bluuebunny/crossref_metadata_2025_split huggingface dataset:
215-OR: Safety and Performance of the Omnipod Hybrid Closed-Loop System in Young Children Aged 2-6 Years with Type 1 Diabetes
Authors: BUCKINGHAM BRUCE A. , FORLENZA GREGORY P. , SHERR JENNIFER , GALDERISI ALFONSO , EKHLASPOUR LAYA , LEE JOON BOK , OCONNOR JASON B. , DUMAIS BONNIE , HUYETT LAUREN M. , LAYNE JENNIFER E. , LY TRANG T. 
Published: June 2019

T1D therapies must be proven safe for young children, who face unique diabetes management challenges. The safety and performance of the Omnipod® hybrid closed-loop (HCL) personalized model predictive control algorithm were assessed in those with T1D aged 2-5.9 y with A1C &lt;10% using an investigational device in a supervised hotel setting. A 7-day at-home standard therapy (ST) phase with CGM use preceded the 48-72 h HCL phase. Meals during HCL were unrestricted, with boluses administered per usual routine. Exercise was performed for ≥30 min/d. The 14 participants were age 4.2 ± 0.9 y, T1D duration 2.4 ± 1.0 y, A1C 7.4 ± 1.0%, and TDD 0.77 ± 0.13 U/kg (mean ± SD). Mean glucose was lower during HCL vs. ST, 148 ± 16 mg/dL vs. 172 ± 27 mg/dL overall and 135 ± 17 mg/dL vs. 167 ± 28 mg/dL overnight. The percent time 70-180 mg/dL was 32% higher during HCL vs. ST overall, 72.6 ± 8.4% vs. 55.2 ± 13.1%, respectively, and 47% higher overnight, 85.3 ± 9.4% vs. 58.2 ± 16.4%. Percent time &lt;70 mg/dL was reduced nearly 2-fold overall and overnight. Glycemic outcomes are reported in the Table. There was 1 severe hypoglycemic event after exercise which was treated with oral carbohydrates. The Omnipod HCL system was safe and performed well in these very young children in a supervised setting, similar to the performance previously observed in older pediatric, adolescent and adult participants.

Disclosure
B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. G.P. Forlenza: Advisory Panel; Self; Dexcom, Inc. Consultant; Self; Medtronic MiniMed, Inc., Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Eli Lilly and Company, Insulet Corporation. Consultant; Self; Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi. Research Support; Self; Dexcom, Inc., Insulet Corporation. A. Galderisi: None. L. Ekhlaspour: None. J. Lee: Employee; Self; Insulet Corporation. J.B. OConnor: Employee; Self; Insulet Corporation. B. Dumais: None. L.M. Huyett: Employee; Self; Insulet Corporation. Stock/Shareholder; Self; Insulet Corporation. J.E. Layne: Employee; Self; Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation.

Funding
Insulet Corporation
2152-P: Impaired Iron-Sulfur-Cluster Redox Regulation in Monogenic Ncb5or Diabetes
Authors: ZHU HAO , MUTO AZUSA , HOME TRISHA , WANG WENFANG , URANO FUMIHIKO 
Published: June 2019

NADH cytochrome b5 oxidoreductase (Ncb5or) is a ferric reductase widely expressed in animal cells. Ncb5or deficiency results in altered iron metabolism, mitochondrial dysfunction and proliferation, and increased oxidative and endoplasmic reticulum (ER) stress. Ncb5or null (KO) mice present early-onset lean diabetes, ataxia and hearing loss. Similar clinical manifestations are observed in patients with type 2 Wolfram Syndrome that is caused by mutations in CISD2 (CDGSH iron-sulfur domains 2). Its [2Fe-2S] iron-sulfur-cluster (ISC) is redox sensitive and becomes labile when oxidized. Because both proteins are associated with ER, Ncb5or may function as a CISD2 reductase for ISC redox regulation. This hypothesis appears to be supported by our recent data. When fed a chow admixture with 400 ppm pioglitazone, a FDA-approved drug capable of stabilizing FeII-ISC in vitro, Ncb5or KO mice exhibit a 4-week delay in developing overt diabetes, specifically, at age 11 weeks vs. 7 weeks under chow. Pioglitazone results in a significant increase in the content of FeII-ISC CISD2 among the total in the liver of prediabetic KO mice when compared to wild type (WT) counterparts, namely, a KO/WT ratio of 0.6 post pioglitazone vs. 0.3 under chow (by native gel electrophoresis and immuno-blot analyses with antibodies that preferentially recognize CISD2 containing FeII-ISC). Pioglitazone also reduces oxidative and ER stress response in the liver of KO mice (qRT-PCR of MT’s, ATF3, and XBP1-spliced transcripts) and attenuates mitochondrial dysfunction in KO mouse embryonic fibroblasts (extracellular flux analysis). However, iron dyshomeostasis, as indicated by transcript profiles of iron genes in KO cells and splenomegaly in KO mice, is not rescued by pioglitazone. Our findings suggest that Ncb5or maintains the redox status of ISC in CISD2 and that, through stabilizing ferrous ISC, pioglitazone can partially rescue defects in Ncb5or-null cells. Studies are underway to characterize the Ncb5or-CISD2 axis in beta-cells.

