bluuebunny/crossref_metadata_2025_split huggingface dataset:
220-OR: First-in-Human Study of a Pharmacological Duodenal Exclusion Therapy Mimics a Roux-en-Y Gastric Bypass Biomarker Signature
Authors: FINEMAN MARK , BRYANT CHRISTINE , COLBERT KEVIN , JOZEFIAK THOMAS H. , PETERSEN JOHN S. , VORA JITEN , RAYNER CHRISTOPHER K. , NIMGAONKAR ASHISH 
Published: June 2023

To address the need for non-invasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity, we designed an orally administered therapeutic polymer, GLY-200, that binds to and enhances the barrier function of mucus in the gastrointestinal tract.
Methods: A Phase 1, randomized, double-blind, placebo (PBO)-controlled, multiple ascending dose study was conducted in healthy volunteers. Four cohorts (N=32, 19-61 yrs, BMI 26.2 ± 3.20 kg/m2) received 5 days of BID or TID dosing (total daily dose between 2.0 g and 6.0 g GLY-200 or PBO). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics (PD), including serum glucose, insulin, bile acids, and gut hormones.
Results: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. On Day 5, reductions in glucose and insulin and increases in bile acids, GLP-1, PYY, and glicentin were observed following a non-standardized meal in subjects receiving 2.0 g BID GLY-200 (N=9) vs PBO (N=8).
Conclusions: GLY-200 is safe and generally well tolerated. PD results mimic the biomarker signature observed following RYGB and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine.

Disclosure
M.Fineman: Employee; Glyscend Inc., Stock/Shareholder; Glyscend Inc. C.Bryant: Employee; Glyscend Inc. K.Colbert: Consultant; LifeSprout, Employee; Glyscend Inc. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. J.S.Petersen: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. C.K.Rayner: Advisory Panel; Glyscend Inc. A.Nimgaonkar: Employee; Glyscend Inc.
221-LB: Identification of PAM as Novel Monogenic Diabetes Gene
Authors: FEINER JAMES , PERROT NICOLAS , CHONG MICHAEL , LALI RICKY , MORTON ROBERT , MOHAMMADI-SHEMIRANI PEDRUM , YUSUF SALIM , GERSTEIN HERTZEL C. , PARE GUILLAUME , PIGEYRE MARIE 
Published: June 2023

Background/Objectives: Various biological mechanisms involved in type 2 diabetes (T2D) have been unveiled through converging evidence in common variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFV) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both RV/LFV and common variants could yield identification of new pathways involved in T2D.
Methods: Protein-altering RV/LFV burden was tested for T2D association in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. Significant encoded proteins were then investigated using 2-sample Mendelian randomization for causal association with T2D and related variables. Protein quantitative trait loci were estimated in the Prospective Urban and Rural Epidemiological study (N=11,020) and tested against GWAS-summary statistics of T2D and related traits from 10 consortia.
Results: At the EXWAS significance threshold (P=0.05/19,589=2.55×10-6), we identified loss-of-function RV/LFV in GCK and PAM, which encode the proteins glucokinase and peptidylgycine α-amidating monooxygenase respectively, to be associated with T2D risk. Deleterious mutations in the PAM gene were associated with an 29% increase in T2D risk (OR per RV/LFV=1.29; 95%CI=1.17-1.43; P=7.17×10-7). This association was driven by a low frequency variant, rs78408340-G present in 2.6% of T2D cases and only in 1.8% of controls. MR analyses confirmed that 1 SD decrease in PAM circulating levels was consistently associated with increased T2D risk (OR=1.16; 95%CI=1.14-1.19; P=9.54×10-52) and HbA1c (%) (β=0.0047; 95%CI= 0.00051-0.0090; P=0.028), and decreased post-prandial insulin (mU/L) secretion (β=-0.060; 95% CI=-0.083(-)-0.036; P=8.32×10-7).
Conclusion: We identified PAM variants as a novel cause of monogenic diabetes and demonstrated a strong causal effect of circulating PAM levels on T2D risk and post-prandial insulin secretion. This supports further investigation of PAM as a therapeutic T2D target.

Disclosure
J. Feiner: None. N. Perrot: None. M. Chong: Research Support; Bayer Inc. R. Lali: None. R. Morton: None. P. Mohammadi-Shemirani: None. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott Diagnostics, Eli Lilly and Company, Sanofi. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk. Research Support; Eli Lilly and Company, Sanofi. Advisory Panel; Kowa Company, Ltd., Hanmi Pharm. Co., Ltd. Other Relationship; Zuellig Pharma Holdings Pte. Ltd., DKSH, AstraZeneca. G. Pare: Research Support; Bayer Inc. Advisory Panel; Bayer Inc., Amgen Inc., Novartis AG. M. Pigeyre: None.

