bluuebunny/crossref_metadata_2025_split huggingface dataset:
842-P: Development of Long-Acting GLP-1 Receptor Antagonist for the Treatment of Congenital Hyperinsulinism
Authors: YUAN YUE , JIANG HAOWEN , MENG SHI , HAN DONGNA , ZHU QIUSHA , WANG MANCHEN , LI HUSHAN , LI JIA , LI CHANGHONG 
Published: June 2023

Targeting beta-cell GLP-1 receptors has proven to be a viable strategy for the treatment of congenital hyperinsulinism (CHI), especially CHI due to loss of function mutations of KATP channels. Currently, Phase II clinical study of the GLP-1 receptor antagonist, Exendin-(9-39) has been successfully initiated. However, Exendin-(9-39) has a short half-life (less than 2 hrs), which limits its clinical applications. We are therefore trying to develop a long-acting GLP-1 receptor antagonist. AR-GLP1R-01 was synthesized based on chemical modification of Exendin-9-39. In order to test its efficacy in disease mouse models, SUR1 knockout mice was created by targeted deletion of abcc8 gene using CRISPR/Cas9. Exendin-9-39 and AR-GLP1R-01 were injected subcutaneously at doses of 216 nmol/kg. Plasma concentrations were determined by UPLC-MS at 30 min, 2 hrs and 10 hrs after injection. Plasma levels of Exendin-9-39 were 0.5 µM at 30 min after injection and were later undetectable at 2 and 10 hrs. In contrast, plasma levels of AR-GLP1R-01 were 2.0 µM at 30 min, peaked at 2 hrs, and remained at 2.9 µM after 10 hrs of injection. Compared to Exendin-(9-39), AR-GLP1R-01 has similar inhibitory effects in amino acid mixture-stimulated insulin secretion in perifused islets isolated from SUR1 knockout mice. In vivo experiments were performed by subcutaneous injection at a dosage of 216 nmol/kg twice a day at 10 am and 5 pm for 4 days. Similar to Exendin-9-39, AR-GLP1R-01 caused plasma glucose to increase 1 hr after injection. However, the glucose-increasing effects of AR-GLP1R-01 were maintained overnight before the 10 am injection for 4 days, while the effects of Exendin-9-39 failed to do so. In the separate experiments, the effects of AR-GLP1R-01 on glucose elevation can last for 24 hrs after a single dose injection. This early phase “proof of concept” study has shown that AR-GLP1R-01 is a long-acting GLP-1 antagonist and has potential to be developed into a once-a-day injection for the treatment of CHI.

Disclosure
Y.Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. H.Jiang: None. S.Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. D.Han: Employee; Nanjing AscendRare Pharmaceutical Technology. Q.Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. M.Wang: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. H.Li: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. J.Li: None. C.Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology.

Funding
Shandong Innovation Project (2019JZZY021012)
844-P: Lanifibranor Improves Markers of Cardiometabolic Health in Patients with NASH and Type 2 Diabetes, Correlated with Responses in Adiponectin Levels
Authors: GRIFFEL LOUIS H. , FRANCQUE SVEN , ABDELMALEK MANAL F. , HUOT-MARCHAND PHILIPPE , DZEN LUCILE , BAUDIN MARTINE , JUNIEN JEAN L. , BROQUA PIERRE , COOREMAN MICHAEL P. 
Published: June 2023

