bluuebunny/crossref_metadata_2025 huggingface dataset:
2113-P: Metabolic Effects of Bariatric Surgery in a Group of Patients Aged 65 Years Old or More Compared with a Group of Adults Younger Than 65 Years Old—A Prospective Cohort
Authors: MUSSO CARLA , FERMO GOMEZ FERNANDO AGUSTIN DI , ROSENFARB JOHANNA , BOSIO LUCILA , SANTAMARIA JIMENA , HANSEN MARTIN , GIMENEZ CRISTINA , ERRASTI ANA G. , CARUSO DIEGO , FAINGOLD MARIA CRISTINA
Published: June 2019

Aim: We compared the anthropometric and metabolic parameters before and after six months of bariatric surgery (BS) between a group of patients aged ≥65 and <65 years old (y/o) with or without comorbidities.

Materials and Methods: We did a prospective study with patients who had undergone BS and followed them for six months from July, 2015 to May, 2018 at Milstein hospital, Argentina and divided them into two cohorts: older and younger than 65 y/o. Outcomes were compared (lost weight [LW], excess weight loss percentage [EWLP], BMI, A1c hemoglobin [HbA1c], HDL, Triglycerides [Tg] and Tg/HDL ratio) and we considered a p <0.05 as statistically significant.

Results: We included 36 patients, 15 were ≥65 y/o and 21 <65 y/o. There were more patients with type 2 diabetes mellitus (DM2) in the oldest group. We found no statistical difference between groups in WL and the EWLP but observed a statistical rise in the levels of HDL (43, RIQ 95% CI: 39-48 vs. 51, RIQ 95% CI: 44-55, p=0.026) and the decrease of the Tg/HDL ratio (1.6 RIQ 95% CI: 1.4-2.1 vs. 3.1 RIQ 95% CI: 2.2-4.6, p=0.02) in the group of ≥65 y/o. The HbA1c levels were significantly higher in the > 65 y/o with DM2 and the decrease was statistically greater after the follow-up. When we compared initial treatment for DM2 after 3 and 6 months of BS, there was a statistically significant decrease in the use of oral antidiabetic drugs and insulin (chi2= 19%, p=0.004 at 3 months, chi2: 27%, p<0.001 at 6 months after surgery). If we analyzed this result by age, there was no difference between both cohorts (chi2=3.73, p=0.15 and chi2=1.46, p=0.4 at 3 and 6 months after surgery respectively).

Conclusion: We found a significant benefit in metabolic effects of BS in the ≥65 y/o cohort, especially by decreasing insulin resistance, even in those patients without diagnosis of DM2. We need more studies and a greater sample size to generalize these results.

Disclosure

C. Musso: None. F.A. Di Fermo Gomez: None. J. Rosenfarb: None. L. Bosio: None. J. Santamaria: None. M. Hansen: None. C. Gimenez: None. A.G. Errasti: None. D. Caruso: Other Relationship; Self; Novartis Pharmaceuticals Corporation. M.C. Faingold: None.
2116-P: A Pipeline to Explore Rare Variation Which Can Contribute to Extreme Obesity in American Indians
Authors: ALTOK CIGDEM KOROGLU , PIAGGI PAOLO , TRAURIG MICHAEL , HANSON ROBERT L. , KNOWLER WILLIAM C. , KIM HYE IN , GOSALIA NEHAL , VAN HOUT CRISTOPHER V. , YE BIN , CENTER REGENERON GENETICS , SHULDINER ALAN R. , BOGARDUS CLIFTON , BAIER LESLIE J.
Published: June 2019

