bluuebunny/crossref_metadata_2025_split huggingface dataset:
2145-P: Notch1 Has Important Role in Beta-Cell Mass Determination and Development of Diabetes
Authors: EOM YOUNG SIL , KIM KWANG-WON , KIM BYUNG JOON 
Published: June 2019

Notch1 signaling is an important regulator of embryonic development and cell fate decision. Notch1 signaling is also expressed in adult pancreas but there is no study on the role of Notch1 in glucose homeostasis and islet mass in adult pancreas. Here, we investigated the role of Notch1 in glucose homeostasis and islet mass using Notch1 Antisense Transgenic (NAS) mice. We conducted an IPGTT and IPITT in 8-week-old male NAS mice and C57BL/6 mice (control mice). Insulin secretion capacity was measured by GSIS and perifusion. Morphology of pancreatic islet and β cell was conducted in two groups and transcription factors were evaluated. NAS mice showed higher glucose levels and lower insulin secretion in IPGTT. There was no significant difference in insulin resistance. Total islet and β cell masses were decreased in NAS mice. The number of large islets (≥ 250 μm) decreased while that of small islet (&lt; 250 μm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Our study provides that Notch1 inhibition decreased insulin secretion without any alterations in insulin resistance and decreased islet and β cell mass in the adult pancreas in NAS model. It is thought that Notch1 inhibition early suppresses islet proliferation and induces differentiation of not fully proliferated small islets.
In conclusion, the Notch signaling pathway may play an important role in beta cell mass and development of diabetes.

Disclosure
Y. Eom: None. K. Kim: None. B. Kim: None.

Funding
Korea Health Technology R&D Project (A101711, HI14C2539); Korean Ministry of Health, Welfare, and Family Affairs
215-LB: Diabetes and Obesity Are the Main Drivers of Increasing Chronic Liver Disease in the United States (U.S.) in the Past Three Decades
Authors: YOUNOSSI ZOBAIR M. , STEPANOVA MARIA , YOUNOSSI YOUSSEF , GOLABI PEGAH , MISHRA ALITA , RAFIQ NILA 
Published: June 2019

Background: Recently, the face of liver disease (LD) in the U.S. may be changing. The aim was to assess the prevalence of LDs in the U.S. over 3 decades.
Methods: Clinical data from NHANES were used to establish the diagnoses of chronic hepatitis C (CHC), B (CHB) alcoholic LD (ALD), and nonalcoholic fatty LD (NAFLD).
Results: 58,731 adults with LD were included. During the study, prevalence of CHB and ALD remained stable (0.3%-0.4% and 0.8%-1.0%, trend p&gt;0.05); while the prevalence of CHC decreased nearly 2 fold [from 1.6% to 0.9% (p=0.03)]. In contrast, prevalence of NAFLD increased from 20.0% to 28.3% to 33.2% (p&lt;0.0001). At the same time, increases were observed in the rates of obesity (22.2% to 31.0% to 38.9%) and type 2 diabetes (7.2% to 8.2% to 13.5% same years). Yearly trend analyses showed that the only liver disease with consistently increasing prevalence was NAFLD (Kendall tau=0.64, P=0.01). Multivariate regression analysis showed that after adjustment for age, gender, and ethnicity, obesity 10.4 (9.5-11.3), diabetes 3.7 (3.2-4.2), hypertension 2.3 (2.1-2.5) and hyperlipidemia 1.8 (1.6-2.1)) were the major independent predictors of NAFLD.
Conclusions: Over the past 30 years in the U.S., NAFLD is the only liver disease with increasing prevalence. The increasing prevalence of NAFLD is primarily driven by diabetes and obesity.

Disclosure
Z.M. Younossi: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S. Research Support; Self; Bristol-Myers Squibb Company. M. Stepanova: None. Y. Younossi: None. P. Golabi: None. A. Mishra: None. N. Rafiq: None.
2153-P: PDX1- and Nkx6.1-Immunonegative ß Cells in the Developing Human Pancreas
Authors: PROSHCHINA ALEXANDRA , KRIVOVA YULIYA , GUREVICH LARISA , OTLYGA DMITRY , SAVELIEV SERGEY 
Published: June 2019