Disclosure
H. Zhu: None. A. Muto: None. T. Home: None. W. Wang: None. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals.

Funding
University of Kansas Medical Center Research Institute
2159-P: Beta-Cell Compensation to Pubertal Insulin Resistance Is Compromised in High-Fat Fed Rats and Impairs Glucose Homeostasis Later in Life
Authors: CASTELL ANNE-LAURE , ETHIER MÉLANIE , FERGUSSON GRACE , GHISLAIN JULIEN , POITOUT VINCENT 
Published: June 2019

Background: Puberty is a time of hormonal changes that are associated with insulin resistance (IR). Although insulin sensitivity is restored at the end of puberty in healthy youth, it does not resolve in obese adolescents leading to an increased risk of metabolic disease such as type 2 diabetes. In pregnancy and obesity-induced IR, β-cells increase their functional mass to maintain glucose homeostasis. During puberty, however, the mechanism of pancreatic β-cell compensation to IR and its role in glucose metabolism later in life have not been established.
Objective: To characterize pancreatic β-cell adaptation to pubertal IR in rats and study the effect of metabolic stress during puberty on glucose homeostasis in adult animals.
Methods: Male and female Wistar rats were fed a chow diet or a high fat diet (HFD) during puberty. Body weight, fasted plasma insulin, glucose tolerance and hormone levels (estradiol, testosterone, insulin growth factor-1 (IGF1), growth hormone (GH)) were determined every 5 days from weaning to adulthood. β-cell proliferation was assessed by immunostaining of pancreatic cryosections for Ki67 and insulin to mark β-cells and β-cell mass by morphometric analysis of insulin staining.
Results: During puberty, glucose intolerance was associated with an increase in insulin levels in both sexes, suggestive of IR. Correspondingly, β-cell proliferation increased, as did islet size and β-cell mass. β-cell expansion correlated with a rise in IGF1/GH levels. HFD during puberty impaired glucose tolerance in adults.
Conclusion: During puberty in rats, β-cells compensate for increased IR. Metabolic stress during puberty impairs glucose homeostasis later in life. Future studies will address whether β-cell expansion during puberty is under control of the IGF1/GH axis.

Disclosure
A. Castell: None. M. Ethier: None. G. Fergusson: None. J. Ghislain: None. V. Poitout: None.

Funding
National Institutes of Health; Societé Francaise d'Endocrinologie Diabetologie Pediatrique
2165-P: In Vivo Islet Imaging Reveals that GLP-1 Paradoxically Increases Insulin Content
Authors: CRAS-MÉNEUR CORENTIN M.H. , FRIKKE-SCHMIDT HENRIETTE , ARVAN PETER , SEELEY RANDY J. 
Published: June 2019

Glucagon-like peptide-1 (GLP-1) is an incretin, secreted in response to a meal that promotes glucose-stimulated insulin secretion in animal models and diabetic and nondiabetic humans. GLP-1 analogues have been successfully used as an effective treatment for both obesity and type 2 diabetes. While the general mechanisms of actions of GLP-1 on β-cell growth and function have been extensively studied, a number of questions regarding the dynamic and heterogeneity of the response of individual islets to GLP-1 in vivo remain. Using a fluorescent reporter mouse model originally created by the Arvan Lab, we have optimized a platform allowing us to monitor the content of individual islets in live animals. In this model, a super-folded GFP is bound to the C-Peptide, allowing the fluorescent visualization and quantification of insulin content within the islets without altering their normal physiology. After an overnight fast, the pancreas is exposed by laparotomy in anesthetized mice and the reporter in individual islets can be imaged repeatedly to quantify their insulin content. Upon glucose challenge, the GFP intensity within the islets progressively decreases in control mice, correlating with the insulin secretion within the bloodstream. In order to study the effects of GLP-1 on individual islet secretion, mice were either treated either with Liraglutide, a stable GLP-1 analog, or subjected to Vertical Sleeve Gastrectomy (VSG), a surgical procedure known to increase GLP-1 levels in obese mice. Surprisingly, with both approaches, in addition to increasing insulin secretion upon a glucose challenge, we could also observe insulin content actually increasing within the islets over the course of the excursion. This finding was later confirmed by measuring total insulin content in liraglutide-treated mice. This data indicates that despite causing enhanced insulin secretion, GLP-1 can also very rapidly increase insulin content within islets.