Identification of high-impact loss-of-function variants for common disease is challenging because these variants are typically rare and thus statistical power is low when sample sizes are limited. In this study, we utilized whole-exome variant detection, variant prediction programs, tissue expression data, and case-control analysis to identify potentially highly penetrant obesity-susceptibility variants for prioritization for functional testing. Whole-exome sequencing was performed on DNA samples collected from a longitudinal, population-based study of American Indians (N=5432; maximum BMI recorded at ≥18 years). Among the 1 million biallelic SNVs detected in this cohort, those that were exonic or splicing, have minor allele frequency (MAF) ≤0.05, predicted to be damaging (CADD score ≥15), and located in genes expressed in hypothalamus were selected for analysis. These selection criteria resulted in 94,444 SNVs, and odds ratios were calculated for them by comparing the group of individuals with BMI in the top 5th percentile for this population (N=271, BMI ≥53.13 kg/m2) vs. those below the median (N=2,717, BMI <35.92 kg/m2). The resulting 19,382 variants with positive OR values were then divided into 4 bins based on MAFs, and those with a OR in the top 1% of the distribution of each bin were prioritized. In the resulting list of 291variants in 266 different genes, a missense variant p.I330V (rs201597085; OR=2.66; CADD=20.3; MAF=0.02) in GNAS was the best candidate, since GNAS was the only gene linked to obesity in humans. GNAS is a highly complex imprinted locus, and the main transcript derived from this locus (Gs-alpha) encodes the alpha subunit of the stimulatory guanine nucleotide-binding protein. The XLas isoform, a large variant of Gs-alpha, is paternally expressed. An association analysis with accountance for parental origin of the alleles is ongoing. Future functional studies would entail examining the effects of this missense variant on G protein-coupled receptor signaling.

Disclosure

C. Koroglu Altok: None. P. Piaggi: None. M. Traurig: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. N. Gosalia: Employee; Self; Regeneron Pharmaceuticals. C.V. Van Hout: Employee; Self; Regeneron Pharmaceuticals. B. Ye: Employee; Self; Regeneron Pharmaceuticals. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. C. Bogardus: None. L.J. Baier: None.

Funding

National Institutes of Health
212-OR: Factors Associated with Decline of C-Peptide in a Cohort of Young Children Diagnosed with Type 1 Diabetes
Authors: STECK ANDREA , LIU XIANG , KRISCHER JEFFREY , HALLER MICHAEL J. , VEIJOLA RIITTA , AKOLKAR BEENA , TOPPARI JORMA , HAGOPIAN WILLIAM , REWERS MARIAN , ELDING LARSSON HELENA
Published: June 2019

Preservation of C-peptide after diagnosis of type 1 diabetes (T1D) is associated with lower risk of both hypoglycemia and long-term microvascular complications. The decline of C-peptide after T1D onset is highly variable among subjects. The goal of this study was to evaluate factors associated with the rate of C-peptide decline. TEDDY participants identified at birth with high-risk HLA genotype and followed regularly until T1D diagnosis (n=70) and 60 age-matched children diagnosed with T1D in the community (median age at diagnosis = 6.7 years, IQR 5.1-7.9) were enrolled in a 2-year follow-up with mixed meal tolerance tests at 1, 3, 6, 12 and 24 months. Mixed effects models for repeated measures were used adjusting for age at diagnosis and C-peptide at baseline. In univariate analyses, factors associated with rate of C-peptide loss included sex, age at diagnosis, baseline BMI, AUC C-peptide, HbA1c, IA-2A positivity and ZnT8A positivity. Four of these 7 factors remained significant in multivariate analysis (all p ≤ 0.037, see Table). Younger age at diagnosis, higher HbA1c, IA-2A positivity and ZnT8A positivity were associated with higher rate of C-peptide decline in this young cohort of children diagnosed with T1D.

Disclosure

A. Steck: None. X. Liu: None. J. Krischer: None. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. R. Veijola: None. B. Akolkar: None. J. Toppari: None. W. Hagopian: Research Support; Self; Novo Nordisk A/S. M. Rewers: None. H. Elding Larsson: None.

Funding

JDRF; National Institutes of Health
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<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<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<0.01 at 11.1 mM glucose; 1.9-fold, p<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<0.01 vs. vehicle; 1.46% in 1.0 mM imeglimin, p<0.01 vs. vehicle). Imeglimin prevented β-cell apoptosis induced by high glucose (32% of control in imeglimin, p<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<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<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 >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<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<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<0.01).