Background: Lanifibranor, a pan-PPAR agonist, has shown efficacy on liver histology and metabolic-immune markers of NASH in the phase 2b NATIVE study. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D). Adiponectin (ADP) is a pleiotropic adipokine which improves insulin resistance (IR), lipid metabolism, inflammation and fibrosis; low ADP levels are associated with risk for cardiovascular disease and NASH.
Methods: NATIVE evaluated lanifibranor 800 and 1200 mg/d versus placebo in 247 patients with non-cirrhotic NASH for 24 weeks treatment. Of these 103 had T2D, 144 did not have T2D of whom 47 had prediabetes defined by fasting glucose levels (FGL) between 5.6 - 6.9 mmol/l. ADP serum levels, metabolic-immune and hepatic markers (glycemic control, IR, lipids, systemic inflammation) were measured at baseline (BL) and end of treatment (EOT). In each subgroup, we evaluated ADP at BL, ADP fold-change at EOT, and correlation between ADP change and response of markers.
Results: ADP levels were lower in patients with T2D compared to those with pre-DM or normal glycemic control (NGC) (mean 4.6, 5.5, and 5.6 ug/ml, respectively). More patients with T2D had ADP below 5 mg/ml compared to pre-DM or NGC (65% vs 62/54%). In lanifibranor-treated group, ADP folds were similar in the 3 groups, with mean 4.3 fold increase by EOT, versus no increase in the placebo-treated group. In the pooled lanifibranor arms, increase in ADP correlated with improvements in glycemic control, IR, lipid metabolism, and systemic inflammation, consistently in the 3 groups, with higher improvements in patients with T2D and prediabetes compared to the NGC group.
Conclusion: The pan-PPAR agonist lanifibranor significantly improves ADP levels and this improvement correlated with markers of cardiometabolic health in patients with T2D and prediabetes. Lanifibranor improves cardiovascular risk profile in patients with impaired glycemic control and NASH.

Disclosure
L.H.Griffel: Employee; Inventiva Pharma. S.Francque: None. M.F.Abdelmalek: Advisory Panel; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Inventiva Pharma, Novo Nordisk, Merck & Co., Inc., Sonic Incytes, NGM Biopharmaceuticals, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Boehringer Ingelheim Inc., Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk, Poxel SA, DURECT Corporation, Enyo Pharma, Enanta, Genentech, Inc., Celgene, NGM Biopharmaceuticals, TARGET PharmaSolutions, Inc., Allergan. P.Huot-marchand: Employee; Inventiva Pharma. L.Dzen: Employee; Inventiva Pharma. M.Baudin: Employee; Inventiva Pharma. J.L.Junien: Consultant; Inventiva Pharma. P.Broqua: None. M.P.Cooreman: Employee; Inventiva Pharma.
846-P: Risk of Anaphylaxis among New Users of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)
Authors: ANTHONY MARY S. , DJEBARRI LEILA , BEACHLER DANIEL C. , ARODA VANITA R. , CALINGAERT BRIAN , PAN CHUNSHEN , CROWE CHRISTOPHER , LANES STEPHAN , ROTHMAN KENNETH J. , SALTUS CATHERINE W. , BERREGHIS SOFIA , PARLETT LAUREN E. , BOCAGE CLAIRE , WALSH KATHLEEN E. , JUHAERI JUHAERI , JOHANNES CATHERINE 
Published: June 2023

GLP-1 RAs are peptides used to treat patients with T2D. Anaphylaxis has been observed with these treatments, and in the lixisenatide development program, more cases of anaphylaxis were reported for lixisenatide than placebo (0.2% vs 0.1%). The aim was to assess anaphylaxis incidence rates (IRs) among patients with T2D initiating GLP-1 RAs, with a focus on lixisenatide. We conducted a cohort study in 3 large US claims databases using data from 2017-2021. We included new users of GLP-1 RAs with T2D aged ≥18 years and enrolled ≥6 months in the database before GLP-1 RA initiation (start of follow-up). Medications included were: lixisenatide and insulin glargine/lixisenatide, exenatide, liraglutide and insulin degludec/liraglutide, dulaglutide, and semaglutide. We identified the first anaphylaxis event during follow-up using a validated algorithm. We report anaphylaxis crude IRs and 95% confidence intervals (CIs) for each medication cohort, pooled across data sources. There were 696,089 new users with 456,612 person-years (p-y) of exposure to GLP-1 RAs. Baseline characteristics (demographics, medications, medical conditions) were similar across the medication cohorts. IRs ranged from 1.0 (lixisenatide) to 6.0 (exenatide) per 10,000 p-y with wide 95% confidence intervals (Figure). Anaphylaxis is rare with GLP-1 RA treatments. Lixisenatide is unlikely to confer higher risk of anaphylaxis than other GLP-1 RAs.