Disclosure
C.M.H. Cras-Méneur: None. H. Frikke-Schmidt: None. P. Arvan: None. R.J. Seeley: Consultant; Self; Ironwood Pharmaceuticals, Inc., Novo Nordisk A/S, Scohia Pharma Inc. Research Support; Self; MedImmune, Novo Nordisk A/S, Zafgen, Inc. Stock/Shareholder; Self; Zafgen, Inc.
2172-P: Effects of Glucocorticoid on Gene Expression and Secretion of Insulin in Pancreatic ß Cells
Authors: MURASHIMA TOSHITAKA , KONDO TAKUMA , KONDO KEN , MORITA NARU , KITAHARA ATSUKO , SUMITANI YOSHIKAZU , TAKAHASHI KAZUTO , TANAKA TOSHIAKI , HOSAKA TOSHIO , ISHIDA HITOSHI 
Published: June 2019

Glucocorticoids are widely used in clinical practice, while the chronic administration at a high dose often leads to the progression of steroid-induced diabetes. This hyperglycemic state results mainly from the suppression of insulin secretion due to pancreatic β-cell dysfunction and the increment of systemic insulin resistance. However, the mechanisms which underlie glucocorticoid action on expression and secretion of insulin in pancreatic β-cells have not been clarified. The aim of this study is to elucidate the effects of glucocorticoid on insulin synthesis and secretion in pancreatic β-cells. Insulin gene expression was significantly increased in 30nM of dexamethasone and decreased in 300 and 3000 nM of dexamethasone. These changes in the expression were canceled by RU486, a GR antagonist, at any concentrations of dexamethasone. Meanwhile, insulin and proinsulin secretion were significantly reduced at any concentrations of dexamethasone. Interestingly, the proinsulin/insulin ratio was significantly decreased at 30 nM, and increased at 300 and 3000 nM. The changes were completely restored by RU486 at 30 nM of dexamethasone, while the reduction of insulin and proinsulin secretion by 300 or 3000 nM of dexamethasone was not released by RU486. In addition, similar results were obtained in experiments using knockdown of GR expression. Interestingly, the short-term induction of insulin secretion by membrane depolarization treated with 30 mM of KCl was rather enhanced by 3000 nM of dexamethasone, and this enhancement was not canceled by RU486.
In conclusion, glucocorticoid regulates insulin gene expressions via the genomic pathway containing GR in pancreatic β-cells, while particularly high-dose glucocorticoid regulates insulin secretion principally via non-genomic pathway. Since the proinsulin/insulin ratio increased under chronic administration of high-dose glucocorticoid, it was assumed that the non-genomic pathway was involved in insulin processing.

Disclosure
T. Murashima: None. T. Kondo: None. K. Kondo: None. N. Morita: None. A. Kitahara: None. Y. Sumitani: None. K. Takahashi: None. T. Tanaka: None. T. Hosaka: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Ono Pharmaceutical Co., Ltd. H. Ishida: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Kowa pharmaceutical Co. Ltd., MSD, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.

