bluuebunny/crossref_metadata_2025_split huggingface dataset:
180-LB: Standardizing the Hemoglobin Glycation Index (HGI)
Authors: HSIA DANIEL S. , YANG SHENGPING , LIU SHUQIAN , HEMPE JAMES M. 
Published: June 2020

HGI measures how far a person’s HbA1c lies above or below average compared to other people with similar blood glucose concentrations. Multiple studies confirm that high HGI is associated with greater risk for iatrogenic hypoglycemia in diabetes patients and chronic vascular disease in diabetic and nondiabetic populations. However, significant differences in how blood glucose is assessed and in the demographic composition of different study populations have resulted in marked interstudy differences in the slopes and intercepts of regression equations used to calculate HGI. The purpose of the present study was to develop a standard linear regression equation that could be widely used to calculate HGI in diverse human populations. To accomplish this, we used data from the demographically diverse 1999-2016 National Health and Nutrition Examination Survey (NHANES) to identify 18,675 participants age ≥20 y without self-reported diabetes. The regression equation developed from this treatment naïve adult reference population was HbA1c = 0.024 FPG + 3.1. HGI was calculated for reference population participants who were then subdivided into 1) low, moderate, and high subgroups, and 2) normal, prediabetic and diabetic subgroups based on OGTT results. Novel observations include lack of association between HGI and hemoglobin concentration, plasma insulin or HOMA-IR. Consistent with previous reports, high HGI was associated with 1) black race regardless of diabetes status, 2) older age and higher BMI in nondiabetic but not diabetic participants, and 3) no difference in 2 h OGTT results in normal, prediabetic or treatment naïve diabetic participants. Standardizing how HGI is calculated across studies will facilitate clinical and basic research to better understand 1) why some people have lower or higher than average HbA1c levels independent of blood glucose concentration, 2) why high HGI is associated with greater risk for chronic vascular disease in diabetic and nondiabetic people, and 3) what can be done to reduce risk in high HGI people.

Disclosure
D.S. Hsia: None. S. Yang: None. S. Liu: None. J.M. Hempe: None.

Funding
National Institute of General Medical Sciences (U54GM104940)
1800-P: Cotadutide, a GLP-1/GCG Receptor Co-Agonist, Improves Insulin Sensitivity and Restores Normal Insulin Secretory Capacity in DIO Mice
Authors: LAKER RHIANNA C. , LANTIER LOUISE , MCGUINNESS OWEN , WILL SARAH , KUSZPIT KYLE , ALFARO ALEX R. , JERMUTUS LUTZ , RHODES CHRISTOPHER J. 
Published: June 2020

Cotadutide (MEDI0382) is a peptide with targeted GLP-1/glucagon (Gcg) receptor activity that has beneficial effects on T2D and obesity in humans and mice, and shows marked improvements in NAFLD/NASH in mice. We performed hyperinsulinemic clamps in diet induced obese (DIO) mice to better understand whether improved insulin sensitivity and β-cell function are responsible for the improved glycemia in our clinical studies. Following 28 days of daily dosing with Cotadutide (10 nmol/kg), Liraglutide (5 nmol/kg; GLP-1 agonist) or g1437 (5 nmol/kg; Gcg analog) mice underwent continuous infusion of 4mU/kg/min insulin and [3H]-glucose to assess glucose turnover. Tissue-specific glucose uptake was assessed using 14C-2-deoxyglucose. We observed lower body weight in all groups compared with vehicle control, with g1437 eliciting the largest response and Liraglutide the least. Fasting glucose was significantly higher in g1437 treated mice. Fasting insulin was dramatically lower in Cotadutide and g1437 groups compared with vehicle. Despite an equal rate of human insulin infusion between groups, the total insulin levels during the clamp remained lower in Cotadutide and g1437 treated mice. The glucose infusion rate, to maintain euglycemia ∼130 mg/dL, was significantly higher in Cotadutide treated mice in line with increased glucose disposal rate. Hepatic glucose production was suppressed in all groups, despite significantly lower levels of insulin in Cotadutide and g1437 treated mice. Finally, glucose uptake was elevated in brown adipose tissue in Cotadutide treated mice, which was confirmed in a separate study of [18F]FDG uptake by PET imaging. These experiments demonstrate that Cotadutide improved insulin sensitivity in concert with dramatic reductions for insulin demand, which may result in recovery of endogenous β-cell function in T2D.

