bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tobacco Smoking Results in Reduced Pancreatic Islet Mass in Humans
Authors: CHETBOUN MIKAËL , KERR-CONTE JULIE A. , GMYR VALERY , THUILLIER DOROTHÉE , EZZOUAOUI RIMED , HUBERT THOMAS , RAVERDY VIOLETA , BONGIOVANNI ANTONINO , DAOUDI MEHDI , VANTYGHEM MARIE-CHRISTINE , PATTOU FRANCOIS 
Published: June 2018

Epidemiological studies identify tobacco as an independent risk factor for T2D, however, the mechanisms involved remains unclear. Clinical studies incriminate an increase of insulin resistance but a direct effect on pancreatic islet mass is suggested by some animal studies. The aim of this study was to document the association between tobacco smoking and pancreatic islet mass in humans.Total islet mass (TIM) was measured in 484 pancreata from organ donors processed with standardized islet isolation technique for clinical islet transplantation. Number and size of islets were assessed following enzymatic digestion. Functional islet mass was estimated in a cohort of 845 obese subjects, by measuring c-peptide to glucose ratio at 30 min (CP/G-30) following an oral glucose load. Pancreatic islet mass proxies were correlated with donor smoking status and tobacco consumption (generalized linear model).TIM was negatively associated with smoking status in organ donors (estimate:-0.131;P=0.017), independently of other known predictors: BMI (-0.019; P=0.001), age (-0.009; P=0.0001). CP/G-30 was also reduced in vivo in subjects with smoking history. TIM (Figure A-B) and CP/G-30 (Figure C-D) were negatively correlated with the level of tobacco consumption.Pancreatic islet mass was reduced in subjects with smoking history, with a dose-response relationship with tobacco consumption. Our results support the direct implication of smoking in T2D.

Disclosure
M. Chetboun: None. J.A. Kerr-Conte: None. V. Gmyr: None. D. Thuillier: None. R. Ezzouaoui: None. T. Hubert: None. V. Raverdy: None. A. Bongiovanni: None. M. Daoudi: None. M. Vantyghem: Board Member; Self; Aegerion Pharmaceuticals. Other Relationship; Self; Elsevier. Research Support; Self; Ipsen Biopharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. F. Pattou: None.
Novel Use of Agent 11C-PHNO for Pet CT Imaging of Pancreatic Beta-Cell Mass
Authors: RANGEL ELIZABETH SANCHEZ , BINI JASON , NABULSI NABEEL B. , HUANG YIYUN , HEROLD KEVAN C. , SHERWIN ROBERT , CARSON RICHARD E. , CLINE GARY 
Published: June 2018

There is growing interest in developing a method to measure pancreatic beta-cell mass (BCM) so as to: 1) monitor progression of beta cell changes in type 1 and type 2 diabetes; 2) identify therapies to preserve, restore or regenerate beta cells; and 3) monitor viability of islets after transplantation therapy. Given that beta cells and neurons have functional similarities, we tested the hypothesis that receptors, transporters, or proteins essential for signal detection and propagation, may be common to both cell types. Hence, we assessed if Positron Emission Tomography (PET) imaging ligands originally developed for neuroimaging may provide a means for imaging BCM as well. Previous studies have shown higher uptake of 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO), a dopamine D2/D3 agonist radioligand (D3-preferring), in the pancreatic tissue of healthy controls vs. T1DM in humans. In this study, we sought to determine whether 11C-PHNO, would be useful for measuring BCM. Eleven subjects (6 with T1DM, 4 males and 2 females, age 30.8 ± 11.4 years, BMI 24.4 ± 2.0, and 5 matched healthy controls, 3 males and 2 females, age 32.2 ± 11.4 years, BMI 26.4 ± 2.1) underwent abdominal PET/CT imaging using 11C-PHNO. Regions-of-interest (ROIs) were applied to the pancreas, liver, spleen, and kidney and time-activity curves (TACs) were produced and converted to standard uptake value (SUV) units. The distribution of activity between the head, body, and tail of the pancreas was also assessed. We observed that there was a 41% reduction in 11C-PHNO SUV in T1DM patients as compared to the healthy control group (p = 0.026). Moreover, there was a positive correlation between plasma c-peptide concentrations and 11C-PHNO SUV in the pancreas (r = 0.78), although this relationship did not reach statistical significance (p = 0.1), most likely due to the small sample size. These data suggest that dopamine D3 expression in pancreatic tissue might serve as a useful biomarker for assessing beta cell mass in diabetic humans.