Funding
Japan Ministry of Education, Culture, Sports, Science and Technology
2186-P: Circulating Exosomes from Simple Obese Humans Inhibited Islet ß-Cell Proliferation through Increasing Cellular Inflammation
Authors: XIE XINXIN , GE QIAN , HUANG RONGFENG , XIAO XIAOQIU , LI XI 
Published: June 2019

The progressive decline of the β cell function is one major pathogenesis of type 2 diabetes mellitus. The obese people with normal glucose have already had β cell dysfunction. We aim to investigate whether the circulating exosome vesicles (EVs) could be a new mechanism linking obesity to β cell dysfunction. A total of 43 healthy lean and 44 simple obese volunteers were recruited from June 2017 to February 2018. Compared to lean subjects, obese subjects had lower glucose disposition index (DI) and Secretion-sensitivity index (ISSI-2). Compared to EVs isolated from circulations of lean subjects (L-EVs), EVs from obese subjects (O-EVs) inhibited β cell proliferation while did not affect its apoptosis. Moreover, the O-EVs induced β cell inflammation via activating the NF-kB and increasing the gene expression of chemokine CCL-2. By Quantitative Proteomic Analysis, we further explored that 29 proteins were differentially regulated in O-EVs compared to L-EVs. Among them, the Rapamycin-insensitive companion of mTOR (Rictor) and the Omentin-1 were downregulated by 65% (P&lt;0.01) and by 27% (P=0.03) respectively. The existences and downregulations of both the total and phosphorylated forms of the Rictor, as well as the omentin-1, were verified by Western blot and ELISA (total Rictor: 0.21±0.04 vs. 0.15±0.05, P&lt;0.01; phosphorylated Rictor: 0.33±0.09 vs. 0.25±0.08, P=0.02; Omentin-1: 33.5±5.2 vs.16.3±2.5, P&lt;0.01). Both the phosphorylated Rictor and the Omentin-1 in EVs correlated negatively with the visceral fat mass, the HOMA insulin resistance index, and the fasting insulin secretion. Additionally, the Omentin-1 correlated positively with the DI and the ISSI-2. Thus, circulating EVs from simple obese humans inhibited β cell proliferation through increasing cellular inflammation. This effect may result from the changed protein cargos of EVs during obesity. The two newly identified exosomal proteins may be new therapeutic targets for improvingβcell function.

Disclosure
X. Xie: None. Q. Ge: None. R. Huang: None. X. Xiao: None. X. Li: None.
219-OR: Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing Total Pancreatectomy and Autologous Islet Transplantation
Authors: MCDOWELL RUTH , ALI KHAWLA F. , SAN MARTIN VICENTE T. , BOTTINO RITA , KIRWAN JOHN P. , HATIPOGLU BETUL 
Published: June 2019

Rationale: Although autologous islet transplantation aims to prevent surgically-induced insulin-dependent diabetes in patients undergoing total pancreatectomy, only approximately one third of patients achieve insulin independence. To test the hypothesis that reducing nonspecific inflammation improves graft function post-AIT, we conducted a pilot clinical study using oral hydroxychloroquine (HCQ), an FDA-approved anti-malarial that inhibits thrombosis and a broad spectrum of inflammatory cytokines.
Methods: We used a phase II, randomized, double-blinded, placebo-controlled trial to determine the effect of peri-transplant HCQ on individuals (n=8) undergoing total pancreatectomy with autologous islet transplantation (TPAIT). In vivo islet function was assessed via Mixed Meal Tolerance Test (MMTT) before and 6-12 months after surgery. We found that islet grafts were viable for at least 24 hours in culture and we optimized conditions for in vitro assessment of islet graft metabolic function via Seahorse Extracellular Flux.
Results and Conclusions: Islet grafts from HCQ-treated patients showed a 4.7-fold greater mitochondrial spare respiratory capacity compared with placebo-treated patients (64.9 ± 20.7 vs. 13.7 ± 7.1% basal respiration, p = 0.058), suggesting that HCQ may improve metabolic function in the islet graft. We also found that the insulin incremental area under the curve after MMTT was 8.2-fold greater in HCQ-treated patients 6-12 months after surgery compared to that of placebo-treated patients (1154 ± 290 vs. 185 ± 180 mU/L, p = 0.026), suggesting that HCQ may also improve islet engraftment and/or function. Our results warrant further investigation into HCQ using a larger-scale clinical trial with the goal of reducing inflammatory islet destruction and enhancing mitochondrial function to improve metabolic outcomes in TPAIT.

Disclosure
R. McDowell: None. K.F. Ali: None. V.T. San Martin: None. R. Bottino: Research Support; Self; Imagine Pharma. J.P. Kirwan: None. B. Hatipoglu: Advisory Panel; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Merck & Co., Inc.

