bluuebunny/crossref_metadata_2025_split huggingface dataset:
2121-P: nAChR Signaling Protects ß Cells from Apoptosis Induced by ER Stress and Specific Activation of IRE1α in INS1 Cells
Authors: ISHIBASHI TATSUYA , MORITA SHUHEI , DOI ASAKO , IWAKURA HIROSHI , ARIYASU HIROYUKI , NISHI MASAHIRO , FURUTA HIROTO , AKAMIZU TAKASHI 
Published: June 2019

Background: We previously showed that nAChR signaling regulates activation of IRE1α and markers of terminal-unfolded protein response (T-UPR) under endoplasmic reticulum stress (ERS) in β-cells. However, it is still unknown if nAChR signaling affects the apoptosis under ERS or specific activation of IRE1α in β-cells. We also previously reported that IRE1α specific inhibitor, KIRA-Kinase Inhibiting RNase Attenuator-, suppresses apoptosis induced by ERS in INS1 cells and β-cells in Akita mice, which suggest that IRE1α plays a critical role in ERS-induced apoptosis. The aim of this study is to determine if and how nAChR signaling regulates the apoptosis induced by ERS or specific activation of IRE1α in β-cells.
Methods: We investigated the role of nAChR signaling on IRE1α signaling under ERS inducers or doxycycline-inducible IRE1α-overexpression (OE) in INS-1 cells. Cells were treated with Nicotine as an agonist of nAChR, and Tunicamycin or Thapsigargin as ERS inducers. Activation of IRE1α was confirmed by XBP1 mRNA splicing and phosphorylation of IRE1α. That of T-UPR was determined by Insulin1/proinsulin and TXNIP mRNA and protein expression. Translocation of phosphatidylserine to the external cell surface was detected by flow cytometry with Annexin V-FITC staining. Activation of caspase-3 and -7, markers of activation of caspase cascade, was detected by the active caspase-3/-7 specific substrate.
Results: Nicotine reduced XBP1 mRNA splicing and phosphorylation of IRE1α induced by ERS. Nicotine reversed increase of TXNIP and decrease of Insulin1/proinsulin expressions induced by both ERS and IRE1α OE. Increased Annexin positive cells and caspase-3/7 activation by ERS were reduced by Nicotine. Finally, increased caspase-3/7 activation by IRE1α OE was reversed by Nicotine as well as KIRA.
Conclusion: nAChR signaling could regulate IRE1α signaling and protect β-cells from apoptosis induced by ERS and specific activation of IRE1α in INS1 cells.

Disclosure
T. Ishibashi: None. S. Morita: None. A. Doi: None. H. Iwakura: None. H. Ariyasu: None. M. Nishi: None. H. Furuta: None. T. Akamizu: None.
2124-P: The Tissue Plasminogen Activator (tPA)/Plasmin System Reduces Amyloid Formation by Cleaving Human Islet Amyloid Polypeptide (hIAPP)
Authors: ESSER NATHALIE , HOGAN MEGHAN F. , APLIN ALFRED , TEMPLIN ANDREW T. , EL-OSTA SAM , RALEIGH DANIEL , EDGAR JOHN S. , ZRAIKA SAKENEH , HULL REBECCA L. , KAHN STEVEN E. 
Published: June 2019