Disclosure
E. Sanchez Rangel: None. J. Bini: None. N.B. Nabulsi: None. Y. Huang: None. K.C. Herold: None. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc. R.E. Carson: Research Support; Self; Pfizer Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, UCB, Inc., Siemens. G. Cline: None.
miR-204 Antagomir Enhances GLP-1 Receptor Function and Glucose Control
Authors: JO SEONGHO , CHEN JUNQIN , XU GUANLAN , GRAYSON TRUMAN , THIELEN LANCE , SHALEV ANATH 
Published: June 2018

Glucagon-like peptide 1 receptor (GLP-1R) is a G protein-coupled receptor that is highly expressed on pancreatic beta-cells and activated by endogenous incretins or antidiabetic GLP-1R agonist drugs. GLP-1R function is important in maintaining glucose homeostasis and involves stimulation of glucose-induced beta-cell insulin secretion via cAMP generation. While GLP-1R expression has been shown to be downregulated in diabetes, the molecular mechanisms have not been fully elucidated. In this study, we have discovered that miR-204, a highly beta-cell-enriched microRNA that is upregulated in diabetes, directly targets the 3’ UTR of GLP-1R and decreases its expression in INS-1 cells as well as primary mouse and human islets. Moreover, genetic knockout of miR-204 in vivo increased islet GLP-1R expression and enhanced GLP-1R agonist-induced cAMP production and insulin secretion, resulting in improved glucose tolerance as well as protection against diabetes. In addition, miR-204 antagomir administration was able to mimic the effects of genetic miR-204 deletion and resulted again in GLP-1R agonist-induced insulin secretion as well as improved glucose tolerance. Thus, these results indicate for the first time that GLP-1R is under the control of a micro RNA and suggest that antagomir-mediated inhibition of miR-204 represents a potential novel therapeutic approach to promote the actions of GLP-1R agonist drugs in a beta-cell-specific manner and thereby help treat diabetes.

Disclosure
S. Jo: None. J. Chen: None. G. Xu: None. T. Grayson: None. L. Thielen: None. A. Shalev: None.
Replication of Previously Type 2 Diabetes Associated Loci in 35,000 Samples of Korean Population
Authors: KIM YOUNG JIN , HWANG MI YEONG , SHIN DONG MUN 
Published: June 2018

In the last decade, genome-wide association studies (GWAS) have revealed about hundreds of loci associated with type 2 diabetes(T2D) and related traits. However, most of loci have been discovered based on Europeans and a few GWAS conducted in populations with East Asian ancestry. To identify genetic variants responsible for complex traits such as T2D, obesity, and blood biochemical traits in Koreans, Korea Biobank Array(KBA) project was initiated in 2014. KBA is designed to contain about 830K tagging and functional variants optimized for Korean genome. In this study, quality controlled genotype data of about 35,000 samples was used. Among them, we conducted genome-wide association scan in 3,022 T2D case subjects and 27,195 control subjects. As a result, we replicated five previously known loci (CDKAL1, SLC30A8, CDKN2A, KCNQ1, and HNF1B) at genome-wide significance (P &lt;= 5x10-8). We further compared genetic effects in Koreans with those of previously reported loci. As of March 2018, there were 373 unique variants of 50 T2D GWAS papers listed in GWAS catalogue. Among 373 variants, 359 variants were available after excluding variants with low imputation quality (&lt;0.3). We compared odds ratios of 359 variants between KBA T2D GWAS and previously reported results. In overall, Pearson correlation coefficient of odds ratios was -0.04. For replicated results (130 variants with P&lt;0.05 in KBA T2D GWAS), however, we observed high correlation (r&lt;0.58). Our study identified five known T2D loci and confirmed consistent genetic effects across populations for 130 previously reported T2D associated variants. Further study is warranted to examine genetic diversity and lack of statistical power due to insufficient sample size in non-replicated loci. These results will be valuable scientific evidence in T2D precision medicine considering genetic effects across populations.