Disclosure
R.C. Laker: Employee; Self; AstraZeneca. L. Lantier: None. O. McGuinness: None. S. Will: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. K. Kuszpit: None. A.R. Alfaro: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca.
1804-P: HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist, Exhibits Anti-inflammatory and Fibrotic Effects in AMLN/TAA–Induced Liver Inflammation and Fibrosis Mice
Authors: KIM JUNG KUK , LEE JONG SUK , PARK EUNJIN , LEE JONGSOO , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG 
Published: June 2020

Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, is characterized by hepatic steatosis, inflammation, and fibrosis. Despite increased prevalence and related mortality, no approved medication is available, leading to a significant burden for public health. Although advances in targeting hepatic steatosis demonstrate meaningful benefits, their overall impact in inflammation and fibrosis remains elusive. Hence, recent approaches directly modulating inflammation and fibrosis still showed marginal efficacy. Thus, to provide novel option for NASH treatment, HM15211, a novel long-acting GLP-1/GIP/Glucagon triple agonist, is developed. Because of the benefits of GLP-1, GIP, and Glucagon in liver inflammation and fibrosis in addition to steatosis, HM15211 might confer more effective treatment in NASH. Previously, HM1521 treatment led to potent liver fat reduction along with weight loss in DIO mice. Here, we investigated the potential effect of HM15211 in animal model of liver inflammation and fibrosis. To induce liver inflammation and fibrosis, mice fed with AMLN diet were concomitantly treated with thioacetamide (AMLN/TAA mice) for 16 weeks, and HM15211 was administered during last 8 weeks. Of note, HM15211 treatment reduced the hepatic marker expression for inflammation (-92.8, -34.7 and -34.9% vs. vehicle (Veh) for F4/80, MCP-1 and IL-6) and fibrosis (-53.9, -41.4 and -51.9 % vs. Veh for α-SMA, TIMP-1 and collagen1a1). Similar reduction in blood level of TIMP-1, PIIINP and hyaluronic acid (-49.3, -48.0 and -49.1% vs. Veh) was observed. Strikingly, HM15211 significantly reduced both hepatic hydroxyproline (-53.1 % vs. Veh) and sirius red positive area (-70.6% vs. Veh). Therefore, in addition to steatosis improvement, HM15211 may provide anti-inflammatory and -fibrotic effect. Human studies are ongoing to assess the clinical relevance of these findings.

Disclosure
J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1813-P: Coadministration of a GLP-1/Glucagon Receptor Agonist with an FXR Agonist and ACC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice
Authors: TREVASKIS JAMES L. , NORLIN JENNY , MIRANDA DIEGO A. , BATES JAMIE G. , ZOIS NORA E. , VEIDAL SANNE , FEIGH MICHAEL , LATTA MARKUS 
Published: June 2020

Combination approaches for the treatment of NASH are being actively pursued. We examined the effects of administration of a dual GLP-1 and glucagon receptor agonist (GLP-1:GCG, 0.015 mg/kg, s.c., q.d.) alone and combined with an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analog, ACCi; 5 mg/kg, both p.o., q.d) on NASH endpoints in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, GLP-1:GCG reduced body weight 15%, being slightly greater in the GLP-1:GCG + CILO group (22%). Liver triglyceride was reduced by GLP-1:GCG (by 76% vs. vehicle, p&lt;0.001). Addition of CILO, ACCi or both to GLP-1:GCG further reduced liver lipid (by 82%, 88% and 91%, respectively). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 7/16 (44%) of vehicle controls and in all mice (100%) in the GLP-1:GCG-containing groups. In vehicle controls, 0/16 mice had a final NAS of 0-1 whereas this increased to 5/15 mice (33%) with GLP-1:GCG, and was not significantly improved by addition of CILO (7/15, 47%) or ACCi (6/16, 38%). Triple therapy increased number of mice with NAS of 0-1 to 11/16 (69%). GLP-1:GCG was associated with 1/15 mice (7%) improving pre-to-post fibrosis stage which was not altered by addition of CILO or ACCi, but increased to 7/16 (44%) with triple therapy. Collagen-1a and α-SMA immunoreactivity (% area) revealed no significant effect of GLP-1:GCG for collagen (5.7%), but reduction in α-SMA (1.4%, p&lt;0.001) vs. vehicle (6.8% and 4.9%, respectively). Triple therapy reduced both collagen and α-SMA area (3.8% and 1.5%, respectively, both p&lt;0.001 vs. vehicle).
In conclusion, GLP-1:GCG effectively reduced hepatic lipid and the addition of an FXR agonist and ACC inhibitor further improved pre-to-post NAS and fibrosis stage in DIO-NASH mice, supporting development of combination approaches for NASH.