Funding
Bayer; Canadian Institutes of Health Research
223-OR: Identification of Novel Therapies for Monogenic Diabetes Using Connectivity Map (CMap)
Authors: KREIENKAMP RAYMOND J. , BRYAN CHRISTOPHER , FLOREZ JOSE C. , UDLER MIRIAM 
Published: June 2023

Monogenic diabetes is an underdiagnosed form of diabetes that is caused by DNA variation of strong effect in a single gene. While it is an exciting area for targeted drug development, as some forms of monogenic diabetes can be treated with gene-specific therapies, there are currently few targeted therapies available. Additionally, existing treatments are not able to cure or modify the underlying disease. Therefore, to identify novel therapies, we leveraged CMap, a data resource developed at the Broad Institute that contains over one million gene expression signatures from treatment of cell types with perturbagens including drugs, bioactive small molecules, gene overexpression, and gene knockdown reagents. We analyzed connectivity, or the similarity between two gene expression signatures, to search for perturbagen gene expression signatures opposing gene expression changes associated with monogenic diabetes. We were able to identify 15 classes of medications with significantly enriched connectivity with HNF1A-knockdown by Mann-Whitney U-test (BH-adjusted P&lt; 0.05). Included in these classes were sulfonylureas, which are known to have preferential therapeutic benefit for this specific condition, supporting this method for drug discovery. Other medications included HDAC inhibitors, tyrosine kinase inhibitors, and riboflavin. We also surveyed other genes causing monogenic syndromes that include diabetes, such as PPARG, where CMap indicated high connectivity with thiazolidinediones (BH-adjusted P=0.015), a type 2 diabetes drug class with known mechanism targeting PPARγ, opposing PPARγ-knockdown and beneficial for treating patients with PPARγ-driven familial partial lipodystrophy. Our findings support the use of expression signature mapping as a novel approach for identifying therapies for monogenic diabetes. Further exploration of databases like CMap and validation of identified medication classes could lead to new pharmacological treatments for diabetes.

Disclosure
R.J.Kreienkamp: None. C.Bryan: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. M.Udler: None.

Funding
National Institutes of Health (T32GM774844, K24HL157960, K23DK114551); Pediatric Endocrine Society
225-LB: Reciprocal Regulatory Interactions of Adipocytes and B Lymphocytes
Authors: BREWER JOSEPH W. , ALLMAN MARY K. , CARROLL STEVEN R. , GRANGER SARAH , HALL ALEXANDER , POWNALL KEELEY , QUINTANA JOSHUA , ARELLANO RANGEL NANCY , THOMAS JADE , JUDD ROBERT L. 
Published: June 2023

Obesity, a global health problem, leads to chronic inflammation of adipose tissue (AT), an immune-mediated process linked to metabolic dysfunction and disease, including type II diabetes mellitus. Adipocytes, the most abundant cellular constituent of AT, store lipids and secrete adipokines, a group of hormone-like molecules such as adiponectin and adipsin that regulate metabolism and immune cell functions. In mouse models of diet-induced obesity, distinct subsets of B lymphocytes have been implicated in both exacerbating and mitigating AT inflammation and insulin resistance, but the immunoregulatory mechanisms underlying these effects are incompletely understood. Similarly, whether B lymphocytes and adipocytes engage in regulatory interactions with each other is not known. To investigate this question, we performed in vitro co-culture studies using murine 3T3-L1 adipocytes and I.29µ+ B cells, a murine B cell lymphoma that initiates robust secretion of IgM antibodies and the anti-inflammatory cytokine interleukin (IL)-10 upon activation by lipopolysaccharide (LPS). The induction of IgM and IL-10 secretion was markedly attenuated when I.29µ+ B cells were stimulated with LPS while co-cultured in direct contact with 3T3-L1 adipocytes. This inhibitory effect was also observed, albeit to a lesser degree, when the two cell types were co-cultured but separated by a semipermeable membrane. Conversely, secretion of adiponectin and adipsin by 3T3-L1 adipocytes was reduced when the adipocytes were co-cultured with I.29µ+ B cells, both in direct contact and when separated by a semipermeable membrane. This reduction of adipokine output was observed in both the absence and presence of LPS to activate the B cells. These data support the hypothesis that B lymphocytes and adipocytes can engage in reciprocal interactions that modulate the functions of these two secretory cell types and, in turn, may influence AT homeostasis and inflammation in healthy and obese states.