Disclosure
M.S.Anthony: Other Relationship; Sanofi. C.W.Saltus: Other Relationship; Sanofi. S.Berreghis: Employee; Sanofi. L.E.Parlett: Employee; HealthCore Inc., Research Support; Sanofi. C.Bocage: Employee; Anthem, Inc, Stock/Shareholder; Anthem, Inc. K.E.Walsh: Consultant; Sanofi. J.Juhaeri: Employee; Sanofi. C.Johannes: Other Relationship; Sanofi-Aventis U.S. L.Djebarri: Employee; Sanofi. D.C.Beachler: Employee; Anthem, Inc, HealthCore Inc. V.R.Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. B.Calingaert: Other Relationship; Sanofi. C.Pan: None. C.Crowe: Employee; HealthCore Inc. S.Lanes: None. K.J.Rothman: None.
855-P: Evolution of KT-A112, an AAV-Mediated Gene Therapy for the Treatment of Type 1 Diabetes
Authors: SMITH CHARI , HARRINGTON WILLIAM W. , STONE MICHELE , KARADGE UMA , LIU JIEWU , QUINN WILLIAM J. , BASSIRI ASHLYN , MALLORY JASON , JIMENEZ VERONICA , BOSCH FATIMA , RHODES MELISSA 
Published: June 2023

Type 1 Diabetes (T1D) is a chronic, life-threatening autoimmune disorder characterized by profound insulin deficiency that results from progressive destruction of insulin-producing pancreatic β-cells. For over a century, exogenous insulin delivery was the only option to help T1D patients manage persistent hyperglycemia and reduce the risk of severe microvascular and macrovascular complications. Recent exploratory treatments use complex cell-based therapies requiring long-term immunosuppression. This abstract describes a unique AAV-mediated gene therapy approach to drive skeletal muscle expression of human glucokinase (GcK) and human insulin (INS). One-time IM administration to the quadriceps, gastrocnemius and tibialis anterior muscles of STZ-induced diabetic mice resulted in dose-related increases of pharmacologically active INS at fasting levels (~1 ng/mL) and human C-peptide that decreased fed and fasted blood glucose, lowered HbA1c by &gt;5% at the highest dose, and reduced AUCGlu upon oral glucose challenge. Elevated triglycerides seen in control STZ-treated animals were normalized. No hypoglycemia or other adverse effects were observed through 8 weeks. No immunosuppression was required. Next steps in evaluation of KT-A112 involve a rolling dose-escalation study in STZ-treated NHPs.

Disclosure
C.Smith: Consultant; Horizon Therapeutics plc, Employee; Kriya Therapeutics. F.Bosch: None. M.Rhodes: None. W.W.Harrington: Consultant; Kriya Therapeutics. M.Stone: None. U.Karadge: None. J.Liu: None. W.J.Quinn: Employee; Kriya Therapeutics. A.Bassiri: None. J.Mallory: Employee; Kriya Therapeutics. V.Jimenez: None.
857-P: Quiescence Recovers Adipose Tissue–Derived Stromal Cells from Senescence-Associated Secretory Phenotype, Leading to Enhanced Angiogenesis and Diabetic Wound Healing
Authors: FUNAKI MAKOTO , HATA AKIKO , YOSHIDA MITSUTERU , MIYAMOTO NAOKI , IKUTA TAKAHISA , UEMURA YUTA , AKIZUKI MINATO , TANGOKU AKIRA , YUMOTO HIROMICHI , OGAWA HIROHISA , OYA TAKESHI 
Published: June 2023

Although a number of studies have shown that mesenchymal stem cells (MSCs) promote diabetic wound healing, their clinical applications are still limited. One of the reasons is that MSCs exhibit a senescence-associated secretory phenotype (SASP) in diabetes, which results in attenuation of their anti-inflammatory functions. We previously reported that adipose tissue-derived stromal cells (ADSCs), one type of MSCs used in multiple clinical trials, are able to exhibit their anti-inflammatory functions when they become quiescent in gels with a stiffness mimicking that of adipose tissue. We also showed that transplants containing quiescent ADSCs enhanced diabetic wound healing more than those containing non-quiescent ADSCs. Here, we investigated the effect of inducing quiescence in ADSCs on their angiogenic functions in a high glucose environment both in vitro and in vivo. High glucose-induced attenuated migration and tubular formation of HUVECs, an endothelial cell line, were ameliorated more significantly by conditioned medium from quiescent ADSCs cultured under high glucose than by that from non-quiescent ADSCs cultured under high glucose. Furthermore, ADSCs cultured at a high glucose level in vitro enhanced angiogenesis and wound healing in STZ-induced diabetic mice similarly to ADSCs cultured at a normal glucose level in vitro, when they were made quiescent in gels and subcutaneously injected into the mice. These results suggest that quiescence restores ADSCs from SASP and enhances angiogenesis even under diabetic conditions, which may be crucial for MSC-based cell therapies against diabetic microangiopathy.

