bluuebunny/crossref_metadata_2025_split huggingface dataset:
1017-P: Continuous Glucose Monitoring Reveals Comprehensive Glucose Control with MEDI0382, an Oxyntomodulin-Like Peptide with Targeted GLP-1/Glucagon Receptor Activity
Authors: PARKER VICTORIA E.R. , ROBERTSON DARREN , WANG TAO , HORNIGOLD DAVID C. , POSCH MAXIMILIAN G. , HEISE TIM , PLUM-MOERSCHEL LEONA , MEIER JURIS J. , SCHLICHTHAAR HEIKE , KLAUS BEATE M. , AMBERY PHILIP , HIRSHBERG BOAZ 
Published: June 2019

Background: MEDI0382 is an oxyntomodulin-like peptide with GLP-1/glucagon receptor activity under development for type 2 diabetes mellitus (T2DM). Continuous glucose monitoring (CGM) is valuable for evaluating glucose-lowering efficacy.
Methods: As an exploratory part of a double-blind phase 2a study, CGM was performed for 52 days with a Freestyle Libre. Patients with T2DM received daily SC MEDI0382 (n = 26) or placebo (n = 13) for 49 days; doses were up-titrated weekly from 50 to 300 µg. CGM assessed percent time spent in target range (70-140 mg/dL) and hypoglycemia (&lt;54 mg/dL), as well as 7-day mean 24-h glucose and CV.
Results: Over 52 days, 95% patients had &gt;70% complete CGM data. Time spent in target range was significantly greater with MEDI0382 vs. placebo (64.8-78.0% vs. 42.5-53.0%; min-max; all P ≤ 0.05). Time spent at &lt;54 mg/dL was &lt;1% at all MEDI0382 doses and was not significantly different vs. placebo. A significant reduction in mean glucose with MEDI0382 (118.8-133.2 mg/dL) vs. placebo (153-154.8 mg/dL; all P ≤ 0.033) was observed, and CV was lower with MEDI0382 (0.19-0.21) vs. placebo (0.25-0.26; all P ≤ 0.030).
Discussion: MEDI0382 rapidly stabilized glucose levels, improved glycemic variability, and delivered a consistent decrease in mean glucose. The benefits of more time spent in target range will need to be confirmed in larger trials.

Disclosure
V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. T. Wang: Employee; Self; MedImmune. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.G. Posch: None. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. H. Schlichthaar: None. B.M. Klaus: None. P. Ambery: Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca.

Funding
AstraZeneca
1032-P: Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed-Ratio Combination vs. Insulin Glargine in Japanese Patients with T2DM
Authors: KANETO HIDEAKI , TAKAMI AKANE , SPRANGER ROBERT , AMANO ATSUSHI , WATANABE DAISUKE , NIEMOELLER ELISABETH 
Published: June 2019

The fixed ratio combination of insulin glargine/lixisenatide (iGlarLixi) has been shown in a Western population to improve glycemic control in a convenient single daily injection. This open-label trial assessed the efficacy and safety of 26-week treatment of iGlarLixi and insulin glargine (iGlar) in Japanese patients with T2DM inadequately controlled on basal insulin and oral antidiabetic drugs. After a 12-week run-in with metformin and iGlar, patients were randomized to iGlarLixi (n=255) or iGlar (n=257). Starting from a mean baseline (BL) HbA1c of 8.25%, the decrease in the iGlarLixi group was significantly greater than in the iGlar group (LS mean difference [SE]: -0.74% [0.063], p&lt;0.0001) (Figure). Significantly more patients reached the HbA1c target of &lt;7% at Week 26 with iGlarLixi than with iGlar (51.8% vs. 16.0%, p&lt;0.0001). Change in body weight from BL to Week 26 was -0.51 kg with iGlarLixi and +0.55 kg with iGlar (p&lt;0.0001). Both treatments were well tolerated. Documented symptomatic hypoglycemia (≤70 mg/dL) was similar in the two treatment groups (iGlarLixi: 18.8%, iGlar: 16.7%). Nausea was reported in 16.9% (iGlarLixi) and 0.8% (iGlar).
In conclusion, iGlarLixi showed superior glycemic control to iGlar, with a beneficial effect on body weight, no additional risk of hypoglycemia, and lower rate of nausea than reported with lixisenatide.

Disclosure
H. Kaneto: Research Support; Self; Astellas Pharma Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Nippon Boehringer Ingelheim Co ., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Nippon Boehringer Ingelheim Co ., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. A. Takami: Employee; Self; Sanofi K.K. R. Spranger: Employee; Self; Sanofi-Aventis Deutschland GmbH. A. Amano: Employee; Self; Sanofi K.K. D. Watanabe: Employee; Self; Sanofi K.K. E. Niemoeller: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi.