Disclosure
J. W. Brewer: None. R. L. Judd: None. M. K. Allman: None. S. R. Carroll: None. S. Granger: None. A. Hall: None. K. Pownall: None. J. Quintana: None. N. Arellano rangel: None. J. Thomas: None.

Funding
Edward Via College of Osteopathic Medicine Center for One Health
225-OR: The Effect of Tirzepatide vs. Insulin Degludec on Post-meal Glucose Control in Patients with Type 2 Diabetes (SURPASS-3 CGM)
Authors: BATTELINO TADEJ , JOHNSON JENNAL , KATZ MICHELLE , BRAY ROSS , XUE JIE , BROWN KATELYN 
Published: June 2023

Tirzepatide (TZP) is a GIP/GLP-1 receptor agonist approved for treatment of patients with type 2 diabetes (T2D). This post-hoc analysis evaluated the impact of TZP vs insulin degludec (IDeg) on post-meal glucose control. In this sub-study of the 52-week open label, parallel arm, Phase 3, SURPASS-3 trial, 243 insulin naive adults with T2D (mean age 57 years; T2D duration 8.8 years, HbA1c 8.15%), were randomised (1:1:1:1 to receive weekly TZP 5, 10, 15 mg or titrated IDeg daily). Interstitial glucose values were collected by continuous glucose monitor (CGM) for approx. 7-10 days at baseline and 52 weeks. The 5-hour post-prandial period (PPP) was defined after meals detected via a validated algorithm. The impact of TZP 5, 10, and 15mg vs IDeg on interstitial glucose post meal from area under the curve (AUC) and peak post prandial glucose (PPG) at 52 weeks were assessed. PPG excursions were decreased with all doses of TZP as seen by less AUC &gt;140 mg/dL and &gt;180 mg/dL vs IDeg (Fig). All TZP doses spent significantly less time &gt; 140mg/dL during the PPP 0-5 hrs (135, 96, and 99 mins for TZP 5, 10, and 15mg) vs IDeg (171 mins; p=0.051, p&lt;0.001, p&lt;0.001 respectively). All TZP doses had significantly lower peak PPG at 52 weeks vs IDeg (180.4 ± 4.45 mg/dL, 163.2 ± 4.97 mg/dL, 168.5 ±4.38 mg/dL vs 198.6± 4.98mg/dL respectively, p&lt;0.001). All 3 doses of TZP led to improved AUC and reduced peak PPG vs IDeg as assessed by CGM.

Disclosure
T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc. J.Johnson: Employee; Eli Lilly and Company. M.Katz: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. R.Bray: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Xue: Employee; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company.

Funding
Eli Lilly and Company
228-OR: Accuracy and Reliability of Real-Time Continuous Glucose Monitoring in the Intensive Care Unit after Major Abdominal Surgery
Authors: HAGERF (VOGLOVÁ) BARBORA , PROTUS MAREK , NEMETOVA LENKA , MRAZ MILOS , HALUZIK MARTIN , GIRMAN PETER , FRANEKOVA JANKA , SVIRLOCHOVA VERONIKA , JABOR ANTONIN 
Published: June 2023

Introduction: Blood glucose control in patients requiring intensive care remains a therapeutic challenge; however, recent advancements in glucose sensing technologies have sparked interest in the potential use of real-time continuous glucose monitoring in the subcutaneous compartment (rtCGM) also in the intensive care unit (ICU) setting. We performed a clinical trial assessing the accuracy and reliability of rtCGM in postoperative ICU patients after major abdominal surgery.
Methods: Patients undergoing pancreatic surgery, liver transplantation, pancreas (or pancreatic islets) and kidney transplantation were enrolled in the trial. Dexcom G6 (Dexcom, Inc., San Diego, USA) was used for rtCGM. Arterial blood glucose measured by the amperometric principle (ABL 800, Radiometer, Copenhagen, Denmark) served as reference and to calibrate the Dexcom G6 (every 6 hours on day 1, once daily day 2 and 3). Sensor accuracy was assessed by computing mean absolute relative difference (MARD), bias, modified Bland-Altman plot and surveillance error grid for paired samples of glucose values from CGM and ABL.
Results: Sixty-one patients after major abdominal surgery staying in ICU post-operatively were included into this analysis. Median monitoring length was 7 days with a 97.1 ± 6.5% proportion of active CGM use. Overall, 1566 paired glucose values measured with CGM and ABL were obtained. MARD for CGM compared with ABL-measured glucose was 9.7% with a bias of 0.9% and coefficient of variation of 14%. In the surveillance error grid analysis, 90.9% of pairs were in the 0 risk zone and 7.9% in the risk zone 1 (out of 7). Throughout the study 3 sensors needed to be replaced due to technical problems.
Conclusion: Our results show a clinically applicable accuracy and reliability of the Dexcom G6 continuous glucose monitoring system in postoperative ICU. This opens up new possibilities in intensifying ICU glucose control, lowering hypoglycaemia risk and reducing nursing staff workload.