Type 2 diabetes is characterized by islet amyloid deposition, which is associated with β-cell loss. hIAPP is the unique peptide component of these deposits. We previously found that expression of tPA, the initiator of fibrinolysis, is upregulated in islets by amyloid formation in vitro. As plasmin, the proteolytic product of tPA activity, cleaves Aβ and attenuates amyloid deposition in Alzheimer’s disease, we hypothesized that the increase in islet tPA by amyloid deposition serves a protective function by generating plasmin to limit further accumulation of hIAPP. We therefore sought to determine whether the tPA/plasmin system reduces amyloid formation by hIAPP and, if so, what islet cell type produces tPA. Using a thioflavin T assay, we found 4 µM plasmin abrogated 20 µM hIAPP fibril formation by 91.6±0.9% (n=5; p&lt;0.01). To determine whether this could be by plasmin proteolysis of hIAPP, 20 µM hIAPP was incubated with 4 µM plasmin or buffer and then mass spectrometry was performed. After 10 minutes of incubation with plasmin, intact hIAPP was absent and expected cleavage products were present. As tPA is produced by macrophages and endothelial cells, we next determined whether tPA expression is increased by hIAPP in either or both of these cell types. In rat bone-marrow-derived macrophages treated for 24 h with 10 µM hIAPP, non-amyloidogenic 10 µM rat IAPP (rIAPP) or vehicle, tPA expression was increased only by hIAPP (4.2±1.0 vs. 1.5±0.6 vs. 1.0±0.5 fold, respectively; n=4; p&lt;0.05 for hIAPP vs. rIAPP and vehicle). In contrast, in primary rat islet endothelial cells, tPA expression was not increased by 20 µM hIAPP (0.7±0.3 vs. 1.0±0.4 fold; n=3; p=0.2 for hIAPP vs. vehicle).
In summary, plasmin rapidly degrades hIAPP, curbing its aggregation into amyloid. As tPA is expressed in macrophages, enhancing its activity or its production by islet macrophages may represent a novel strategy to generate plasmin, cleave hIAPP and thus reduce islet amyloid formation and β-cell loss.

Disclosure
N. Esser: None. M.F. Hogan: None. A. Aplin: None. A.T. Templin: None. S. El-Osta: None. D. Raleigh: None. J.S. Edgar: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S.

Funding
U.S. Department of Veterans Affairs (BX001060); National Institutes of Health (GM078114); Belgian American Educational Foundation; Société Francophone du Diabète
2130-P: Imeglimin Modulated ER Stress to Prevent ß-Cell Apoptosis Induced by High Glucose or Thapsigargin
Authors: LI JINGHE , SHIRAKAWA JUN , TOGASHI YU , TERAUCHI YASUO 
Published: June 2019

Imeglimin, a tetrahydrotriazine anti-hyperglycemic agent, is thought to have effects on mitochondrial function of the liver, skeletal muscle, and pancreatic β-cells. However, the molecular mechanisms of imeglimin action have been still unclear. Treatment of mouse islets with 1.0 mM imeglimin significantly increased insulin release in response to glucose (2.1-fold, p&lt;0.01 at 11.1 mM glucose; 1.9-fold, p&lt;0.05 at 16.7 mM glucose, compared to 3.9 mM glucose). Treatment with a combination of liraglutide (100 nM) and imeglimin did not show an additional increase in insulin secretion compared to the treatment with liraglutide alone. Liraglutide and imeglimin significantly increased EdU-incorporated proliferating β-cells in the islets under 11.1 mM glucose (1.02% in vehicle control; 2.21% in liraglutide, p&lt;0.01 vs. vehicle; 1.46% in 1.0 mM imeglimin, p&lt;0.01 vs. vehicle). Imeglimin prevented β-cell apoptosis induced by high glucose (32% of control in imeglimin, p&lt;0.01; 57% of control in liraglutide, p=0.068). We conducted gene expression microarray analysis of islets treated with imeglimin under high glucose and some ER stress-related gene expression were altered by imeglimin. Then, we examined the effects of imeglimin on ER stress-induced β-cell apoptosis in mouse islets. Imeglimin significantly reduced β-cell apoptosis induced by thapsigargin at 5.6 mM glucose (29% of thapsigargin, p&lt;0.01). Imeglimin further upregulated the expression of C/EBP homologous protein (CHOP) under thapsigargin treatment and tended to decrease phosphorylation of eIF2-α. We also confirmed that imeglimin improved β-cell apoptosis induced by high glucose or thapsigargin in human islets. Collectively, imeglimin prevented β-cell apoptosis induced by high glucose or thapsigargin, in addition to increase in insulin secretion and β-cell proliferation. Imeglimin seemed to regulate CHOP/GADD34-mediated dephosphorylation of eIF2-α to recover from translational inhibition.