In conclusion, prevalence of NAFLD among Egyptian young adults is alarmingly high with 50%< 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<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<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<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.
2168-P: A Novel Method for Efficient and Homogeneous Viral Transduction of Pancreatic Islets
Authors: YESILDAG BURCAK , MIR-COLL JOAN , NEELAKANDHAN APARNA , FORSCHLER FELIX , BIERNATH ADELINN , LEIBIGER INGO B. , LEIBIGER BARBARA , BERGGREN PER-OLOF , MOEDE TILO , AMMALA CARINA
Published: June 2019

Modification of gene expression in pancreatic islets can be a powerful strategy for understanding the pathology of diabetes and developing novel therapeutic strategies against it. However, amenability of the isolated islets to genetic manipulation has been limited to only a subset of cells at the periphery due to poor penetration of transduction particles. To address this issue, we developed a standardized islet model, produced by optimized dissociation and controlled scaffold-free reaggregation of primary human islet cells. This process allowed for an ideal experimental window for accessing and manipulating the pancreatic endocrine cells at their single cell state, while enabling production of uniform islet microtissues displaying long-term (>28 days) and robust function. We used an adenovirus that allows tracking of transduced total cells, endocrine cells and beta cells by labeling them with three specific fluorescent reporters expressed from a single back-bone. To define the optimal transduction conditions, we introduced the virus at various titers during three different production stages; after islet dispersion, during and post reaggregation. We quantified transduction efficiency and viral penetration via 3D confocal microscopy followed by assessment of insulin secretory function, insulin content, and cell viability of transduced islet microtissues. Highly efficient (>75%) and uniform transduction was achieved when the virus was added after cell dispersion and during reaggregation. Approximately 80-95% of transduced cells were endocrine cells, of which 50-63% corresponded to β-cells. Although highly transduced islet microtissues displayed decreased chronic (35-50%), basal (55-62%) and stimulated (65-75%) insulin secretion, a significant fold induction of insulin secretion and unaltered insulin/ATP content was observed. Here we present efficient genetic manipulation of functional reaggregated islets by viral transduction as a novel tool for diabetes research.

Disclosure

B. Yesildag: None. J. Mir-Coll: Employee; Self; InSphero. Employee; Spouse/Partner; Roche Pharma. A. Neelakandhan: None. F. Forschler: Employee; Self; InSphero. A. Biernath: None. I.B. Leibiger: Consultant; Self; Biocrine AB. Consultant; Spouse/Partner; Biocrine AB. B. Leibiger: Consultant; Self; Biocrine AB. Consultant; Spouse/Partner; Biocrine AB. P. Berggren: None. T. Moede: None. C. Ammala: None.
217-OR: Islet Transplantation vs. Standard of Care for Type 1 Diabetes Complicated by Severe Hypoglycemia from the Collaborative Islet Transplant Registry (CITR) and T1D Exchange (T1DX) Registry
Authors: RICKELS MICHAEL R. , FOSTER NICOLE C. , BALLOU CASSANDRA M. , HERING BERNHARD J. , ALEJANDRO RODOLFO , BECK ROY , MILLER KELLEE , BARTON FRANCA B.
Published: June 2019

Islet transplantation is an emerging treatment for T1D, in particular for those with long standing disease experiencing severe hypoglycemia events (SHE). A phase 3 trial of islet transplantation in T1D complicated by SHE demonstrated > 80% of islet recipients achieved HbA1c < 7.0% and absence of SHE at 1 year. To better understand the long-term benefit for glycemic control and risk of immunosuppression to kidney function associated with islet transplantation vs. standard of care, we selected patients from CITR with at least one SHE in the year prior to transplant, and compared them to patients from T1DX with at least one SHE in the prior year and followed over 5 years. The cohorts from CITR (n = 58) and T1DX (n = 213) were aged 42 ± 9 and 43 ± 17 with disease duration 29 ± 10 and 26 ± 15 years (P < 0.01) and experienced 5 ± 11 and 2 ± 1 SHE (P < 0.01) in the year prior to baseline with HbA1c 7.3 ± 1.0 vs. 7.8 ± 1.5 (P < 0.001). Mean HbA1c decreased to 6.3% vs. ranging 7.8-7.6% over 5 years (P < 0.001), and the % experiencing recurrent SHE was less in CITR than T1DX (P < 0.01), such that 78-77% vs. 23-28% met the primary endpoint of HbA1c < 7.0% and absence of SHE (P < 0.001). Insulin requirements were slightly less at baseline in CITR than T1DX (0.52 ± 0.14 vs. 0.64 ± 0.31 U/kg/d; P < 0.001), and decreased to 0.06-0.17 vs. remaining 0.66-0.56 U/kg/d over 5 years (P <0.001) with 80-48% insulin independent in CITR. GFR was 92 ± 17 and 90 ± 29 ml/min/1.73 m2 at baseline, and decreased to 83-78 vs. 87-81 ml/min/1.73 m2 over 5 years (P < 0.001). These data demonstrate long-term durability of islet transplantation to achieve near-normal glycemic control in the absence of SHE more often than that observed with standard of care delivered by specialized diabetes practice. Initial reduction in GFR observed during the first-year post-transplant may be attributable to the initiation of immunosuppression, but was not associated with further decline during 5 year follow-up.