Disclosure
B.Hagerf (voglová): None. M.Protus: None. L.Nemetova: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. P.Girman: None. J.Franekova: None. V.Svirlochova: None. A.Jabor: None.

Funding
Charles University; Czech Ministry of Health; Institute for Clinical and Experimental Medicine (IKEM, IN00023001); National Institute for Research of Metabolic and Cardiovascular Diseases (EXCELES, LX22NPO5104)
235-OR: Myc Activity Is Required for Mitochondrial Function and Glucose-Stimulated Insulin Secretion (GSIS) in Pancreatic ß-Cells
Authors: LU GEMING , KANG RANDY , DIAZ-POZO PEDRO , LEE JUNGEUN , LI MINGPEI , VICTOR VICTOR M. , SCOTT DONALD , GARCIA-OCANA ADOLFO 
Published: June 2023

Glucose enhances mitochondrial function, insulin secretion and Myc expression in β-cells. β-cell-specific Myc knockout mice show glucose intolerance, hypoinsulinemia and lack of adaptive β-cell mass expansion following high-fat diet feeding. However, whether Myc regulates GSIS and mitochondrial function in β-cells is unknown. Here, we tested the effects of the Myc activity inhibitor 10058-F4 (1RH) in GSIS, mitochondrial function and metabolism in islets using islet perifusion, Seahorse and metabolomics/transcriptomics approaches. Mouse and human islets incubated 6h with 40µM 1RH displayed impaired phase 1 and phase 2 insulin secretion induced by 11mM glucose. Insulin secretion was not affected in the presence of 25mM KCl suggesting that Myc is required for glucose- but not membrane depolarization-induced insulin secretion. Since adequate mitochondrial function is essential for GSIS, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to analyze mitochondrial respiration and glycolytic flux in these islets. 1RH significantly reduced OCR, ECAR and glucose-induced ATP production. Conversely, the Myc inducer harmine (10µM), increased basal OCR, ATP production, and ECAR and partially reversed 1RH effects on mitochondrial function. RNAseq of mouse islets treated with 1RH in 11mM glucose revealed reduced expression of both oxidative phosphorylation and β-cell signature genes but enhanced gene expression of glycolysis, ROS, fatty acid metabolism and autophagy/mitophagy pathways. Metabolomics analysis of mouse islets treated with 1RH in 11mM glucose confirmed the reduction in ATP and highlighted the accumulation of L-palmitoylcarnitine and palmitic acid suggesting inefficient β-oxidation. In conclusion, Myc is required for GSIS and mitochondrial function in β-cells. Impaired Myc action can lead to unbalanced metabolism and autophagy/mytophagy leading to β-cell dysfunction.

Disclosure
G.Lu: None. R.Kang: None. P.Diaz-pozo: None. J.Lee: None. M.Li: None. V.M.Victor: None. D.Scott: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd.

Funding
National Institutes of Health (R01DK126450)
237-LB: Regulation of Brown Adipose Tissue Neurovasculature by Slit3 Fragments
Authors: NETO FELIPPE M. , CERVANTES HEIDI E. , DUARTE AFONSO SERDAN TAMIRES , SHAMSI FARNAZ 
Published: June 2023

The ability of brown adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a target against obesity. Chronic cold exposure increases brown adipose tissue (BAT) mass by de novo recruitment of brown adipocytes, as well as expanding the number of blood vessels and sympathetic nerves in the tissue. This coordinated expansion of the BAT neurovasculature is essential for enhanced thermogenesis. However, how these distinct processes are coordinated remains unclear. We have recently identified Slit guidance ligand 3 (Slit3) as a new niche factor that mediates crosstalk between preadipocytes, sympathetic neurons, and endothelial cells. We showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT and that loss of Slit3 impairs cold-induced BAT thermogenesis in vivo. However, how Slit3 regulates the expansion of angiogenesis and sympathetic innervation is not known. Members of the Slit family are proteolytically cleaved into a large N-terminal fragment and a shorter C-terminal fragment. We observed that Slit3 undergoes proteolytic cleavage in adipocyte progenitors, generating Slit3 N-terminal (Slit3-N) and C-terminal (Slit3-C) fragments. Overexpression of Slit3-N and Slit3-C in BAT revealed distinct and overlapping functions of Slit3 fragments in the regulation of angiogenesis and sympathetic innervation. Collectively, this study provides important mechanistic insights into the role of Slit3 in regulating angiogenesis and sympathetic innervation in BAT. These findings could lead to the development of new approaches to enhance thermogenesis and combat obesity and related metabolic disorders.