Disclosure
Y. Kim: None. M. Hwang: None. D. Shin: None.
Suicidal Screening in Youth with T1D—Risk or Benefit?
Authors: NAGRA HARPREET , DUKE DANNY C. , JONES MELINDA , KRAUS KIMBERLY , HARRIS MICHAEL A. 
Published: June 2018

Objectives: Insulin access with intent to overdose coupled with limited forethought and higher impulsivity during childhood and adolescence, makes identification of suicidal ideation (SI) among youth with type 1 diabetes (T1D) of high importance. Correlations between SI and poor diabetes self-management have been identified, with 13% of adolescents with T1D endorsing SI in the last 12 months. The present study aimed to determine feasibility and effectiveness of screening for SI in youth with T1D.
Methods: Data were obtained during routine behavioral health screening of youth (ages 11-18) with T1D at a regional diabetes center. SI data were derived from question 9 of the Patient Health Questionnaire-9 (PHQ-9), “Thoughts that you would be better off dead or of hurting yourself in some way.”
Results: PHQ-9 was completed by a total of 587 pediatric patients (Males =289; Females =298) with a mean HbA1c of 9.1% (SD= 2.2). Findings suggest a significant relationship between gender and endorsement of SI with more females endorsing SI (n=52) than males (n = 26). SI was significantly and positively associated with HbA1c. Of the 13% of youth who screened positive for SI, 3/4 indicated SI for several days in the last 7 days and received an on-site behavioral health consultation. Approximately, 1/5 indicated SI for more than 1/2 of the days in the last week and received an onsite referral and a telephone follow-up, and 5% indicated SI nearly every day in the last week and received an on-site clinical assessment with one youth requiring emergency services.
Conclusions: SI screening in youth with T1D is necessary to address this concern. Results suggest our protocol was effective in identifying SI, allowed for rapid clinical assessment, and referral for additional care. In addition, SI rates in youth with T1D were consistent with the general population, suggesting that diabetes does not put youth at higher risk for SI, but imposes greater concern for suicide given the immediate availability of insulin.

Disclosure
H. Nagra: None. D.C. Duke: None. M. Jones: None. K. Kraus: None. M.A. Harris: Consultant; Self; Eli Lilly and Company.
Beneficial Effects of Tamoxifen Treatment in Type 1 Diabetes
Authors: ZHENG JUAN , ZAFAR MOHAMMAD ISHRAQ , CHEN LULU , GUO XIN , LI XIAOMING 
Published: June 2018

Type 1 diabetes (T1D) results from the destruction of pancreatic β-cell through the β-cell specific autoimmune process. β-cell autoantigens, macrophages, dendritic cells (DC), B lymphocytes, and T lymphocytes have been implicated in the pathogenesis of autoimmune diabetes. Tamoxifen is a selective estrogen receptor modulators (SERM), used in the treatment of breast cancer. Research reports have shown that tamoxifen might decrease the strength of immune responses through modulation of DC differentiation and activation, and it may depress immunity. In NOD/ShiLtJ mice (female), which is a polygenic model for T1D, we found that tamoxifen exerts antidiabetic effects through acting on the immune system, leading to the suppression of insulitis and systemic inflammatory cytokine production in the in-vivo model. Tamoxifen therapy preserved the β-cell mass and prevented the development of T1D. Tamoxifen providing β-cell protection and immunoinhibitory effects offer a novel insight into the possible role of tamoxifen in the regulation of islet cell function and glucose homeostasis. These findings are significant and useful for clinical application.

Disclosure
J. Zheng: None. M. Zafar: None. L. Chen: None. X. Guo: None. X. Li: None.
The Complement-1q-Like-3 Inhibits Insulin Secretion by an Adhesion G-Protein Coupled Receptor, BAI3 in Pancreatic ß Cells
Authors: GUPTA RAJESH , SCHAID MIKE , KIMPLE MICHELLE E. , KOLTES JAMES E. , BHATNAGAR SUSHANT 
Published: June 2018

Secreted proteins are important metabolic regulators and our objective was to identify proteins that are important regulators of β-cell function. Microarray data from multiple tissues including liver, adipose, gastrocnemius, islets from lean and obese mice were analyzed to identify candidate regulators. For this, we developed a data filtering approach to identify candidate secreted protein regulators. Next, cross-tissue correlation network and gene enrichment based analyses were performed to determine cellular pathways affected by each candidate secreted protein in the target tissue. By using this methodology, complement-1q-like-3 (C1ql3) was identified to affect ’secretory processes’ in islets. Preliminary data showed that the expression of C1ql3 was increased by 32-fold in islets of obese mice. Incubating islets with C1ql3 containing culture media inhibited high glucose, GLP-1 receptor agonist (exendin-4), cAMP, and potassium-induced insulin secretion in mouse islets. Interestingly, C1ql3 did not affect insulin secretion in response to low and submaximal concentrations of glucose, fatty acids, amino acids, and mitochondrial metabolites. We further observed that the expression of BAI3, a receptor for C1ql3, is elevated in islets of obese compared to lean mice. Knockdown of BAI3 in β-cells increased glucose-stimulated insulin secretion by 2-fold and soluble C1ql3-binding fragment of BAI3 completely blocked the inhibitory effects of C1ql3 on cAMP-stimulated insulin secretion. These findings report the identification of a novel pathway in C1ql3/BAI3 that antagonizes GLP-1/cAMP signaling to inhibit insulin secretion from β-cells. We propose that the activation of C1ql3/BAI3 signaling contributes to type 2 diabetes and may offer therapeutic alternatives to treat type 2 diabetes.