Disclosure

M.R. Rickels: None. N.C. Foster: None. C.M. Ballou: None. B.J. Hering: Other Relationship; Self; Diabetes-Free, Inc. R. Alejandro: None. R. Beck: Other Relationship; Self; Abbott Laboratories, Ascensia Diabetes Care, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Lilly Diabetes, Roche Diabetes Care, Tandem Diabetes Care. K. Miller: None. F.B. Barton: None.

Funding

National Institutes of Health; Leona M. and Harry B. Helmsley Charitable Trust
2171-P: Excessive Drinking Impairs FGF-21/Beta-Klotho-Mediated Protective Effects against Islet Dysfunction and Apoptosis in Mouse Pancreatic Islets
Authors: YANG BAOCHEN , LEUNG POSING
Published: June 2019

Excessive alcohol consumption has negative effects on β-cell insulin secretion and survival, thus increasing the risks of type 2 diabetes mellitus (T2DM). Meanwhile, fibroblast growth factor 21 (FGF-21) is a potent metabolic regulator for lipid and glucose homeostasis. Recently, FGF-21 and its obligate co-receptor β-klotho (KLB) have been shown to inhibit alcohol ingestion and metabolism in mice and human, probably via the mediation of gastric emptying rate and initial alcohol metabolism. Despite this evidence, whether heavy alcohol intake modulates the expression and function of FGF-21 in mouse islets is still ambiguous. Therefore, this study aimed to investigate this issue using in vitro/ex vivo and in vivo cell/animal models. In ex vivo studies, islets isolated from of C57BL/6J mice were cultured and treated with 80 mM alcohol for 24 h, mimicking the excessive alcohol condition. In vivo studies, the mice were gavaged with 3 g/kg ethanol/respective saline up to 3 weeks. Ex vivo results showed that the expression of FGF-21 and KLB was upregulated, whereas its receptor FGFR1, FGFR2, FGFR3 and FGFR4 were downregulated. In addition, islet apoptosis was increased as demonstrated by ELISA kit. Moreover, the expression of bax and SIRT1 were also downregulated. In corroboration, in vivo studies showed that glucose homeostasis and islet function were impaired by excessive alcohol drinking as demonstrated by OGTT and GSIS results. Consistently, the expression profile of FGF-21/its receptors was similar to those observed in ex vivo condition. Meanwhile, the expression of islet function-related genes (insulin1/2, IRS, PDX1, GLUT2, etc.) was also downregulated in in vivo experiments. Our preliminary data indicate that excessive drinking may induce β-cell dysfunction and apoptosis through the inhibition of FGF-21/KLB expression, and that islet FGF-21 signaling is associated with alcohol homeostasis and T2DM.

Disclosure

B. Yang: None. P. Leung: None.

Funding

Research Grants Council of Hong Kong (CUHK14107415)
2179-P: Overexpression Screening Identifies Mitochondrial Carbonic Anhydrase 5b as an Important Regulator of Glucose-Stimulated Insulin Secretion in Beta Cells
Authors: KOSUDA MINAMI , YAMAGUCHI SUGURU , NAGASAWA AKIKO , YAMANA MIDORI , KOIKE MASAO , NISHIOKA HIDENORI , ISHIHARA HISAMITSU
Published: June 2019

