disclosure
C. Lin: None. H. Ji: None. X. Cai: None. W. Yang: None. L. Ji: None.

Funding
National Natural Science Foundation of China (81970698); National Key Research and Development Program of China (2016YFC1304901)
276-OR: A 2-Dimensional (2D) Analysis of Glucose and C-Peptide Shows a Teplizumab Effect in Individuals at Risk for Type 1 Diabetes (T1D) 3 Months after Treatment
Authors: SIMS EMILY K. , WARNOCK MEGAN V. , HEROLD KEVAN C. , SOSENKO JAY 
Published: June 2020

We sought to determine whether a measure combining changes in C-peptide and glucose could show efficacy 3 months after teplizumab treatment among multiple islet autoantibody+ dysglycemic individuals (n=44, age 19.2± 11.9 yrs on teplizumab and n=32, age 17.5± 11.1 yrs on placebo) in the recent TrialNet teplizumab prevention trial (teplizumab delayed T1D onset). In the 2D analysis assessing changes in glucose and C-peptide below (Figure), mean glucose and C-peptide from 30 to 120 minutes are plotted from baseline and 3-month OGTTs. For each OGTT, centroids (central point of OGTT shape) are connected by vectors, showing opposite directionality from baseline to 3 months between groups. Since AUC C-peptide/AUC glucose (AUC Ratio) correlates highly with centroid C-peptide/centroid glucose (r=0.99), to quantify the differences in directionality, we compared AUC Ratio (x1,000; adjusted for baseline) change from baseline to 3 months. The teplizumab group showed a positive change in AUC Ratio: 1.5±2.9 vs. a negative change in placebo: - 0.78±2.7; p=0.001). This difference was sustained after 6 months of treatment (p=0.004).
In summary, a 2D analysis of glucose and C-peptide change provided visual and quantitative evidence of an early treatment effect. As a centroid correlate, the AUC Ratio can be a useful endpoint for performing shorter prevention trials.

Disclosure
E.K. Sims: None. M.V. Warnock: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.

Funding
National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
277-OR: Teplizumab Reverses the Loss of C-Peptide in Relatives at Risk for Type 1 Diabetes (T1D)
Authors: SIMS EMILY K. , BUNDY BRIAN N. , STIER KENNETH D. , SERTI ELISAVET , LIM NOHA , NEPOM GERALD T. , EVANS-MOLINA CARMELLA , HEROLD KEVAN C. 
Published: June 2020

We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia.
In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab.

Disclosure
E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc.

Funding
National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
280-OR: Medical Nutrition Therapy and Glycemic Control in Youth-Onset Diabetes: SEARCH for Diabetes in Youth Study
Authors: SAUDER KATHERINE A. , STAFFORD JEANETTE M. , THE NATALIE S. , MAYER-DAVIS ELIZABETH J. , THOMAS JOAN , LAWRENCE JEAN M. , KIM GRACE , SIEGEL KAREN R. , JENSEN ELIZABETH T. , SHAH AMY S. , DAGOSTINO RALPH , DABELEA DANA 
Published: June 2020

Medical nutrition therapy (MNT) is integral to diabetes (DM) management, but little is known about MNT use in youth and young adults. The SEARCH for Diabetes in Youth study assessed MNT use among 1476 participants with type 1 DM (T1D) and 245 with type 2 DM (T2D) who had up to 3 research visits over 5.2 years (range 1.7-11.5). Participants reported often, sometimes, or never using each of 10 MNT strategies, which we categorized with 5 mutually exclusive groups: often using across visits; start using at later visits; sometimes using across visits; stop using at later visits; or never using at every visit. We used general linear models to examine A1c levels at the most recent visit (mean 11.0 [range 6.3-17.0] years after DM diagnosis) for each MNT strategy, adjusting for sociodemographic and DM-related variables. Most participants with T1D reported often counting carbs (n=1080, 75%), while half (n=107, 47%) of those with T2D reported often limiting sweets. Table presents significant associations of A1c levels with MNT use by DM type. In T1D, mean A1c differed significantly across MNT use of 7 strategies, but only for 2 strategies in T2DM. For both T1D and T2D, A1c did not differ by use of dietary exchanges, drinking more milk, or eating more fruits/vegetables. Our data suggest that often using most MNT strategies is related to relatively better glycemic control in T1D, but this applies to fewer MNT strategies for T2DM.

Disclosure
K.A. Sauder: None. J.M. Stafford: None. N.S. The: None. E.J. Mayer-Davis: None. J. Thomas: None. J.M. Lawrence: None. G. Kim: None. K.R. Siegel: None. E.T. Jensen: None. A.S. Shah: None. R. Dagostino: Consultant; Self; Amgen, AstraZeneca, Celgene, Daiichi Sankyo. D. Dabelea: None.