Disclosure
R. Gupta: None. M. Schaid: None. M.E. Kimple: None. J.E. Koltes: None. S. Bhatnagar: None.
Hyperproinsulinemia in OGlcNAc Transferase Deficient Mice Is Associated with Loss of CPE and eIF4G1, but ß-Cell Deletion of eIF4G1 Induces Glucose Intolerance Independent of CPE Dysregulation
Authors: JO SEOKWON , LOCKRIDGE AMBER D. , ALEJANDRO EMILYN 
Published: June 2018

β cell loss of OGlcNAc transferase (βOGTKO), the sole enzyme that adds OGlcNAc post-translational modification onto target proteins impacting their function and stability, leads to diabetes and islet failure in mice. βOGTKO mice present hyperproinsulinemia, typified by increased serum proinsulin/insulin ratio. Here, we show that βOGTKO islets have reduced carboxypeptidase E protein but not mRNA (CPE, an exopeptidase that converts proinsulin to insulin), independent of sex, age and glucose levels. We identified that CPE is neither the target nor a binding partner of OGT. Eukaryotic initiation factor 4 gamma 1 (eIF4G1), previously shown to regulate CPE in vitro, is reduced at the protein level, but not mRNA, in βOGTKO islets. We identified that eIF4G1 is OGlcNAc-modified in β cells and mutation of the putative OGlcNAc site at serine 61 to alanine led to decreased protein stability, but not on CPE translation. To assess the role of eIF4G1 on CPE regulation in vivo, we generated mice with β cell specific deletion of eIF4G1 (RIPCre; eIF4G1flox/flox (βeIF4G1KO)), in R1207H eIF4G1 (eIF4G1) background. At 6 weeks of age in normal chow diet, glucose intolerance was evident between βeIF4G1KO and littermate control eIF4G1 mice, without alteration in peripheral insulin sensitivity. Surprisingly, no apparent insulin processing deficit was observed between βeIF4G1KO and eIF4G1 mice, consistent with the observed normal level of CPE protein among islets of βeIF4G1 KO, eIF4G1 or wild type mice via immunofluorescence, and comparable serum proinsulin/insulin ratio in βeIF4G1 KO and eIF4G1 mice. Significant reduction in the average β cell size and increased number of α cells was evident in βeIF4G1KO vs. eIF4G1 mice, hinting at loss in β cell mass. Together, these data unveil the regulation of OGT on eIF4G1, and underscore the novel role of eIF4G1 on glucose homeostasis and modulation of β cell size.

Disclosure
S. Jo: None. A.D. Lockridge: None. E. Alejandro: None.
Towards Generating Spatiotemporal Multiscale Models of Human Pancreatic Beta Cells
Authors: WHITE KATE L. , MCCLARY KYLE , SINGLA JITIN , STEVENS RAYMOND C. 
Published: June 2018

Diabetes is a worldwide problem affecting hundreds of millions of people with increasing patient numbers every year. Our goal is to assemble a spatiotemporal, multi-scale (atomic to cellular) model of a human pancreatic β-cell to gain a more holistic understanding of β-cell function in diabetes. This effort requires the convergence of structural biology, electron microscopy, X-ray tomography, -omics, live cell imaging, computational and integrative modeling, systems biology, and digital arts. To best integrate these approaches, we formed a consortium of leaders in each field to help collect the necessary data for assembling such a model. As a first step, we have characterized the cellular ultrastructure and generated a consensus of the components of a cell (proteins, nucleic acids, metabolites, lipids, etc.). Two important aspects of this project are developing new tools for data integration and improving communication between collaborators in distant fields. To achieve this goal, we are collaborating with the USC School of Cinematic Arts to generate a virtual reality experience of a β-cell that serves as a new type of tool that can toggle between experimental techniques and scales. This immersive model will allow researchers, students, and the public to explore the rich biochemical world of a β-cell. Together, these models will represent a sophisticated convergence of our understanding of cellular structure and function, revolutionize biological discovery, open new dimensions of research, and accelerate advancements in healthcare.