Funding
Sanofi K.K.
1035-P: VN-B101 in Combination with Metformin/Sitagliptin or Metformin/Ertugliflozin Synergistically Improves Glycemic Control in db/db Mice
Authors: WANG PEI-RAN , CHEN HUI-LING 
Published: June 2019

Type 2 diabetes mellitus is a common chronic and progressive disease arising from a complex pathophysiology, a single pharmacological agent can only address limited pathophysiologic targets and does not provide adequate glycemic control, leading to an increasingly interest in the development of combination therapies in order to achieve the goal. Though VN-B101, the VitNovo’s leading diabetes drug candidate, has demonstrated its dual combination treatment with metformin is safe and efficacious in patients with type 2 diabetes, VN-B101 triple combination treatment has yet to be studied that may create more treatment options for diabetes patients. The major objective of the present studies was to evaluate the efficacy of VN-B101 triple combination treatment with (1) metformin/sitagliptin (DPP-4i) or (2) metformin/ertugliflozin (SGLT2i) in db/db mice. Oral glucose tolerance test (OGTT) was performed after 4 weeks of combination treatment (VN-B101: 240mg/kg/day; metformin: 150mg/kg/day; sitagliptin: 40mg/kg/day; ertugliflozin: 10mg/kg/day). The % reduction of incremental glucose AUC during OGTT in each group was calculated to evaluate the treatment effects on glycemic control. The results show (1) VN-B101 in combination with metformin/sitagliptin synergistically improves glycemic control (VN-B101 + metformin/sitagliptin: -136.9% vs. VN-B101: -26.1% and metformin/sitagliptin: -55.6%); (2) VN-B101 in combination with metformin/ertugliflozin synergistically improves glycemic control (VN-B101 + metformin/ertugliflozin: -140.1% vs. VN-B101: -26.1% and metformin/ertugliflozin: -61.5%). These exciting results open new therapeutic possibilities in the treatment of type 2 diabetes mellitus. Clinical trial of either triple combination treatments are currently conducted in Australia.

Disclosure
P. Wang: None. H. Chen: None.
1047-P: Can Closed-Loop Overcome High Day-to-Day Variability of Insulin Needs in Inpatients on General Wards?
Authors: BOUGHTON CHARLOTTE K. , BALLY LIA , THABIT HOOD , HARTNELL SARA , HERZIG DAVID , VOGT ANDREAS , ANDEREGGEN EVELINE , RUAN YUE , WILINSKA MALGORZATA E. , EVANS MARK , WERTLI MARIA M. , COLL ANTHONY P. , STETTLER CHRISTOPH , HOVORKA ROMAN 
Published: June 2019

Aim: To assess the ability of fully closed-loop insulin delivery to accommodate day-to-day variability in insulin requirements in noncritical care setting.
Methods: We retrospectively analyzed insulin delivery during closed-loop studies in inpatients with hyperglycaemia requiring insulin on general wards (type 1 diabetes excluded). Coefficient of variation (CV) quantified day-to-day variability of insulin requirements over 5 to 15 days of closed-loop use. Participants were stratified into tertiles according to variability of insulin requirements.
Results: Data from 487 days (55 participants) were analyzed. Participants with higher CV of insulin requirements had comparable mean glucose (149 vs. 153mg/dL; P=0.59; Table) and time in target glucose 100-180mg/dL (67.8 vs. 67.9%; P=0.99) to those with lower CV. There was no increase in hypoglycemia in those with higher CV (P=0.67). Those with higher CV were younger than those with lower CV (66 vs. 72years; P=0.037). Weight, gender, HbA1c, diabetes/insulin duration, use of steroids/dialysis/nutrition support were comparable (ns).
Conclusions: Fully closed-loop insulin delivery can accommodate highly variable insulin requirements without compromising glucose control or increasing the risk of hypoglycaemia in inpatients receiving insulin therapy on general wards.