Disclosure
J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. M. Latta: Employee; Self; Novo Nordisk A/S.
1814-P: JAZF1 Knockout Mice Are Protected against Diet-Induced Metabolic Syndrome
Authors: SRIVASTAVA CHITRANGDA , DORR KERRY , GRIMM SARA , DEGRAFF LAURA M. , GRUZDEV ARTIOM , JETTEN ANTON M. 
Published: June 2020

JAZF1/TIP27 is a 27kD transcriptional co-regulator. GWAS studies have indicated that single nucleotide polymorphisms in the JAZF1 gene are associated with increased risk of typeII diabetes (T2D) and several autoimmune diseases. Diet induced obesity is a major risk factor for different metabolic disorders, including T2D and nonalcoholic fatty liver disease (NAFLD). To obtain greater insights into the physiological functions of JAZF1, we generated Jazf1 null mice (Jazf1-/-) and fed them a high fat diet (HFD) for 8 to 15 weeks. We demonstrated that Jazf1-/- mice fed-HFD exhibit lower body-weight and fat-mass compared to obese WT mice. HFD-fed Jazf1-/- mice maintained normal blood glucose levels and were more insulin sensitive and glucose tolerant than obese WT-littermates. Histological examination showed that Jazf1-/- mice were less susceptible to HFD-induced hepatic steatosis than WT littermates as indicated by the greatly reduced hepatic lipid droplets (LD) in Jazf1-/- liver. Furthermore, HFD-fed Jazf1-/- mice also showed reduced levels of serum aspartate aminotransferase, alkaline phosphatase, and sorbitol dehydrogenase, enzymes indicative of hepatocytoxicity. HFD-fed Jazf1-/- mice exhibited a dramatic decrease in the level of liver triglycerides. HFD-fed WT mice showed induction of Jazf1 expression in liver as compared to WT mice with normal diet. RNA-seq and qPCR analysis of liver demonstrated that LD-formation genes (e.g., Plin2/Plin3/Plin4/Cd36/Cidec/Cidea) were greatly suppressed in Jazf1-/- compared to WT mice. Go-term and IPA analysis revealed that inflammatory (e.g., Ccl7/Lcn2/Cd14) and hepatic fibrosis (Col1a1/Egr2/Timp1) were among top pathways down-regulated in HFD-fed Jazf1-/- liver. Our results indicate that JAZF1 functions as a critical regulator of LD formation and inflammation in NAFLD and loss of JAZF1 function protects against metabolic syndrome. Our study may provide new insights into the development of progression of metabolic syndrome and its complications.

Disclosure
C. Srivastava: None. K. Dorr: None. S. Grimm: None. L.M. DeGraff: None. A. Gruzdev: None. A.M. Jetten: None.

Funding
National Institutes of Health
1818-P: High-Sucrose Diet Causes Increased Hepatic Histone Acetylation Due to Increased Bacterial Acetate Production and Reduced Lipogenesis in ChREPB-Deficient Mice
Authors: IIZUKA KATSUMI , TAKAO KEN , LIU YANYAN , NONOMURA KENTA , KATO TAKEHIRO , MIZUNO MASAMI , HORIKAWA YUKIO , YABE DAISUKE 
Published: June 2020

ChREBP is known to play a critical role in the development of obesity and diabetes by regulating hepatic lipogenesis. High-sucrose diet (HSD) feeding is known to cause irritable bowel syndrome-like phenotype in ChREBP knockout mice (KO) with some alterations in gut microbiota. However, effects of the gut microbiota alteration on whole-body metabolism in KO remains unknown. Twelve-week old wild type mice (WT) and KO, both fed on HSD for 7 days, were analyzed. KO had 3-fold higher cecum contents compared to WT (WT, 71±24.4; and KO, 205.7±46.0 g). KO had a remarkable increase in acetate-producing bacteria (e.g., Bifidobacterium and Bacteroides) in the cecum. Consistently, KO showed 2-fold higher acetate levels in the cecum (WT, 27.5±6.0; and KO, 55.6±22.3 μmoles/g stool). Interestingly, KO also showed higher hepatic acetate contents (WT, 0.81±0.18; and 1.08±0.14 μmoles/g liver). Since acetate is converted into acetyl-CoA; and used for lipogenesis, ketogenesis and protein acetylation, we investigated hepatic triglyceride contents, plasma 3OHBA levels and histone acetylation. While hepatic acetyl-CoA contents and plasma 3-OHBA levels did not differ between the two groups, hepatic triglyceride contents were much lower in KO (WT, 11.45±5.47; and KO, 4,11±0.44 mg/g liver), consistent with reduced expression of hepatic lipogenic genes. In contrast, histone acetylation on selected genes (e.g., Fasn, Chrebp and Pklr) was significantly enhanced in KO. These results together indicated that increased supply of acetyl-CoA in the liver, possibly due to enhanced acetate-production in the gut and reduced hepatic lipogenesis, leads to enhancement of histone acetylation in KO, while physiological relevance awaits further investigation.