Funding
Cleveland Clinic Foundation
2190-P: Sex-Based Differences in Nr4a1 Beta-Cell Activity
Authors: TESSEM JEFFERY S. , HERRING JACOB , SMITH COURTNEY J. , AUSTIN MATTHEW C. , WYNN ADAM G. 
Published: June 2019

The orphan nuclear hormone receptor Nr4a1 plays a critical role in maintaining and expanding functional beta cell mass. Overexpression of Nr4a1 is sufficient to induce beta cell proliferation in primary beta cells by upregulating cell cycle progression, while maintaining glucose-stimulated insulin secretion. Full body deletion of Nr4a1 results in decreased beta cell mass, while resulting in modified fuel utilization in liver and muscle. Knock down of Nr4a1 decreases glycolytic and TCA cycle gene expression, impairs mitochondrial respiration, decreases cellular ATP levels, and ultimately decreases glucose-stimulated insulin secretion. While Nr4a1 is currently considered an orphaned nuclear hormone receptor, recent findings suggest that unsaturated fatty acids may function as a ligand, and that exposure to these fatty acid’s changes Nr4a1 affinity for promoters of genes involved in fuel utilization. To determine the effect of Nr4a1 presence of absence in the beta cell, and the effect of fatty acid exposure, we developed a beta cell specific, inducible, Nr4a1 knock out mouse. Male and female mice, deficient for Nr4a1 beginning at 3 months of age, were fed a normal chow or high fat diet for an additional four months. Here we present data demonstrating a sex specific difference in phenotype. Male mice demonstrated improved glucose tolerance at four months of feeding, while female mice demonstrated impaired glucose tolerance as early as one month of feeding. Here we present data regarding differences in beta cell mass, glucose stimulated insulin secretion, as well as Nr4a1 DNA binding from in islets from male and female mice exposed to unsaturated and saturated fatty acids. These data begin to demonstrate the role of Nr4a1 in controlling gene expression as a function of nutrient exposure, as well as sex-based differences in Nr4a1 activity.

Disclosure
J.S. Tessem: None. J. Herring: None. C.J. Smith: None. M.C. Austin: None. A.G. Wynn: None.

Funding
American Diabetes Association (1-17-IBS-101 to J.S.T.)
2191-P: PPM1K Regulates ß-Cell Proliferation, Insulin Content, and GSIS
Authors: DELEYE YANN , HERRING JACOB , HESS KAVAN H. , LEININGER BRENNAN R. , HANNOU SARAH A. , ASTAPOVA INNA , HERMAN MARK A. , TESSEM JEFFERY S. , WHITE PHILLIP J. 
Published: June 2019

A single nucleotide polymorphism in the gene encoding the protein phosphatase m1K (PPm1K) is associated with increased risk for the development of type 2 diabetes but not insulin resistance in humans. We recently discovered that expression of the PPM1K gene in liver is suppressed by the carbohydrate response element binding protein (ChREBP) which controls transcriptional responses to changes in carbohydrate availability. Taken together these findings suggest that PPM1K might play an important role in the glucose responsive pancreatic β cell; however, little is known about the role of PPm1K in this cell type. Here we studied how changes in glucose concentration affect PPm1K expression in β cells and explored the effect of modulating PPM1K expression on β cell proliferation, insulin content and glucose stimulated insulin secretion. Studies were carried out in INS1-832/13 β cells in culture and key findings were validated in isolated rat islets. In line with our previous observations in liver, we found that increasing glucose concentrations in INS1 cells results in elevated ChREBP activity, measured by expression of the ChREBP β isoform, and lower PPM1K mRNA expression (P&lt;0.01). Treatment of INS-1 cells with adenovirus expressing recombinant human PPM1K for 96h increased β cell proliferation (P&lt;0.05) but robustly lowered GSIS (P&lt;0.001). This effect was due to substantially lower insulin content in the Ad-PPm1K treated cells (P&lt;0.01). Importantly, there was no effect of the control GFP adenovirus compared to non-transfected cells for any of these measures. Moreover, siRNA mediated knock down of PPM1K resulted in increased expression of INS1 and INS2 mRNA suggesting that altered transcription of the insulin gene likely accounts for the effect of PPm1K on β cell insulin content and release.
In conclusion, our data clearly demonstrate that PPM1K plays an important role in the regulation of β cell insulin production and proliferation.

Disclosure
Y. Deleye: None. J. Herring: None. K.H. Hess: None. B.R. Leininger: None. S.A. Hannou: None. I. Astapova: None. M.A. Herman: None. J.S. Tessem: None. P.J. White: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-16-INI-17 to P.J.W.)