Disclosure
K.L. White: None. K. McClary: None. J. Singla: None. R.C. Stevens: None.
Does Continuous Glucose Monitoring (CGM) Restore Hypoglycemia Awareness in Patients with Type 1 Diabetes (T1D) Who Previously Had Impaired Awareness of Hypoglycemia (IAH)?
Authors: ZEKARIAS KIDMEALEM , MOHEET AMIR , KUMAR ANJALI , SEAQUIST ELIZABETH R. 
Published: June 2018

IAH occurs in up to 1/3 of adults with T1D and it increases the risk of severe hypoglycemia (SH).Studies demonstrate that using CGM reduces the time spent in hypoglycemia (HG), but the effect of CGM on reversing IAH is not clear. We have enrolled many study subjects with T1D and IAH over the years and recently contacted them to determine how many continue to have IAH, how many have used CGM, and if there is a correlation between CGM use and restoration of HG awareness.
Thirty six with T1D and IAH according to the Clarke/Cox questionnaire (CC) administered 2009-2015 were contacted to complete an online survey that included the CC, the Gold questionnaire, and questions about their diabetes. 12 M, 11 F responded. One had an islet cell transplant and was excluded. Median duration was 36 ± 12 years, mean age was 50 ± 12 years and the median HgB A1C was 6.8 ± 1%.
Persistent IAH defined by both questionnaires was typical. Nineteen of 22 classified as IAH on the current survey reported severe HG over the last 6 mo. While there was a trend that showed consistent use of CGM was higher among people with no episodes of severe HG over the last 6 months this was not statistically significant.
These observations show that persistent IAH is common in T1D. While the consistent use of CGM among our participants was high it did not translate into restoration of HG awareness in this population.
Consistent use of CGM defined as more than 75% of the time over the last six monthsNo consistent use of CGMParticipants with persistent IAH (n = 18/22 using Gold)126Participants with persistent IAH (n = 19/22 using Cox)137Participants without persistent IAH (n= 4/22 using Gold)22Participants without persistent IAH (n= 3/22 using Cox)12Participants with severe HG in 6 months before survey (n = 19/22)118Participants without severe HG in 6 months before survey (n = 3/22)21

Disclosure
K. Zekarias: None. A. Moheet: None. A. Kumar: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..
Effects of Hypoglycemia Unawareness on Exercise Management
Authors: COSSEN KRISTINA , PATTERSON BRIANA , MUIR ANDREW 
Published: June 2018

Objective: Recent guidelines for management of T1D with exercise prompted us to determine if exercise management differs in T1D patients &lt;15 yo with high or low hypoglycemia (hypo) awareness.
Methods: 229 subjects or caretakers in a single academic practice completed a modified T1D Exchange questionnaire, describing hypo awareness and exercise management (changes of carbohydrate (carb) intake and insulin doses). Hypo awareness was self-scored on a 5-point scale. Hypo awareness was defined as high (always/often) or low (never/rarely) (n=167). Patients had to exercise at least 1 day/week (mean 4.9) (n=158). Changes to carb intake for exercise were scored on a Never-to-Always 5-point scale. Insulin changes for exercise were scored on a yes/no scale. Because of differences in hypo awareness (p=0.0002), patients were divided into ages &lt;8 year olds (yo) (n=35) and 8-14 yo (n=123). Fisher exact or Student t-test was applied.
Results: Between high and low hypo awareness groups, no significant differences were seen within each age category for: age at diagnosis, duration of T1D, insulin administration method, daily insulin dose, HbA1C, glucose meter checks/day, glucose checks &lt;70mg/dL, and mean blood glucose. Children &lt;8 yo were more likely to wear continuous glucose monitors (CGM) than 8-14 yo (34% vs. 24%; p=0.0002). Across all ages, hypo awareness was not associated with differences with insulin management (p=0.43) or carb use (p=0.18) before or during exercise. Increased CGM use was observed in low hypo awareness (48%) compared to high hypo awareness children (21%) (p=0.005), particularly among children &lt;8 yo (57% vs. 19%; p=0.03) vs. 8-14 yo (40% vs. 21%; p=0.2).
Discussion: Increased CGM use was observed among patients &lt;8 yo with low hypo awareness. Nonetheless, hypo awareness did not relate to adjustments of carb intake or insulin dose for exercise. This presents an educational opportunity to improve exercise-induced blood glucose fluctuation.

Disclosure
K. Cossen: None. B. Patterson: None. A. Muir: None.