Disclosure
J. Li: 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.
2133-P: Protein Kinase C Delta Mediates Cytokine-Induced Apoptosis in the Pancreatic Beta Cell
Authors: FARNSWORTH NIKKI L. , PISCOPIO ROBERT A. , BENNINGER RICHARD K. 
Published: June 2019

T1D is characterized by a loss of insulin-producing β-cells in pancreatic islets. The immune destruction of β-cells is partly mediated by high levels of Th1 cytokines. Previously we have shown that cytokines alter islet function via protein kinase C δ (PKCδ) dependent mechanisms. Previous studies have suggested a role for PKCδ in mediating β-cell death, however little is known about the pro-apoptotic role of PKCδ in T1D. I hypothesize that PKCδ mediates cytokine-induced β-cell apoptosis via translocation to the nucleus and cleavage into a constitutively active fragment.
To test this hypothesis, we utilized mice with an inducible β-cell specific knockout of PKCδ (PKCδ-βKO). Isolated WT and PKCδ-βKO islets were treated with 10ng/ml TNF-α, 5ng/ml IL-1β, and 100ng/ml IFN-γ for 24h. Human islets were treated with 10μM of the PKCδ inhibitor δV1-1 for 24h with or without cytokines. PKCδ-βKO islets were virally transduced with GFP tagged PKCδ and incubated with or without cytokines for 3 or 24h. MIN6 cells were transfected with a FRET-based sensor for PKCδ and were incubated with or without cytokines.
Cytokine treatment increased β-cell apoptosis in mouse (p=0.003) and human islets (p=0.007). Isolated PKCδ-βKO islets showed significantly reduced cytokine-induced apoptosis compared to WT controls (p=0.003). Human islets treated with δV1-1 had reduced cytokine-induced apoptosis (p=0.020) compared to cytokine treatment alone. After 24h cytokine treatment PKCδ translocated to the nucleus (p=0.003) where it showed increased activity as measured by FRET, and an increase in a ~40kDa cleavage product of PKCδ as measured by western blot.
In conclusion, our results implicate a role for PKCδ in mediating cytokine-induced β-cell apoptosis via translocation to the nucleus and cleavage into a constitutively active fragment in both mouse and human islets. The role of PKCδ in mediating cytokine-induced death presents a novel β-cell specific mechanism which may be targeted for therapies to preserve β-cell mass in T1D.

Disclosure
N.L. Farnsworth: None. R.A. Piscopio: None. R.K. Benninger: None.

Funding
JDRF (5-CDA-2014-198-A-NJDRF, 3-APF-2019-749-A-N)
214-LB: Vibration-Controlled Transient Elastography Reveals Alarming Prevalence of Nonalcoholic Fatty Liver Disease and Fibrosis among Young Adults in Egypt
Authors: TOMAH SHAHEEN , MOHAMED EID ELSAYED , ABOUELMAGD MEGAHED MOH , HASSAN ATTIA H. , ELDIB AHMED H. , HAMDY OSAMA 
Published: June 2019

The spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. The rising prevalence of NAFLD in western societies has been paralleling the obesity epidemic, however, data on young adults in countries with high obesity rates like Egypt are lacking.
We evaluated 120 healthy Egyptian undergraduates (54.2% female, age range 19-22 years) using Controlled Attenuation Parameter (CAP) and Liver Stiffness Measurement (LSM) (Fibroscan®): Mean body weight was 73.3±18.1 kg, BMI 25.7±6 kg/m2, and A1C 5.1±0.24%. Variable steatosis stages were present in 47.5% of this cohort (15.8% mild, 19.2% moderate, and 12.5% severe), whereas 56.7% had fibrosis (48.35% mild, 8.35% moderate). We stratified subjects according to their BMI into 4 groups: Underweight (UW) with BMI&lt;20 kg/m2 (25.83%, mean CAP 202.65±29.1 dB/m, and LSM 5.2±1.2 kPa), Normal weight (NW) with BMI 20-24.9 kg/m2 (25%, mean CAP 204.8±27.9 dB/m, and LSM 4.65±1.1 kPa), Overweight (OW) with BMI 25-29.9 kg/m2 (23.33%, mean CAP 243.5±43.4 dB/m, and LSM 5.9±1.7 kPa), and Obese (OB) with BMI &gt;30 kg/m2 (25.83%, mean CAP 266.9±74 dB/m, and LSM 5.3±1.4 kPa).
Higher BMI values were significantly associated with higher CAP values (β=4.17, p&lt;0.0001). Severe steatosis was significantly higher in OB group compared to other groups (29% vs. 7.14% in OW and none in NW or UW, p&lt;0.0001). Moreover, CAP values were inversely associated with serum HDL-C (β=-1.42, p=0.001), and positively associated with serum triglycerides (TG) (β=0.33, p&lt;0.01).
In conclusion, prevalence of NAFLD among Egyptian young adults is alarmingly high with 50%&lt; having mild or moderate fibrosis. Obesity, high serum TG and low serum HDL-C are strong predictors of severe steatosis which warrants an urgent need for intervention programs aimed at reducing body weight and improving lipid profile in this population.