Disclosure
M.Funaki: Board Member; Mechanogenic, Inc. H.Ogawa: None. T.Oya: None. A.Hata: None. M.Yoshida: None. N.Miyamoto: None. T.Ikuta: None. Y.Uemura: None. M.Akizuki: None. A.Tangoku: None. H.Yumoto: None.
868-P: Empagliflozin (EMPA) Improves Vascular Insulin Sensitivity and Enhances Skeletal and Cardiac Muscle Microvascular Perfusion in Persons with Type 2 Diabetes
Authors: JAHN LINDA , HARTLINE LEE , AYLOR KEVIN W. , HORTON WILLIAM B. , BARRETT EUGENE 
Published: June 2023

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) decreased cardiac events in large clinical trials; however, an understanding of the physiology driving this benefit is lacking. To investigate this, we measured micro- and macrovascular insulin sensitivity in 10 adults with T2DM before and after 12 weeks of EMPA 10 mg daily. We also measured endothelial function (FMD), peripheral and central aortic pressures, and skeletal (SM) and cardiac (CM) muscle microvascular perfusion (MBV- microvascular blood volume; MFV-microvascular flow velocity; MBF-microvascular blood flow) before and during a 120 min euglycemic insulin clamp at weeks 0 and 12. We hypothesized that EMPA would diminish micro- and macro-vascular insulin resistance and improve vascular function. At week 0, insulin infusion lowered peripheral SBP (132±6 vs 125±5, p&lt;0.05) but diminished SM perfusion MBV (1.75±0.2 vs 1.29±0.1, p&lt;0.01) MFV (0.08±0.01 vs 0.05±0.01, p&lt;0.001) and MBF (0.14±3 vs 0.07±0.01, p&lt;0.01). After 12 weeks of EMPA, insulin infusion improved FMD (7.6 ± 1.2 vs 8.7 ±1.6%, p &lt;0.03), lowered peripheral SBP (127±6 vs 107±5, p&lt;0.001); DBP (74±4 vs 65±3, p&lt;0.04); MAP (92±3 vs 79±3, p&lt;0.01); and PP (53±5 vs 42±3, p&lt;0.05) as well as aortic SBP (117±5 vs 96±4, p&lt;0.001); DBP (75±4 vs 66±3, p&lt;0.03); MAP (89±3 vs 76±3, p&lt;0.01); and PP (43±4 vs 30±2, p&lt;0.01). In addition, EMPA improved SM perfusion (MBV: 1.29±0.1 vs 2.02±0.3, p&lt;0.02; MFV: 0.05±0.01 vs 0.08±0.01, p&lt;0.02; MBF: 0.07±0.01 vs 0.18±0.04, p&lt;0.03) and CM perfusion (MBV: 4.51±0.6 vs 5.11±0.4, p=0.18; MFV: 0.37±0.04 vs 0.52±0.06, p&lt;0.05; MBF: 1.80±0.4 vs 2.74±0.5, p&lt;0.05). In conclusion, 12 weeks of EMPA in adults with T2D improved endothelial function (FMD), reduced central and peripheral blood pressures, and augmented SM and CM microvascular perfusion in response to insulin. These changes may contribute to the improved CV outcomes seen with SGLT2i therapy.

Disclosure
L.Jahn: None. L.Hartline: None. K.W.Aylor: None. W.B.Horton: None. E.Barrett: None.