Disclosure
C.K. Boughton: None. L. Bally: None. H. Thabit: Research Support; Self; Dexcom, Inc. S. Hartnell: Advisory Panel; Self; Dexcom, Inc., JDRF. Speaker's Bureau; Self; Sanofi. D. Herzig: None. A. Vogt: None. E. Andereggen: None. Y. Ruan: None. M.E. Wilinska: None. M. Evans: Advisory Panel; Self; Dexcom, Inc., Medtronic, Roche Diabetes Care, Zucara Therapeutics Inc. Research Support; Self; MedImmune, Sanofi. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc. M.M. Wertli: None. A.P. Coll: None. C. Stettler: None. R. Hovorka: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Abbott, Dexcom, Inc., Medtronic. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; B. Braun Medical Inc., Medtronic.
105-OR: Lineage Determination of Endocrine Progenitors in Murine and Human Pancreatic Development
Authors: WONG DANIEL M. , BYRNES LAUREN , BOUZA JACQUELYN O. , PEIXOTO GABRIEL , MCMULLEN REED , SNEDDON JULIE B. 
Published: June 2019

Generation of functional beta cells for regenerative medicine would benefit from an increased understanding of pancreatic endocrine cell differentiation. During pancreatic development, expression of Ngn3 defines the progenitor cells that will differentiate into one of five endocrine lineages, including the beta cell. Here, we identify and further characterize a distinct endocrine progenitor population defined by differential expression of a transcription factor named Fev in murine and human endocrine cell development. Using single-cell RNA-sequencing and genetic lineage tracing, we build a transcriptomic profile of murine Fev+ progenitors that is distinct from that of Ngn3+ progenitors and reconstruct lineage relationships among Ngn3+, Fev+, and differentiated, hormone+ cells. We further identify candidate transcriptional regulators along the differentiation trajectory of this Fev+ progenitor population toward the alpha or beta cell lineages. Translating our findings in murine pancreatic development to that of human, we identify an analogous FEV+ population and putative gene regulators of endocrine cell fate in human fetal pancreas. In a stepwise differentiation platform designed to generate beta cells from human embryonic stem cells (hESCs), we also uncover robust FEV expression in endocrine progenitors prior to their differentiation into insulin-producing beta cells. Single-cell RNA-sequencing and lineage reconstruction of hESC-derived cells at the differentiated beta cell stage reveal FEV+ cells that may represent endocrine progenitors that have failed to acquire a beta cell identity; this failure of FEV+ endocrine cell differentiation may facilitate in uncovering the required molecular signals and genetic circuitry that push endocrine progenitors toward a beta cell fate. This work establishes a new model of pancreatic endocrine cell differentiation and identifies a Fev+ endocrine progenitor as a new cell stage in endocrine lineage determination.

Disclosure
D.M. Wong: None. L. Byrnes: None. J.O. Bouza: None. G. Peixoto: None. R. McMullen: None. J.B. Sneddon: Advisory Panel; Spouse/Partner; Akouos. Advisory Panel; Self; Encellin. Advisory Panel; Spouse/Partner; Encellin. Consultant; Self; Semma Therapeutics, Inc.

Funding
Nora Eccles Treadwell Foundation; University of California, San Francisco
1054-P: Insulin Sensitivity from Sensor and Pump Data in Youths with Type 1 Diabetes: Hybrid Closed-Loop Validation
Authors: SCHIAVON MICHELE , GALDERISI ALFONSO , KRAEMER KRISTEN A. , COBELLI CLAUDIO , MAN CHIARA DALLA , CENGIZ EDA 
Published: June 2019

Estimate of insulin sensitivity (SI) and its daily variation are essential for optimizing insulin therapy in type 1 diabetes (T1D). Recently, a SI index based on continuous glucose monitoring (CGM) and insulin pump (CSII) data (SISP) has been validated in adults with T1D. Herein, we validated the SISP index against the oral minimal model (MM) one (SIMM) during two sequential meals in youth with T1D during hybrid closed-loop (HCL) treatment. Ten youths with T1D (4F; age=20.9±3.7 y; BMI=23.6±4.5 kg/m2; TDD= 50.6±16.3 U/day; HbA1c 7.3±0.6%) underwent two consecutive, standardized meal studies (breakfast, B, and lunch, L) while wearing the UVA-DiAS HCL (Dexcom CGM and t-slim CSII) system. Plasma glucose and insulin concentration data (measured every 10 min for 4 h during each meal) were used for SIMM estimation, while the corresponding CGM and CSII data, derived from the HCL system, were used for SISP calculation. SISP well correlated with SIMM (Fig. 1) for both B (18.1±7.6 vs. 21.5±12.1 10-4dL/kg/min per uU/mL, R=0.70) and L (26.5±10.1 vs. 26.0±13.8 10-4dL/kg/min per uU/mL, R=0.77). Between-meal (L-B) variation of SISP was also well correlated with its MM counterpart (R= 0.82). SISPis a reliable proxy of the oral minimal model derived SI and can be used to customize both open- and closed-loop treatments to improve glycemic outcomes in young people with T1D.