Disclosure
S. Tomah: Stock/Shareholder; Self; Amarin Corporation. E.M. Eid: None. M.M. Abouelmagd: None. A.H. Hassan: None. A.H. Eldib: None. O. Hamdy: Advisory Panel; Self; AstraZeneca, Sanofi-Aventis. Consultant; Self; Abbott, Merck & Co., Inc. Research Support; Self; National Dairy Council. Stock/Shareholder; Self; Healthimation, LLC.
2146-P: Offspring Exposed to Maternal High-Fat Diet Exhibits Decreased REG3G, Pancreatic Islet Dysfunction, and Systemic Inflammation
Authors: CASASNOVAS JOSE , PINEROS ALVAREZ ANNIE ROCIO , JARRELL JAMES C. , KUA KOK LIM 
Published: June 2019

Offspring exposed to in-utero overnutritive state, such as hyperglycemia and hyperlipidemia, are more likely to develop altered immune response and pancreatic islet dysfunction. Recently, we reported that fetal rats exposed to in-utero hyperglycemia had decreased fetal β-cell REG3G, and then developed lower β-cell mass and insulin secretion at adulthood. We hypothesize that exposure to maternal high fat diet not only suppresses offspring β-cell REG3G, but also increases inflammation thereby instigating offspring islet dysfunction. Female mice were fed 42% high fat diet (HFD) 4 weeks before pregnancy until weaning, and offspring were evaluated at different ages. P0 mice born to HFD mothers had lower pancreatic islet REG3G expression (n=3/group*). On postnatal day 21 (P21), HFD weanlings had impaired glucose [GTT AUC: male HFD 37± 3%* higher: 8-11/group; female HFD 22 ± 3%* higher: 3-9/group]. Glucose intolerance persisted in 8-week-old male from HFD mothers (n=5-9/group*), with decreased pancreatic islets glucose induced calcium response measured using Fura-2AM calcium imaging (F1/F0: Con:2.00 ± 0.06, HFD2w: 1.69±0.12*, HFD4w: 0.71±0.09*, n =3-6/group). Since members of the Reg3 subclass are reported to mediate macrophage polarization and chemotaxis in pancreatic cancer and heart, we assessed bone marrow derived macrophages response at P21 and at 8 weeks. Compared to controls, HFD P21 weanling had increased in M1 macrophages polarization, as well as an increase in macrophage IL-1b secretion when stimulated with LPS(3/group*). We also found that, at 8 weeks of age, HFD male offspring had increased activation markers of splenic dendritic cells (3/group*) indicating development of systemic inflammation early in life. Taken together, our findings suggest that mice offspring from HFD mothers have decreased REG3G expression early, followed by pancreatic dysfunction and a heightened inflammatory response. [*p&lt;0.05 when compared to control].

Disclosure
J. Casasnovas: None. A. Pineros Alvarez: None. J.C. Jarrell: None. K. Kua: None.