Funding
National Institutes of Health
283-OR: Changes in HbA1c between 2011-2017 in Austria/Germany, Sweden, and the United States: A Lifespan Perspective
Authors: ALBANESE-O’NEILL ANASTASIA , HERMANN JULIA , SVENSSON ANN-MARIE , MILLER KELLEE , RAILE KLEMENS , AKESSON KARIN , CALHOUN PETER , EEG-OLOFSSON KATARINA , MAAHS DAVID M. , HOLL REINHARD W. , HANAS RAGNAR 
Published: June 2020

This study assessed HbA1c across the lifespan in people with T1D in Austria/Germany, Sweden, and the United States (U.S.) between 2011 and 2017. Data extracted from the DPV, Austria/Germany (n = 25651 in 2011, n = 29442 in 2017); SWEDIABKIDS/NDR, Sweden (n = 44474 in 2011, n = 53690 in 2017); and T1D Exchange, U.S. (n = 16198 in 2011, n= 17087 in 2017) registries were included in the analysis. Mean HbA1c across the lifespan in 2017 and changes in mean HbA1c between 2011 and 2017 overall and by age cohorts were analyzed. In 2017 mean HbA1c for adults ≥45 years converged across registries; HbA1c levels for subjects &lt;25 years were highest in the U.S. (Figure). Controlling for age, sex, and T1D duration, overall HbA1c increased in the U.S. between 2011 and 2017 (2011=8.02%, 2017=8.26%, p&lt;.01); decreased in Sweden (8.06%, 7.74%, p&lt;.01); and did not change in Austria/Germany (7.84%, 7.84%, p=.49). Controlling for sex and T1D duration, mean HbA1c decreased between 2011 and 2017 in all age cohorts in Sweden (all p&lt;.01). In the U.S., HbA1c increased in subjects &lt;45 years and ≥65 years (all p&lt;.05) and did not change in subjects 45-&lt;65 years (p=.06). In Austria/Germany, HbA1c decreased in subjects 13-&lt;19 years (p&lt;.01), did not change in subjects &lt;13 years (p=.26) and 19-&lt;25 years (p=.88), and increased in subjects ≥25 years (all p&lt;.05). Further research is warranted to better understand causes of geographic disparities in glycemic control.

Disclosure
A. Albanese-O’Neill: Consultant; Self; American Diabetes Association. J. Hermann: None. A. Svensson: None. K. Miller: None. K. Raile: None. K. Akesson: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. K. Eeg-Olofsson: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. R.W. Holl: None. R. Hanas: Advisory Panel; Self; Abbott, Novo Nordisk A/S. Speaker’s Bureau; Self; Sanofi. Other Relationship; Self; AstraZeneca.

Funding
German Center for Diabetes Research; The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)
288-OR: Myeloid-Specific Deletion of Alox15 Decreases Pancreatic Inflammation and Protects from Spontaneous Diabetes Development in Nonobese Diabetic (NOD) Mice
Authors: PINEROS ANNIE , KULKARNI ABHISHEK , ORR KARA , GLENN LINDSEY , REISSAUS CHRISTOPHER A. , HERNANDEZ-PEREZ MARIMAR , MCDUFFIE MARCIA J. , NADLER JERRY , MORRIS MARGARET A. , MIRMIRA RAGHAVENDRA , TERSEY SARAH A. 
Published: June 2020

The pathogenesis of type 1 diabetes (T1D) involves the interaction of the immune system with β cells. 12/15-lipoxygenase (12/15-LOX), an enzyme involved in arachidonic acid metabolism, is highly expressed in both β cells and macrophages. Global deletion of the gene encoding 12/15-LOX (Alox15) prevents diabetes in the NOD mouse (animal model for T1D) via reduction of proinflammatory cytokines produced by macrophages and islets. However, the role of 12/15-LOX in the macrophages during T1D development remains unclear. To address this issue, we generated myeloid lineage-specific Alox15 knockout mice (Alox15∆myel) on the NOD background and evaluated immune cell infiltration into the pancreas and in pancreatic lymph nodes, as well as diabetes outcome in these animals. Pancreas sections of Alox15∆Myel mice showed a decrease of lymphocyte infiltration compared to control littermates. Alox15∆Myel mice also showed a decreased frequency of IL-1β produced by macrophages (F480+IL1β+) and dendritic cells (CD11c+IL1β+) in the pLNs when compared to control mice. To clarify if Alox15 in myeloid cells mediates proinflammatory cytokines production by T cells, we performed a co-culture assay of Alox15-/- macrophages with naïve T cells. Alox15 deletion in macrophages impaired IFN-γ production from CD4+ T cells compared to WT macrophages. Furthermore, Alox15∆Myel mice showed a significant decrease in the incidence of spontaneous type 1 diabetes (&lt;10%) compared to control mice (80%) (P&lt;0.05). Alox15 deletion in macrophages led to increased β-cell mass and decreased insulitis in nondiabetic mice. Gene expression analysis in the islets showed increased expression of Pdx1 and Il-10 in islets of Alox15∆Myel mice. Together, these data suggest that myeloid-derived Alox15 promotes immune cell infiltration and inflammation in the pancreas leading to β-cell destruction and development of T1D.

Disclosure
A. Pineros: None. A. Kulkarni: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Hernandez-Perez: None. M.J. McDuffie: None. J. Nadler: None. M.A. Morris: Stock/Shareholder; Spouse/Partner; Becton, Dickinson and Company, Bristol-Myers Squibb, Johnson & Johnson, Medtronic, Sanofi. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. S.A. Tersey: None.

Funding
National Institutes of Health (R01DK105588, P30DK097512 to R.M.)