Disclosure
K. Iizuka: Speaker’s Bureau; Self; Kowa Company, Ltd., Novo Nordisk Inc. K. Takao: None. Y. Liu: None. K. Nonomura: None. T. Kato: None. M. Mizuno: None. Y. Horikawa: None. D. Yabe: Research Support; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Eli Lilly Japan K.K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo, Eli Lilly Japan K.K., Fukuda Denshi, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., LifeScan, Inc., Medtronic, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Novo Nordisk Inc., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Other Relationship; Self; Japan Diabetes Society.

Funding
Grant-in-Aid for Scientific Research (17K00850)
183-LB: Prediction of Osteoporosis in Patients with Newly Diagnosed Type 2 Diabetes Based on Their Impaired Bone Turnover: A Retrospective Study in Chinese Population
Authors: SONG LIGE , LI HUIJUAN , WEN YUHUA , ZHANG XIAOYA , LIU PEIPEI 
Published: June 2020

The patients with type 2 diabetes (T2DM) have higher fracture risk, and this study is conducted to identify the contributors of the abnormal bone turnover in newly diagnosed T2DM patients and to set a prediction model for osteoporosis in this population. This retrospective study includes 244 newly diagnosed patients with T2DM and 218 individuals without diabetes. Demographic characteristics, clinical history, biochemical indexes, bone turnover markers were detected. BMD was measured by DEXA. SPSS 20.0 software is hired for statistical analysis. Comparing to the patients without diabetes, the patients with T2DM have lower levels of P1NP, CTX, OC, PTH, 25(OH)D and higher level of BALP. The patients with T2DM have higher BMD in lumbar, femur neck and total hip comparing to the controls. In T2DM group, HbA1c level is negatively related to P1NP and OC, and total cholesterol is positively related to BALP, independently. In the patients without diabetes, HbA1c level is negatively related to the level of OC and positively related to 25(OH)D, and HDL is positively related to P1NP, independently. The level of PTH is negatively related to HbA1c in all the participants. After adjusted with age, BMI and menopausal status, BALP and OC were positively correlated with the risk of osteoporosis in all the participants, moreover in the patients with T2DM, HbA1c, TRAP5b and P1NP were also positively correlated with the onset of osteoporosis. The prediction model including age, BMI, menopausal status, TRAP-5b and OC for osteoporosis in T2DM patients had the area under the ROC curve as 0.817 with the sensitivity and specificity at 70% and 82% respectively. The above data indicate that increased glucose level contributes to impaired maturation of osteoblasts, and the prediction model including age, BMI, menopausal status and bone turnover markers may find out the T2DM patients with high fracture risk. However, this result needs to be proven with fracture data.

Disclosure
L. Song: None. H. Li: None. Y. Wen: None. X. Zhang: None. P. Liu: None.

Funding
Shanghai Municipal Health Commission (201840217 to L.S.); Clinical Science and Technology Innovation Program of Hospital Development Center (SHDC12018X10 to L.S.); Tongji Hospital (ITJ(ZD)1904 to L.S.); Fundamental Research Funds for the Central Universities of Tongji University (22120180355 to L.S.); Shanghai Science and Technology Foundation (19ZR1448600 to L.S.)
1836-P: Nonalcoholic Steatohepatitis (NASH) Significantly Contribute to ß-Cell Function Impairment Independently of Glucose Tolerance Status
Authors: VONGHIA LUISA , DIRINCK EVELINE , CARLI FABRIZIA , VERRIJKEN AN , WEYLER JONAS , MICHIELSEN PETER , VANWOLLEGHEM THOMAS , DRIESSEN ANN , GAAL LUC VAN , FRANCQUE SVEN , DE BLOCK CHRISTOPHE , GASTALDELLI AMALIA 
Published: June 2020