Disclosure
M. Schiavon: None. A. Galderisi: None. K.A. Kraemer: None. C. Cobelli: None. C. Dalla Man: None. E. Cengiz: Advisory Panel; Self; Abvance, ADOCIA, MannKind Corporation, Novo Nordisk Inc. Speaker's Bureau; Self; Novo Nordisk Inc.

Funding
JDRF (to E.C.); International Society for Pediatric and Adolescent Diabetes; Patterson Foundation (to A.G.); European Medical Information Framework (to A.G.); University of Padova (to M.S., C.D.M.)
1069-P: Safety and Efficacy of a Novel Basal-Bolus Insulin Delivery Device (IDD) in Adults with T2D Using Rapid-Acting or Regular Human Insulin
Authors: ARONSON RONNIE , MAHONEY EDWARD T. , SALIU DRILON , BERGQUIST LEYA , HIRSCH LAURENCE 
Published: June 2019

Objective: To assess usability, 24-hour glycemic profiles, and safety of an investigational basal/bolus IDD in people with T2D transitioning from MDI.
Research Design and Methods: This single-center, open-label, two-period pilot study enrolled people with T2D and HbA1c 7-11%. Subjects continued their usual MDI therapy during a 2-3 -day in-clinic MDI period and then were switched to the IDD for a 6-day in-clinic IDD period, without changing insulin dose. Subjects wore blinded CGM throughout each in-clinic period.
Results: Twenty-one people (mean±SD age 57±8 years; HbA1c 8.2±0.9%) using U-100 insulin lispro (n=11) or U-100 regular human insulin RHI (n=10) were enrolled. Glycemic measures improved from the MDI to the IDD period, including FBG: 141.2 ± 38.3 mg/dl vs. 121.2 ± 35.0 mg/dl (P=0.002), respectively; 24-hour mean glucose: 137.0 ± 20.5 mg/dl vs.125.0 ± 16.5 mg/dl (P=0.004), and time-in-range (70-180 mg/dL): 81.0 ± 14.4% vs. 87.5 ± 10.6% (P=0.008). There were no significant differences between MDI and IDD for time in hypoglycemia (&lt;70 mg/dL), CV%, nor mean of daily differences (MODD). Mean amplitude of glycemic excursions (MAGE) was significantly lower with IDD (P=0.011). There were no serious AEs. There were no significant differences between insulin lispro and RHI for any glycemic measures, within either phase. *Disclaimer: RHI is not approved for use in pumps. IDD not available for sale.
Conclusions: Results of this pilot study suggest that the IDD, used with insulin lispro or RHI, is as safe and effective for adults previously prescribed MDI therapy, without requiring dose change, in the short term. Administering either insulin lispro or RHI in the IDD led to similar glycemic responses and outcomes based on 24-hour glycemic profiles in people with T2D. To our knowledge, this is the first study to evaluate RHI in people with T2D using CGM for 24-hour glycemic profiles. Additional trials are warranted to further evaluate this novel IDD in larger populations.

Disclosure
R. Aronson: Research Support; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Senseonics. E.T. Mahoney: Employee; Self; Becton, Dickinson and Company. D. Saliu: Employee; Spouse/Partner; Allergan. Employee; Self; Becton, Dickinson and Company. L. Bergquist: Employee; Self; Becton, Dickinson and Company. L. Hirsch: Employee; Self; Becton, Dickinson and Company. Stock/Shareholder; Self; Merck & Co., Inc.
1102-P: High vs. Standard Starting Dose of Insulin Glargine 100 U/ml in Patients with Overweight/Obesity and Type 2 Diabetes Uncontrolled with Oral Antidiabetic Drugs in China: A Multicenter, Open-Label Randomized Controlled Trial
Authors: JI LINONG , WAN HAILONG , WEN BINHONG , WANG XUEYING , WANG JUNFEN , BIAN RONGWEN , PANG WUYAN , FENG WEI , ZHANG XIA , CUI NAN 
Published: June 2019