Pancreatic endocrine and exocrine cells are of endodermal origin and differentiate during prenatal development from the epithelial cells of the primitive ducts. A specific program of transcription factor genes expression is subsequently activated and defines the fate of pancreatic progenitors. In our studies we have analyzed the distribution of two transcription factors - PDX1 and Nkx6.1 in the developing human pancreas. The study was performed on pancreatic samples from 22 fetuses (gestational age 10-40 weeks) using double and triple immunohistochemistry with antibodies to Pdx1, Nkx6.1, insulin and glucagon. In the adult human pancreas, the maintenance of β-cell identity is associated with the presence of key transcription factors (in particular Pdx1 and Nkx6.1), and changes in their expression and/or localisation have been described in the islets of type 2 diabetic individuals. In agreement with the literature, we have shown that Pdx1 and Nkx6.1 are present in the fetal pancreas already at 10th g.w. In all investigated pancreatic samples, we have observed two types of β-cells: Pdx1-positive β-cells and population of β-cells with the Pdx1-immunonegative nuclei. The results of reactions with antibodies to Nkx6.1 were similar: β-cells with both Nkx6.1 -positive and negative nuclei were detected in the human fetal pancreas. It can be suggested, that Pdx1 and Nkx6.1 are transiently expressed in the differentiating β-cells, thereafter their expression decreases and further restores in the mature β-cells. On the other hand, differentiation of some β-cells may possibly occur without Pdx1 or Nkx6.1 expression. In addition, Pdx1-positive glucagon-containing cells were observed in the developing human pancreas. Moreover, in contrast to other researchers, we found rare glucagon-containing cells with Nkx6.1-positive nuclei. This activation of Pdx1 and Nkx6.1 possibly indicates a partial transformation of α-cells toward a β-cell phenotype (and vice-versa).

Disclosure
A. Proshchina: None. Y. Krivova: None. L. Gurevich: None. D. Otlyga: None. S. Saveliev: None.

Funding
Russian Foundation for Basic Research (18-015-00147)
2155-P: Peripheral Nervous System Innervation of the Developing Pancreas
Authors: LA O SEAN DE , BYRNES LAUREN , WONG DANIEL M. , KNOX SARAH , SNEDDON JULIE B. 
Published: June 2019

Pancreatic organogenesis is a complex, multistep process whereby multiple cell types must migrate, proliferate, and differentiate in a strict spatiotemporal manner to ultimately form the complete organ. Although pancreatic epithelial organogenesis is well characterized, the peripheral nervous system (PNS) innervating the organ is poorly understood. Although the PNS has been shown to be critical in the formation of other budding exocrine organs, and therefore likely plays a role in the formation of the pancreas, there is a dearth of information on innervation of this developing organ. To this end, our lab has taken advantage of an explant culture system and single-cell RNA-sequencing (scRNAseq) to characterize the nerves supplying the developing pancreas. Imaging of whole pancreata reveals that peripheral nerves develop in parallel with the pancreas, with intrapancreatic ganglia being present from early stages. Using scRNAseq analysis we have begun to decipher the timing of pancreatic PNS progenitor cell differentiation, and the potential signaling pathways guiding axonal growth and morphogenesis. Continued investigation of the mechanisms guiding innervation of the pancreas, deciphering how nerve-epithelial interactions are established and defining signaling pathways activated by the nerves will allow us to discover the role of the PNS in pancreatic morphogenesis, as well as mis-regulation during disease.

Disclosure
S. de la O: None. L. Byrnes: None. D.M. Wong: None. S. Knox: None. J.B. Sneddon: Advisory Panel; Spouse/Partner; Akouos. Advisory Panel; Self; Encellin. Advisory Panel; Spouse/Partner; Encellin. Consultant; Self; Semma Therapeutics, Inc.
216-LB: Risk Factors of Pancreatic Cancer in Persons with Advancing Diabetes
Authors: JEON CHRISTIE Y. , GOODARZI MARK O. , LIN YU-CHEN , KIM SUNGJIN , MOIN TANNAZ , PISEGNA JOSEPH R. 
Published: June 2019

Background: People with new-onset diabetes face higher risk of pancreatic cancer (PC). However, data on PC risk in people with more advanced stages of diabetes are lacking. We aimed to identify factors associated with PC among people with progressing diabetes.
Methods: We conducted a retrospective cohort study on veterans aged ≥50, who were treated with either combination oral hypoglycemic therapy (n=578,543) or insulin (n=609,687) at the VA in 2000-2016. Incident PC was determined through the electronic health records and cancer registries. We examined the association of multiple risk factors with PC using Cox regression analyses.
Results: In both people initiating combination therapy and in those initiating insulin, increasing age, male sex, non-Hispanic ancestry, current smoking, acute and chronic pancreatitis, abdominal pain, alcoholism, increase in A1c, and decrease in weight were associated with increased risk of PC (Table). Based on the multivariable model, we can identify sub-populations with ≥5% risk of PC, such as ≥75 year-old non-Hispanic white males initiating insulin who have a history of alcoholism, and who show ≥2% increase in A1c and ≥15% decrease in weight prior to insulin initiation.
Conclusion: We identified risk factors associated with PC among people initiating combination oral hypoglycemics or insulin, which may be useful for stratifying people who may benefit from screening for PC.