ß-cell dysfunction is a strong risk factor for type 2 diabetes (T2D). The liver plays a central role since insulin clearance (ClearIns) is up to 80% of the insulin secretion rate (ISR). ClearIns is reduced with insulin resistance (IR) and in patients with nonalcoholic fatty liver disease (NAFLD) . Our aim was to evaluate if ISR and ß-cell function were decreased in NASH vs. NAFL thus increasing their risk of T2D and the impact of ClearIns and IR. We measured glucose, insulin and c-peptide during a 3h oral glucose tolerance test in 341 subjects with liver biopsy and evaluated ISR (from deconvolution of c-peptide), ClearIns, Matsuda insulin sensitivity index (ISI) and disposition index (DI=ISI∙ΔAUC-I/ΔAUC-G); a low DI indicates a risk to develop T2D. Subjects were grouped according to glucose tolerance, normal (NGT), impaired (IGT) or T2D, and liver histology (noNAFL, NAFL, NASH-Fibrosis F0-F1 and F2-F4). The groups had similar BMI (∼34kg/m2). Severity of NAFLD was associated with increased IR, fasting and postprandial ISR and decreased ClearIns, after adjusting for age and BMI. DI was significantly lower in NASH-F24 in each glucose tolerance group (Figure).
Conclusion: Disposition index is reduced in relation to presence and severity of NASH independent of glucose tolerance status supporting an independent role of NASH in the development of T2D.

Disclosure
L. Vonghia: None. E. Dirinck: None. F. Carli: None. A. Verrijken: None. J. Weyler: None. P. Michielsen: None. T. Vanwolleghem: None. A. Driessen: None. L. Van Gaal: None. S. Francque: None. C. De Block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc.

Funding
Horizon2020 (634413)
1848-P: Insulin Sensitivity and Metabolic Profile of Subjects with Type 2 Diabetes and Nonalcoholic Steatohepatitis after Exposure to Cenicriviroc: A Subanalysis of the CENTAUR Study
Authors: COVIELLO ANDREA D. , RODRIGUEZ GERARDO , MARTINS EDUARDO B. , ALKHOURI NAIM , ABDELMALEK MANAL F. 
Published: June 2020

Introduction: In mice, C-C motif chemokine receptor (CCR)5 deletion protects against insulin resistance, hepatic steatosis, and glucose intolerance. We aimed to characterize the metabolic effects of cenicriviroc (CVC), a potent CCR2/5 inhibitor, in type 2 diabetes mellitus (T2DM) patients with nonalcoholic steatohepatitis (NASH) fibrosis from the Phase 2b CENTAUR study.
Methods: Subjects from CENTAUR with T2DM, biopsy-proven NASH, and fibrosis Stages F1-3 were included. CVC-exposed subjects for 1 year (Arm A) and placebo (PBO) [Arms B and C] were analyzed. Liver, metabolic, and inflammatory biomarkers were analyzed. Homeostatic model assessments (HOMA-IR and -b) were calculated. Change (from baseline to Year 1) was compared between groups using a general parametric linear model analysis of covariance (2-sided ANCOVA) based on the mITT population.
Results: Of the 289 subjects in CENTAUR, 134 (46%) had T2DM and were included in this analysis. Baseline characteristics were similar for CVC (n=76) and PBO (n=58) groups (mean ±SD): age 57.5 ±7.75 years vs. 55.41 ±8.65 years, HbA1c 7.30 ±1.29 vs. 7.20 ±1.21 %, BMI 33.02 ±5.25 vs. 35.16 ±7.67 kg/m2, NAS 5.25 ±1.06 vs. 5.52 ±1.13, and fibrosis scores of F1 (31.6%), F2 (21%), and F3 (47.4%) vs. F1 (24.2%), F2 (22.4%), and F3 (53.4%), respectively. At 1 year, there was a significant decrease in HOMA-IR and interleukin (IL)-6 in the CVC group. The least squares mean changes (SE) in HOMA-IR (p=0.0159) and IL-6 (p=0.0094), respectively, were −2.75 (1.27) and −1.9 (0.35) for CVC and 1.94 (1.45) and −0.5 (0.39) for PBO. After 1-year exposure to CVC or PBO, no significant differences vs. baseline in HOMA-b, HDL cholesterol, LDL cholesterol, ALT, and AST were noted.
Conclusion: CVC may improve HOMA-IR and pro-inflammatory cytokine IL-6, suggesting that CVC could potentially improve insulin resistance in NASH patients. These findings warrant further investigation.

Disclosure
A.D. Coviello: Consultant; Self; GI Dynamics Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., GENFIT, Orthus Health. Speaker’s Bureau; Self; Novo Nordisk Inc. G. Rodriguez: Employee; Self; Allergan plc. E.B. Martins: Employee; Self; Allergan plc. Stock/Shareholder; Self; Allergan plc. N. Alkhouri: Research Support; Self; Allergan plc. M.F. Abdelmalek: None.

Funding
Allergan plc