Funding
Riley Children's Foundation
2147-P: Pancreatic Specific Deletion of NOS1AP Lowered Islet Mass
Authors: WANG CHEN , MAO QIANYUN , LI QIAN , JIA WEIPING 
Published: June 2019

Objective: Nitric oxide synthase associated protein (NOS1AP) is an adaptor protein regulating neuronal functions through NMDAR/nNOS-dependent pathway. We previously reported that NOS1AP SNP rs12742393 was associated with type 2 diabetes. In the present study we aimed to investigate the effect of NOS1AP on beta-cell function.
Methods: Pancreatic specific deletion (CKO) of NOS1AP mice were generated from floxed nos1ap (exon 3-5) mice and pdx1-cre mice. These mice were fed with either chow or high fat diet (HFD,60% kcal fat).
Results: NOS1AP was highly expression in mouse islets. Deletion of NOS1AP in pancreas had no effect on food intake and body weight in mice either fed with chow and high fat diet. However, deletion of NOS1AP impaired glucose tolerance in HFD fed mice. The blood glucose levels at 15min and 30min were higher in CKO than in its littermate control mice. The AUC of IPGTT in CKO was 20% higher than that in control mice. Insulin levels in CKO mice were lower than that in control mice after glucose load (P&lt;0.05). Similarly, glucose stimulated insulin secretion from islets isolated from CKO was decreased compared with that from control mice. Moreover, islet mass in mice with pancreatic NOS1AP deletion decreased significantly (P&lt;0.05). BrdU staining showed that the BrdU positive cells in islets were lower in NOS1AP CKO mice than in control mice. Overexpression of NOS1AP protected beta-cells from high levels of glucose and FFA (palmitate)-induced cell death.
Conclusion: Our data demonstrate that NOS1AP plays a role in regulating beta-cell function and mass through regulation of cell proliferation and cytoprotection.

Disclosure
C. Wang: None. Q. Mao: None. Q. Li: None. W. Jia: None.

Funding
National Natural Science Foundation of China (81670707)
2151-P: Quantification of Tissue Structure in Human and Mouse Islets
Authors: CREASEY OLIVIA A. , ELNATAN DANIEL , SNEDDON JULIE B. , GARTNER ZEV J. 
Published: June 2019

The pancreatic islet is a complex tissue consisting of multiple endocrine cell types, capillaries, and a peri-islet basement membrane. The 3D organization of cells, blood vessels, and basement membrane (BM), enhances islet function by (1) supporting beta cell electrochemical coupling and synchronization through gap junctions between adjacent cells and (2) providing access to nutrients and integrin-mediated signals for beta cell survival and function through contact with capillaries and BM. Though a quantitative understanding of islet structure is lacking, there is strong evidence linking islet structural changes to diabetes progression. Studies of these changes in islet structure will enhance understanding of diabetes-related losses in islet function and lead to the development of new therapeutics for diabetic and prediabetic patients. Here, we present a novel method for quantitative analysis of islet structure in terms of local cell-cell and cell-BM interactions at endocrine cell plasma membrane surfaces. The number and surface area of individual cell-cell and cell-BM interfaces are measured from high-resolution 3D confocal images of human and mouse islets immunolabeled for endocrine cell markers, epithelial cell plasma membranes, and BM. These measurements quantify both cellular interconnectivity and access to signals supporting beta cell survival and function. We report a baseline quantification of structure for healthy adult human and mouse islets. These data both provide a definitive answer to the ongoing debate regarding the differences in structure between human and mouse islets and set the stage for future quantification of islet structure in diabetes.

Disclosure
O.A. Creasey: None. D. Elnatan: None. J.B. Sneddon: Advisory Panel; Spouse/Partner; Akouos. Advisory Panel; Self; Encellin. Advisory Panel; Spouse/Partner; Encellin. Consultant; Self; Semma Therapeutics, Inc. Z.J. Gartner: Stock/Shareholder; Self; Provenance, Scribe Biosciences.