Disclosure
C.Y. Jeon: None. M.O. Goodarzi: None. Y. Lin: None. S. Kim: None. T. Moin: None. J.R. Pisegna: None.

Funding
National Cancer Institute (R21CA220073)
2160-P: Islet Aggregation around Early Duct Lesions in Human Donor Pancreas
Authors: CHIEN HUNG JEN , CHIANG TSAI-CHEN , PENG SHIH-JUNG , CHUNG MEI-HSIN , LEE CHIH-YUAN , TIEN YU-WEN , TANG SHIUE-CHENG 
Published: June 2019

Background: The link of pancreatic cancer to diabetes (type 3c) suggests that islets are influenced by the cancer lesion progression. However, at an early stage, i.e., when the pancreas appears to be normal, how the endocrine pancreas is affected by the initial duct lesion formation remains unclear. Aims. To apply panoramic 3-D histology to detect early duct lesions in human cadaveric donor pancreases and examine the peri-lesional islet environment.
Methods: Tissue clearing was applied to the freshly perfused donor pancreases (target) and cancer surgical biopsies (malignant control) for 3-D microscopy.
Results: Large-scale tissue scanning detects early duct lesions (PanIN 1A/B) in three donor pancreases (3/5; nondiabetic; age (yr)/BMI: 40/24, 53/28, and 51/20). High-definition 3-D fluorescence and 2-D transmitted-light and H&E images reveal: 1) peri-lesional islet aggregation, 2) epithelium-islet complex (e.g., intra-islet duct), 3) adipocyte association, 4) inflammation, 5) stromal activation, and 6) Ki-67+ ductal and stromal cells but not the β- or α-cells.
Conclusions: We systematically developed a 3-D/2-D integrative imaging approach to detect and characterize the islet microenvironment around early duct lesions. Our data indicate a proliferative setting, but the islet aggregation appears not to arise from β- or α-cell division; instead, it may be due to lobular atrophy and/or evolve from duct-to-islet differentiation.

Disclosure
H. Chien: None. T. Chiang: None. S. Peng: None. M. Chung: None. C. Lee: None. Y. Tien: None. S. Tang: None.
2161-P: Overexpression of UCP2 in Pancreatic Beta Cells Caused Impaired Insulin Secretion through Mitochondrial Dysfunction and Aldolase B Expression
Authors: INOUE RYOTA , SHIRAKAWA JUN , TOGASHI YU , TERAUCHI YASUO 
Published: June 2019

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of the increase in UCP2 expression remained unclear. In this study, we investigated the regulatory mechanisms of UCP2 expression and its effects on β-cell functions. The mRNA expression of UCP2 in mouse islets was upregulated by the treatment with glucose, glucokinase activator, or insulin (p&lt;0.05), while metformin downregulated it (p&lt;0.01). Islets from db/db mice and insulin receptor substrate-2 knockout (IRS-2KO) mice showed the increment in the UCP2 expression. Transgenic mouse with specific UCP2 overexpression in β-cells (βUCP2Tg) demonstrated impaired glucose tolerance due to reduced insulin secretion. Adenoviral expression of UCP2 in MIN6-M9 β-cell line also attenuated glucose-induced insulin secretion. The ATP production in response to glucose and mitochondrial Complex I protein level were reduced (p&lt;0.01) in βUCP2Tg islets. Dilatation (1.8-fold, p&lt;0.05) and morphological alteration of mitochondria were observed in βUCP2Tg β-cells. Gene expression microarray analysis revealed 18 upregulated genes (1.5-fold, p&lt;0.05) and 2 downregulated genes (&lt;67%, p&lt;0.05) in βUCP2Tg islets. The most upregulated mRNA by UCP2 expression encoded the aldolase B (Aldob) (77-fold), whose expression was reported to be negatively associated with insulin secretion in human islets (J Clin Endocrinol Metab. 103(12):4373-4383, 2018). We validated increased Aldob expression in islets from βUCP2Tg mice, db/db mice, and IRS-2KO mice. Taken together, UCP2 expression seemed to be increased under T2DM conditions including hyperglycemia or hyperinsulinemia. Our data also suggested that the increase in UCP2 expression in T2DM β-cells cell-autonomously attenuated glucose-induced insulin secretion, possibly via mitochondrial abnormality and Aldob expression.