Despite extensive research efforts, a precise picture of how glucose itself and its metabolites initiates insulin secretion in a concentration-dependent manner has unveiled. To identify candidate genes important for glucose-stimulated insulin secretion (GSIS), we have conducted screening of differentially expressed genes identified by microarray analyses between highly glucose-responsive and less responsive MIN6 subclones. For this purpose, a platform containing zeocin resistant gene flanked with a wild type and mutated flippase recognition target sites was integrated in the genome of MIN6 cells expressing Tet3G. The modified MIN6 cells have been used to generate stable transfectants expressing mRNA or shRNA of genes of interest by means of the recombinease-mediated cassette exchange method. Using this system, more than ten stable MIN6 cell transformants can be gnenerated at a time. By creating approximately 100 overexpressing transfectants, we have identified mitochondrial carbonic anhydrase 5b (Car5b) as an important regulator of GSIS. Car5b is a one of 15 members of carbonic anhydrases, which catalyze the interconversion of carbon dioxide and water to bicarbonate and protons, and modulate various intracellular processes, such as urea formation, HCO3- supply for carboxylation and regulation of intracellular acid-base balance. Car5b overexpression in MIN6 cells increased 14CO2 formation from H14CO3- (37 ± 14% increases, p < 0.05) in isolated mitochondria and resulted in 32 ± 12% increases (P < 0.05) in GSIS at 20 mM, while shCar5b expression reduced Car5b protein levels to 31.4 ± 4.4% (p < 0.05), 14CO2 formation to 68.7 ± 8.1% (p < 0.05), and GSIS at 20 mM to 77 ± 5% (p < 0.05). In addition, we found that Car5b expressions in ob/ob mice were 3.7 ± 0.4-fold higher (p < 0.01) and tended to be higher (p = 0.073) in HFD-mice. These data indicated that mitochondrial carbonic anhydrase Car5b plays a role in GSIS in pancreatic β-cells.

Disclosure

M. Kosuda: None. S. Yamaguchi: None. A. Nagasawa: None. M. Yamana: None. M. Koike: None. H. Nishioka: None. H. Ishihara: Research Support; Self; Daiichi Sankyo Company, Limited, Lilly Diabetes. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
2180-P: HERG2 Channel Plays a Key Role in Insulin Secretion
Authors: ZHAO MIAOMIAO , YANG JINKUI
Published: June 2019

Background: Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is mainly mediated by KATP channels. A problem commonly associated with drugs like the sulfonylureas, KATP channel inhibitor, is that KATP current inhibition is independent of the basal glucose levels and hypoglycemia is frequently observed. Nevertheless, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a voltage-gated K+ (Kv) channel, HERG2, plays a key role in insulin secretion.

Aims: To investigate the effects of HERG2 channel in β-cells.

Methods: Using TALEN-based method, we created Herg2 gene knock out (KO) mice. Patch-clamp experiments were performed to record Kv currents and action potential in primary cultured β-cells from wild type (WT) and KO mice. INS-1 cells, rat β-cell line, were transfected with shRNA of Herg2 gene or scramble shRNA to generated Herg2 transiently knock down (KD) or WT cells. Glucose-stimulated calcium levels were measured and GSIS experiments were performed in INS-1WT and INS-1KD cells.

Results: The Kv currents of β-cells from the KO mice decreased approximately 37.6% compared with that of the WT mice, indicating HERG2 channel constitutes 37.6% of all Kv currents. The action potential duration was significantly prolonged in KO β-cells, whereas the action potential magnitude and resting potential remained unchanged compared with WT β-cells. INS-1KD showed enhanced glucose-induced elevation of the intracellular Ca2+ concentrations, the most important ion that triggers insulin secretion in β-cell. Consistently, Herg2 knockdown significantly enhanced insulin secretion at a high glucose concentration, but did not potentiate insulin secretion at basal glucose concentration, suggesting the glucose-dependent insulin secretion of HERG2 channel.

Conclusions HERG2, as a non-KATP K+ channel, regulates the action potential duration of β-cells and plays a key role in insulin secretion. Inhibition of HERG2 currents leads to enhanced insulin secretion only in high glucose levels.