Funding
National Institutes of Health (1R01HL142250-01A1)
87-OR: Engineered Vasculature Induces Functional Maturation of Pluripotent Stem Cell–Derived Islet Organoids
Authors: NGUYEN-NGOC KIM-VY 
Published: June 2023

Blood vessels play a critical role in islet health and function. Native islets are richly vascularized and their interaction with blood vessels is important for β-cell function. Therefore, vasculature ought to be an integral component of a model for studying human islet physiology and diabetes pathobiology. Here, we develop a vascularized islet organoid model by integrating hPSC-derived islets (SC-islets) with human endothelial cells (ECs) and fibroblasts (FBs). To analyze β-cell function, we generated an hPSC line carrying GCaMP6f, a Ca2+ reporter, as Ca2+ oscillation can be used as a proxy for insulin secretion. Comparing β-cell Ca2+ responses of non-vascularized and vascularized SC-islets revealed more frequent and stronger Ca2+ influx in response to high glucose and the GLP-1 analogue in vascularized SC-islets. To identify vasculature-derived signals beneficial to β-cell function, we performed cell-cell interaction network analyses based on single-cell transcriptomic data from SC-islets, ECs, and FBs. Among the top candidates were integrin receptors that interact with extracellular matrix proteins. Consistent with these predictions, a higher number of β-cells were in contact with EC-derived basement membrane proteins (e.g., laminin α1, collagen IV) and exhibited activation of integrin β1. The analysis also revealed BMP4-BMPR2 as a potential crosstalk between ECs and β-cells. Indeed, BMP4 addition augmented Ca2+ response and insulin secretion of β-cells under glucose stimulation. Finally, to develop a system mimicking in vivo physiology, we integrated SC-islets into a microfluidic platform where the organoids are supported by a network of perfused microvessels. Our newly-established model of vascularized SC-islet organoids will enable further studies of crosstalk between β-cells and vasculature under conditions mimicking the native islet microenvironment. The model will serve as a platform to study disease mechanisms of diabetes and test therapeutics.

Disclosure
K.Nguyen-ngoc: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (UG3DK1226390); JDRF (3-PDF-2017-386-A-N, 3-PDF-2020-932-A-N)
88-OR: Targeted Drug Delivery to Human ß-Cells Using Novel Nanocapsule Delivery Vehicle for T1D Treatment
Authors: COLLINS JILLIAN , HOLCOMB KEIFER , OCAMPO ANDRES , SHILLEH ALI , RUSS HOLGER A. , FARNSWORTH NIKKI L. 
Published: June 2023

In type 1 diabetes (T1D), autoreactive immune cells destroy insulin secreting β-cells in pancreatic islets. Islet transplantation shows promise in restoring glucose homeostasis without exogenous insulin; however, long-term graft survival remains a critical barrier to the success of this treatment. Therapies aimed to protect or proliferate endogenous β-cells have off target affects and require targeted delivery to improve efficacy. We have developed a nanocapsule (NC) delivery system to specifically target and deliver cargo to human β-cells. We hypothesize NCs will selectively be taken up by human β-cells and deliver therapeutic cargo. NCs were synthesized with a water in oil emulsion evaporation technique. NCs were coated via ionic interactions with ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) antibody, a human β-cell specific marker or Exendin-4 conjugated to hyaluronic acid (HA-Ex4). NC size, size distribution, charge, stability, and drug release profiles were determined. NCs loaded with pentamidine (PTM) or Cy5 were cultured for 24-168h with human iPSC-derived β-cells (sBC) or injected into the tail vein of NOD-SCID mice. Confocal microscopy confirmed delivery of cargo to β-cells and pancreatic islets, viability, and cytotoxicity. NCs were 271 ± 7nm in size with excellent size homogeneity (polydispersity index 0.06 ± 0.03, n=3). NCs displayed a sustained release of cargo for &gt;45 days (n=5). In vitro, we observed no cytotoxicity of NCs up to 168h (n=3) and a significant increase in β-cell death with PTM loaded ENTPD3 coated NCs compared to controls at 24 (p&lt;0.001, n=4) and 72h (p&lt;0.01, n=4). sBCs treated with PTM loaded ENTPD3 coated NCs had more insulin+ dead cells (88 ± 4%) than controls (p&lt;0.01, n=4). ENTPD3 or HA-Ex4 NCs were internalized into sBCs in vitro and pancreatic islets in vivo respectively. Our data shows long term stability and in vivo targeting of NCs to β-cells and supports use of our NCs for targeted delivery of therapeutics to human β-cells to treat T1D.

Disclosure
J.Collins: None. K.Holcomb: None. A.Ocampo: None. A.Shilleh: None. H.A.Russ: Advisory Panel; Sigilon Therapeutics, Inc., Consultant; Prellis, Minutia, Eli Lilly and Company. N.L.Farnsworth: None.