Disclosure
R. Inoue: None. J. Shirakawa: None. Y. Togashi: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
2163-P: Characterizing Peptide Hormone and Metabolite Variability in Individual Islets and Individual Cells of the Human Islets via Mass Spectrometry
Authors: SWEEDLER JONATHAN V. 
Published: June 2019

Chemical profiles and heterogeneity of islets may contribute to diabetes, but this chemical heterogeneity has been difficult to study. While significant progress has been achieved in uncovering of transcriptional diversity of cells composing pancreatic islets, the direct measurement of the hormones and metabolites has been difficult. We have created new approaches using direct matrix assisted laser desorption/ionization mass spectrometry (MALDI MS) to investigate the metabolite, and peptide contents of human pancreatic islets and of populations of individual islet cells. As illustrated in Figure 1, we observe multiple molecular features in the m/z 20-7000 mass range, including expected peptide hormones, lipids and transmitters. The specific peptide profiles vary cell to cell. Besides the expected peptide hormones, we also observe rarer peptides such as apelin and spexin. We also characterize unusual peptide profiles from rare cells that remain to be characterized. We observe five major cell types including a group of cells that appear only to contain thymosin beta four. We are extending our measurements to important molecules such as dopamine and d-serine. We are in the process of determining how the peptide hormones and metabolites co-localize, and are exploring how the molecular portraits change during disease progression.

Disclosure
J.V. Sweedler: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-19)
2169-P: A Gene Expression Network Analysis of the Pancreatic Islets from Lean and Obese Mice Identifies Complement 1q-Like-3 Secreted Protein as a Regulator of Beta-Cell Function
Authors: KOLTES JAMES , ARORA ITIKA , GUPTA RAJESH , NGUYEN DAN C. , BHATNAGAR SUSHANT 
Published: June 2019

Secreted proteins are important metabolic regulators that function in healthy and disease states. Our objective was to identify those secreted proteins that are important regulators of pancreatic islet function in obesity. To facilitate this, we used Weighted Gene Co-Expression Network Analysis-based approach on the expression data that was obtained from the pancreatic islets of lean and obese mice to identify gene modules that enriched with obesity. Subsequently, filtering the data for transcripts expressing secreted protein based on the intramodular connectivity, module membership, and differential expression identified complement-1q-like-3 (C1ql3) secreted protein as a top candidate to affect islet function. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified C1ql3 to affect ‘secretory processes’ in islets. Biological validation showed that C1ql3 is expressed in human and mouse islets, and inhibits insulin secretion from pancreatic β-cells. Its expression in islets is increased by &gt;32-fold with obesity. Moreover, C1ql3 in the islet β-cells specifically reduced the expression of genes that are critical for regulating insulin secretion. These findings demonstrate a streamlined approach to screen for the putative novel secreted protein regulators that function in an autocrine/paracrine manner to affect islet function in obesity. Herein, we have identified a critical role of C1ql3 in β-cells and propose that the increased secretion of C1ql3 from islets during obesity contributes to the reduced β-cell function in a paracrine/autocrine-dependent pathway to increase the susceptibility to type 2 diabetes.

Disclosure
J. Koltes: None. I. Arora: None. R. Gupta: None. D.C. Nguyen: None. S. Bhatnagar: None.

Funding
American Diabetes Association (1-18-PDF-103 to R.G.)
2174-P: FBW7 Regulates Beta-Cell Dedifferentiation
Authors: XU JING , LI XIAOMU 
Published: June 2019

Tumor suppressor F-box and WD repeat domain-containing 7 (FBW7), an E3 ubiquitin-ligase, also plays important roles in the regulation of metabolism. However, the contribution of FBW7 on β-cells remains largely unknown. Our study indicated that the expression of FBW7 in pancreatic β-cells was significantly higher than that in exocrine cells. The expression of FBW7 in β- cells from high-fat diet (HFD) fed mice significantly decreased than chow diet fed mice. Similarly, the expression of FBW7 in β-cells from db/db mice were also decreased. The reduced expression of FBW7 in β-cells from these animal models accompanied with the elevated expression of dedifferentiation marker ALDH1A3. In vitro study suggested that overexpression of FBW7 suppressed expression of ALDH1A3 protein levels, but not mRNA levels, in MIN6 β-cells. We also found that FBW7 regulated ALDH1A3 stability by promoting its ubiquitination and degradation. Bioinformatic analysis revealed the conserved sequence in ALDH1A3 protein as the potential FBW7 substrates. Together, our study suggested that FBW7 may play important role in the regulation of β-cell dedifferentiation via its novel substrate ALDH1A3.