With type 2 diabetes (T2D) progression, patients require insulin, but insufficient titration often leads to poor glycemic control. A higher insulin starting dose may reduce the optimal dose deficit, but whether this procedure increases hypoglycemia risk is unknown. This open-label, multicenter trial (NCT02836704) evaluated safety and efficacy of a high (0.3 U/kg) vs. standard (0.2 U/kg) starting dose of glargine 100 U/ml (Gla-100) followed by titration over 16 weeks to achieve self-monitored FBG 4.4-5.6 mmol/L using the same algorithm in each group. Overall, 892 patients with overweight/obesity (BMI 25-40 kg/m2) and uncontrolled T2D (HbA1c 7.5-11.0%; lab FPG &gt;9.0 mmol/L) on stable doses of 2-3 OADs were randomized to receive a high (n=444) or standard (n=448) starting dose of Gla-100. At week 16, 92% of patients completed the study and 866 were analyzed. The primary endpoint (percentage of patients with ≥1 confirmed hypoglycemia, BG &lt;3.9 mmol/L) met the pre-specified threshold (upper bound 95% CI &lt;10%) for non-inferiority of Gla-100 0.3 U/kg vs. 0.2 U/kg with 11.0% and 8.6% in the respective groups (log-binomial regression estimated difference 2.1%; 95% CI: −1.68%, 5.89%). At week 16, symptomatic (9.8% vs. 7.0%, p=0.13) and nocturnal hypoglycemia (2.7% vs. 1.2%, p=0.10), percentage of patients achieving HbA1c &lt;7.0% without hypoglycemia (37.1% vs. 37.1%), and percentage of patients achieving lab FPG targets &lt;5.6 mmol/L (15.9% vs. 16.3%), &lt;6.1 mmol/L (27.6% vs. 26.1%), or &lt;7.0 mmol/L (48.8% vs. 48.3%) were all similar in both groups. However, time to achieve first self-monitored FBG &lt;5.6, &lt;6.1, or &lt;7 mmol/L was 6, 9, and 7 days shorter in the 0.3 U/kg group (all p&lt;0.01).
In conclusion, among patients with overweight/obesity and T2D, a higher Gla-100 starting dose was as safe as a standard Gla-100 starting dose and achieved FBG targets earlier during the course of therapy.

Disclosure
L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. H. Wan: None. B. Wen: None. X. Wang: None. J. Wang: Research Support; Self; Sanofi. R. Bian: None. W. Pang: None. W. Feng: Employee; Self; Sanofi. X. Zhang: None. N. Cui: Employee; Self; Sanofi.

Funding
Sanofi China
111-OR: Pancreatic Elastase Regulates Human Beta-Cell Proliferation via the Focal Adhesion and PAR2 Signaling Pathways
Authors: BASILE GIORGIO , VETERE AMEDEO , LIU KA-CHEUK , HU JIANG , ANDERSSON OLOV , WAGNER BRIDGET , KULKARNI ROHIT 
Published: June 2019

Pancreatic elastase (PE) is a serine protease produced by pancreatic acinar cells. PE is mainly secreted in the intestine during digestion, and is also detectable in stromal pancreatic tissue, including the ECM of islets. Recently, we identified serpinB1 (SB1), a protease inhibitor, as a promoter of human β-cell proliferation by inhibiting PE activity and demonstrated that the PE inhibitor, sivelestat, also induced β-cell regeneration. Here, we report the identification two novel PE inhibitors: telaprevir, an antiviral drug, and tebipenem, an antibiotic. We observed that telaprevir and tebipenem inhibited human PE (hPE) with greater or similar potency than sivelestat respectively (IC50: telaprevir 15.7nM, tebipenem 3.6µM, sivelestat 2.3 µM; n=3). We then tested the effects of the compounds in in vitro cultures of human islets. Telaprevir and tebipenem each increased proliferating human β-cells (∼4-fold and 1.5-fold increase respectively; n=6) compared to vehicle-treated islets. Furthermore, in an independent study, both compounds (at 10µM), stimulated β-cell regeneration in a zebrafish model resulting in ∼1.5-fold increase in insulin+ cells in treated versus non-treated groups. Finally, to identify pathways modulated by PE we treated human islets with the two compounds for 10 or 30 minutes and performed a phosphoprotein microarray assay (Kinexus, CA). We discovered that inhibition of hPE increased phosphorylation levels of PXN-PAK proteins belonging to the focal adhesion pathway. In addition, phosphorylation on the effectors of Protease-activated receptor 2 (PAR2) signaling (i.e., PKC, PYK2 and Src) were increased, resulting in the activation of ERK1/2 proteins and the mitogenic pathway in β-cells. These findings provide new insights regarding the molecular mechanisms underlying regulation of β-cell proliferation processes by PE, leading to identification of potential molecular targets that can be modulated in the long-term goal of treating diabetes.

Disclosure
G. Basile: None. A. Vetere: None. K. Liu: None. J. Hu: None. O. Andersson: None. B. Wagner: None. R. Kulkarni: None.