Funding
JDRF (1-INO-2022-1231-S-B); National Institutes of Health (P30-DK116073)
880-P: Effects of Sodium–Glucose Cotransporter-2 Inhibitors on the Risk of Atrial Fibrillation in Older Adults with Type 2 Diabetes
Authors: LI YUJIA , GUO YI , KIMMEL STEPHEN , BIAN JIANG , SCHATZ DESMOND , GUO JINGCHUAN 
Published: June 2023

Clinical evidence suggested a protective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the risk of atrial fibrillation (AF) in type 2 diabetes (T2D) patients, but the results were mixed. We aimed to compare the risk of AF in SGLT2i users compared to dipeptidyl peptidase-4 inhibitors (DPP4i) users and determine the effect in different subgroups. Using a 15% random sample of 2017-2018 Medicare claims data, we identified individuals with T2D, no preexisting AF, and initiated SGLT2i or DPP4i. The index date was defined as the date of the first filled prescription of SGLT2i or DPP4i. The outcome was the first incident of diagnosed AF. Inverse probability treatment weighted Cox regression models were used for analyses. Of the 97,660 eligible individuals (age 71.2±9.8 years, 54.6% women), 1.01% (n=989) had incident AF over a median follow-up of 361 days. The crude incidence rate was 8.39 (95% CI: 6.67-9.99) and 11.70 (95% CI: 10.9-12.55) per 1000 person-years in the SGLT2i group and DPP4i group, respectively. SGLT2i was associated with a significantly lower risk of incident AF (HR 0.72 [95% CI 0.56-0.89]) than DPP4i. The risk reduction of incident AF was more pronounced in Hispanic individuals and subgroups with existing cardiovascular (CV) and renal conditions. (Figure) Use of SGLT2i was associated with a lower risk of AF in individuals with T2D.

Disclosure
Y.Li: None. Y.Guo: None. S.Kimmel: Consultant; GlaxoSmithKline plc., Other Relationship; Janssen Research & Development, LLC. J.Bian: None. D.Schatz: Advisory Panel; Medtronic, Avotres Inc., QuLab Medical Ltd., Kriya Therapeutics. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health.
882-P: Effects of YG1699 and Sotagliflozin on Intestinal Glucose Absorption and GLP-1 in Mice
Authors: LI JACKY , XU ROGER W. , HE JIAOJUAN , LAPUERTA PABLO 
Published: June 2023

Background and Aims: YG1699, a dual inhibitor of SGLT1 and SGLT2, recently showed greater glucose reduction than dapagliflozin in patients with type 1 diabetes. This study examined whether YG1699 provides gastrointestinal SGLT1 inhibition.
Materials and Methods: Male BALB/c mice (n=105) were randomly divided into five groups: vehicle, YG1699 at low (1mg/kg), medium (3mg/kg), and high doses (10mg/kg), and LX4211 (sotagliflozin) 10mg/kg by oral gavage. Animals received a 5g/kg glucose challenge 15 minutes after study drug. Animals were euthanized at various times to examine intestinal plasma GLP-1 and glucose content in small intestine, cecum, and colon. Differences between groups were evaluated by ANOVA.
Results (See Table 1): Small intestinal glucose content 1 hour after glucose challenge increased in a dose-related fashion with YG1699 compared to vehicle (p&lt;0.001 for each YG1699 group vs. vehicle). Similar results were found in cecum (p&lt;0.05 for each YG1699 group vs. vehicle). Plasma GLP-1 and PYY concentrations at 1 hour were higher on YG1699 vs. vehicle. Intestinal glucose content in the sotagliflozin group was similar to vehicle and the plasma GLP-1 were only numerically increased in this group.
Conclusion: YG1699 delays intestinal glucose absorption and induces an incretin response in BALB/c mice, indicating significant gastrointestinal SGLT1 inhibition.

Disclosure
J.Li: None. R.W.Xu: Consultant; Youngene Therapeutics. J.He: None. P.Lapuerta: Board Member; 4M Therapeutics, Consultant; Youngene Therapeutics, ViaCyte, Inc., Encuragen, Capsida, Provention Bio, Inc., Decibel Therapeutics, Crinetics, Next Phase Therapeutics.