Disclosure
J. Xu: None. X. Li: None.
2178-P: Beta-Cell Gene Expression Pattern in Food Restricted db/db Mice and Moderate Dedifferentiation Status in ob/ob Islets
Authors: LEI XIAO , ISHIDA EMI , YAMADA EIJIRO , OKADA SHUICHI , YAMADA MASANOBU 
Published: June 2019

In clinical, the 'fatigue' of beta cells is a famous phenomenon from way back. Nowadays, researchers describe how glucolipotoxicity, endoplasmic reticulum (ER) stress and oxidative stress impair beta cell function. In 2012, Talchai et al. revealed the novel machinery of beta cell dysfunction in diabetes - dedifferentiation. It's a gradual process along with the progressive feature of diabetes, and in several reports, it's proven to be preventable by existing diabetic treatment. Previously, we showed that each diabetic treatment had a different effect on beta cell dedifferentiation. For instance, food restriction had more manifold good effects to restore beta cell gene expression than SGLT inhibitor. In the current study, we aimed to unveil the molecular mechanism of beta cell dedifferentiation. First, we investigated the microarray analysis of islet RNAs in food-restricted db/db mice. Compared to the control db/db, the islets of food-restricted group had higher expressions of genes related to matured beta cell markers and ER maintenance. On the other hand, Gene expressions related to cell stress, cell growth and cell division were lowered by calorie restriction. To understand more about the relationship between beta cell dedifferentiation and ER stress, we utilized the other obese mice model, ob/ob, which is known to have more moderate hyperglycemia than db/db. The other study group demonstrated that ER and oxidative stress markers were maintained in ob/ob islets than that in db/db (Chan, Diabetes 2013). We found that beta cell dedifferentiation markers, such as Aldh1a3 and Sox9, were also lowered in ob/ob. But it's still unknown, whether the dedifferentiated beta cells are feeble against the ER and oxidative stress, or, these stress triggers the beta cell dedifferentiation.

Disclosure
X. Lei: None. E. Ishida: None. E. Yamada: None. S. Okada: None. M. Yamada: None.
2194-P: Il-6/Stat3 Pathway Contribute to the Islet Failure in High-Fat Diet-Induced Mouse Model of Obesity
Authors: JIANG ZONGZHE , TENG FANGYUAN , XU YONG 
Published: June 2019

Objective: This study was aimed at revealing a new mechanism mediated by IL-6/Stat3 signaling pathway on islet failure in high fat diet-induced obesity through activation of inflammation.
Methods: We produced mice with non-obesity, moderate obesity and severe obesity respectively by feeding with normal diet (control), three months’ high fat diet (HFD-3M) and six months’ high fat diet (HFD-6M). Then 200 islets were isolated from the three groups and lysed for RNA extraction, following RNA-Seq analysis with MAPS (Multiplex Analysis of PolyA-linked Sequences) approach. Normal islets were cultured in vitro for IL-6 stimulation and mice with stat3 specific deletion in islet were used to prevent HFD-resulted islet failure.
Results: Mice with HFD for three months and six months show significantly higher fast glucose and severe glucose intolerance than control and the morphology of islets from HFD group was obviously abnormal. Additionally, these diabetic symptoms were aggravated in pace with HFD feeding. Further analysis of RNA-seq shows that the expressions of hormones secreted by different endocrine cells were all down-regulated, including INS1, GCG, SST and PPY. On the other hand, expression of IL-6/Stat3 pathway related genes were significantly elevated, including IL-6, CCL2, CCL5, CCL11, CCL28, Tnfrsf11 and NF-kB. Stat3 in islets from HFD-3M and HFD-6M group was also activated by phosphorylation of Y705. Cultured islets with IL-6 treatment show impaired insulin secretion and increased inflammation level. Notably, mice with stat3 specific deletion in islet were able to attenuate the HFD-induced increase of inflammation and secretory deficiency of islet.
Conclusions: HFD-induced obesity resulted in islet failure and the high level of serum IL-6 participate in the obesity induced islet failure through IL-6/Stat3 pathway mediated inflammation.

Disclosure
Z. Jiang: None. F. Teng: None. Y. Xu: None.

Funding
National Natural Science Foundation of China (81600597)