Disclosure
F. M. Neto: None. H. E. Cervantes: None. T. Duarte afonso serdan: None. F. Shamsi: None.

Funding
National Institutes of Health (K01DK125608)
237-OR: Gastrin Improves Single Islet Transplant Outcomes
Authors: HACKER-STRATTON JEANNETTE , ORR CHRIS , OMORI KEIKO , QI MEIRIGENG , FOROUHAR ELENA , EL-SHAHAWY MOHAMED , KANDEEL FOUAD R. 
Published: June 2023

Background: Multiple allogenic islet transplants (ITs) are usually required to supply adequate islet mass (~10,000 IEQ/kg) to induce insulin independence. Improving outcomes of a SINGLE islet transplant are needed. Gastrin is a gut hormone that is involved in normal fetal pancreas development. Evidence by our group and others have shown gastrin can support islet cell expansion/function and have anti-inflammatory and pro-angiogenesis effects. We compared outcomes of IT alone across 3 clinical trials using: Edmonton-based (ITA), T-cell depleting (TCD), and TCD immunosuppression with an investigational gastrin analogue (GAS).
Methods: Between 2004-2022, a total of 31 evaluable T1D patients without a prior history of transplant received IT-alone under the ITA (n=17), TCD (n=7), and GAS (n=7) clinical trials. Participants in ITA and TCD were eligible to receive up to 3 ITs each. GAS participants received only a single IT and two 30-day courses of gastrin (SQ, BID) at the time of IT and again 6 months later. Immunosuppression included basiliximab or daclizumab + etanercept (ITA) and T-cell depletion (anti-thymoglobulin) + etanercept + anakinra (TCD and GAS).
Results: Progressive improvements in engraftment were observed in the ITA, TCD, and GAS trials. Average insulin requirements were reduced by 18, 26, and 33 u/day. GAS subjects showed the most rapid reduction of 30.9 u/day (94%) in the first 2 weeks post-IT, compared to 17.5 u/day (67%) in TCD. Rates of subjects achieving insulin independence with a SINGLE islet transplant were 0, 15, and 57%. Subjects required an average of 3 ITs in ITA, 2 in TCD, and only one IT in GAS to achieve insulin independence. Average numbers of islets required to achieve insulin independence were 13,280, 8,433 and 4,837 IEQ/kg.
Conclusion: Gastrin use in the peri-transplant period leads to rapid engraftment, larger magnitude of insulin reduction, and permitted achievement of insulin independence in more than half of subjects after a single islet transplant of less than half the normally targeted islet dose.

Disclosure
J.Hacker-stratton: None. C.Orr: None. K.Omori: None. M.Qi: None. E.Forouhar: None. M.El-shahawy: None. F.R.Kandeel: None.

Funding
National Institutes of Health (U24DK098085)
238-LB: Cold-Dependent Regulation of GOT1 Activity in Brown Adipose Tissue and Its Effect on Thermogenesis
Authors: PARK CHUL-HONG , SUK CHANG JI 
Published: June 2023

The malate-aspartate shuttle (MAS) is a biochemical system that can transfer electrons from cytosolic NADH to the mitochondrial electron transport chain. The MAS regulates various biological processes in a tissue-specific manner, but its function in brown adipose tissue (BAT) thermogenesis has not been investigated. We found that glutamic-oxaloacetic transaminase 1 (GOT1), one of the key MAS enzymes, exists at very low levels in BAT but is markedly induced during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Our studies showed that cold-activated transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α were recruited to the Got1 promoter at the estrogen-related receptor response element (ERRE), leading to an increase in Got1 gene expression. Moreover, GOT1 protein stability was increased by reduced targeting to the proteasomal degradation. BAT-specific overexpression of Got1 in mice by using the Cre-loxP system increased energy expenditure at room temperature and improved BAT theromogeneis upon cold exposure or β3-adrenergic stimulation. Collectively, our data suggest that the β3AR-FL/NT-PGC-1α-GOT1 axis enhances BAT activity through the activation of the malate-aspartate shuttle.

Disclosure
C. Park: None. J. Chang: None.