Funding
National Institutes of Health; National Science Foundation Graduate Research Fellowship Program; National Science Foundation; University of California, San Francisco Center for Cellular Construction; University of California, San Francisco Diabetes Research Center
2157-P: Tyrosine Hydroxylase-Containing Cells in the Human Fetal Pancreas
Authors: KRIVOVA YULIYA , PROSHCHINA ALEXANDRA , OTLYGA DMITRY , LEONOVA OLGA , POPENKO VLADIMIR , BARABANOV VALERIY , SAVELIEV SERGEY 
Published: June 2019

Tyrosine hydroxylase (TH) - the specific marker of the catecholamine synthesizing cells, has been detected in the pancreatic endocrine, acinar and ductal cells in some mammals. In the developing mouse pancreas, TH+ cells are often contained glucagon and shared some features that are characteristics for differentiated endocrine cells. As it was shown in experimental studies on mice, a non-neural catecholaminergic pathway appears to modulate pancreatic endocrine precursor and insulin producing cell neogenesis. Our aim was to evaluate whether TH+ cells are present in the developing human pancreas. We have analyzed pancreatic autopsies from 34 human fetuses (10-37 gestational weeks (g.w.)) using double immunofluorescent labeling with antibodies to TH and either insulin or glucagon. Rare TH+ cells were found in the pancreas of all fetuses from 10th to 21th g.w., which were not detected later in development. At early stages (10-12 g.w.), such cells were located among the epithelial cells of primitive ducts, often in close proximity to the endocrine cell clusters, or were associated with the TH+ nerve bundles. In the pancreas of fetuses from 14th to 21th g.w., TH+ cells were observed in the nerve bundles, nerve ganglia and in the neuro-inular complexes type 1 (endocrine cells integrated with the neurons and nerve fibers). Some of the TH+ cells simultaneously contained glucagon. However, the majority of the TH+ cells were negative for insulin or glucagon. Thus, we first detected TH+ cells in the human fetal pancreas. These cells may be differentiating endocrine cells, because some of the TH+ cells were located in the ductal epithelium and rarely contained glucagon. Similarly with mice, non-neural catecholamines may be involved in the endocrine cells differentiation during human pancreas development.

Disclosure
Y. Krivova: None. A. Proshchina: None. D. Otlyga: None. O. Leonova: None. V. Popenko: None. V. Barabanov: None. S. Saveliev: None.

Funding
Russian Foundation for Basic Research (18-015-00146)
2158-P: GLIS3 Is Crucial for Maintenance of Neonatal ß Cells
Authors: KANG HONG SOON , SCOVILLE DAVID , JEON KILSOO , GRIMM SARA , JETTEN ANTON M. 
Published: June 2019

The Krüpple-like zinc finger transcription factor, GLI-similar 3 (GLIS3), is critical for pancreatic β cell development and insulin production. Mutations and single nucleotide variants in the GLIS3 gene have been linked to the development of neonatal diabetes and increased risk of type 1 and 2 diabetes. Early during postnatal development pancreatic β cells proliferate and mature; however, little is known about the role of GLIS3 during this stage of β cell development. In this study, we examined the role of GLIS3 on gene expression in β cells during early mouse postnatal development. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal GLIS3KO islets still contain a large population of β cells that express PDX1, NKX6.1, and ISL-1; however, neonatal insulin production and insulin-secretory granules were greatly reduced in INSlowPDX1+NKX6.1+ cells. Gene expression profiling by RNA-Seq with islets from WT and GLIS3KO mouse and identification of GLIS3 target genes by ChIP-Seq analysis showed that GLIS3 directly regulates the expression of a number of genes involved in β cell function and maturation, including Insulin1 and 2 (Ins1, Ins2), Solute Carrier Family 2 member 2 and 1(Slc2a2, Slc2a1), Activating Transcription Factor 4 and 6b (Atf4, Atf6b), and MAF BZIP Transcription Factor A (MafA), and as well as the expression of a number of metabolic genes. Our study indicates that GLIS3 plays a critical role in the maturation and maintenance of pancreatic β cells during early postnatal development by directly regulating genes with key β cell functions.

Disclosure
H. Kang: None. D. Scoville: None. K. Jeon: None. S. Grimm: None. A.M. Jetten: None.