Disclosure

M. Zhao: None. J. Yang: None.
2181-P: Glucose-Induced Hyperphosphorylation of Microtubule-Associated Protein Tau Potentiates Islet Beta-Cell Insulin Secretion by Destabilizing the Microtubule Network
Authors: HO KUNG-HSIEN , GU GUOQIANG , KAVERINA IRINA
Published: June 2019

The microtubule (MT) cytoskeleton of pancreatic β cells is important for glucose-stimulated insulin secretion (GSIS). We have recently shown that the MT-mediated transportation of insulin vesicles away from the plasma membrane limits insulin secretion, and that the disassembly of MTs is necessary for robust GSIS. Here, we report that high glucose induces rapid MT disassembly at the cell periphery measured by real-time imaging of photoconverted MTs in islet β cells. The MT-associated protein Tau regulates this process. Tau is known to stabilize MTs by direct association, and Tau hyperphosphorylation leads to MT disassembly. Along this line, we found that high glucose induced Tau hyperphosphorylation and dissociation from MTs in mouse islet β cells. ShRNA-based Tau knockdown in islets directly destabilized MTs, eliminating the glucose responsiveness of the MT dynamics, increasing basal insulin secretion, and impairing GSIS. Moreover, we showed that the glucose-induced Tau hyperphosphorylation relied on kinase GSK3, which is likely regulated by the PI3K-Akt, but not insulin signaling. We propose that Tau stabilizes MTs in low glucose to restrict basal secretion. In high glucose, Tau is hyperphosphorylated by GSK3 to promote MT disassembly at cell periphery to facilitate the release of the secretable insulin pool.

Disclosure

K. Ho: Research Support; Self; Eli Lilly and Company. G. Gu: None. I. Kaverina: None.
2183-P: miR-125b Is Regulated by Glucose via AMPK and Impairs ß-Cell Function
Authors: CHEUNG REBECCA , PIZZA GRAZIA , ROLANDO DELPHINE M. , CHABOSSEAU PAULINE L. , NGUYEN-TU MARIE-SOPHIE , LECLERC ISABELLE , RUTTER GUY A. , MARTINEZ-SANCHEZ AIDA
Published: June 2019

miRNAs are tiny RNAs that repress gene expression post-transcriptionally, necessary for normal endocrine function. AMPK is essential for glucose homeostasis and a suggested target of metformin. β-cell-specific inactivation of AMPK in mice (AMPKdKO) impairs glucose homeostasis and β-cell function. AMPKdKO mice present dysregulation of several miRNAs that may contribute to these defects, including miR-125b (∼2.5 fold upregulated). High levels of miR-125b are associated with hyperglycaemia (HbA1c) in prediabetic, T2D and T1D subjects, suggesting miR-125b as a biomarker or contributor to the development of diabetes. The role of miR-125b in β-cells remains elusive although in other cell types regulates apoptosis, growth and differentiation. We aim to determine miR-125b function in β-cells and the role of glucose and AMPK in the regulation of its expression. miR-125b level in human islets strongly correlates with BMI and is induced by glucose in both mouse and human islets, while feeding mice a ketogenic (low sugar) diet reduced islet miR-125b. These effects disappeared in islets with β-cell specific deletion of AMPK whereas treatment of human islets with highly specific AMPK activators significantly decreased miR-125b, indicating that glucose regulates miR-125b via AMPK in both mice and humans. miR-125b overexpression in MIN6 cells limited cytokine-induced apoptosis whilst strongly reducing insulin content. RNA-Seq on these cells suggests a role for miR-125b in metabolism, respiration and cytokine receptor interactions and RNA-IP of the miRNA-induced silencing complex revealed novel miR-125b targets such as mannose-6-phosphate receptor (MPR), important for enzyme sorting within secretory granules. Preliminary data show that β-cell-specific inhibition of miR-125b using a molecular “sponge” improves glucose tolerance in mice fed a high-fat diet.

In summary, we reveal miR-125b as an important regulator of β-cell function that might contribute to the deleterious effects of hyperglycaemia on β-cells.

Disclosure

R. Cheung: None. G. Pizza: None. D.M. Rolando: None. P.L. Chabosseau: None. M. Nguyen-Tu: None. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma. A. Martinez-Sanchez: None.

Funding

Medical Research Council UK