bluuebunny/crossref_metadata_2025_split huggingface dataset:
26-PUB: Early Assessment of Imeglimin in India—Patient Profiling and Prescription Patterns in Type 2 Diabetes Management—Early Reassure Study Pool
Authors: SABOO BHARAT , ANUJ MAHESHWARI , GHOSH SUBHAJYOTI , PATIL SHUBHASHREE M. 
Published: June 2024

Background and Objectives: Given the increasing prevalence of diabetes, there is a pressing need for effective management strategies. This study focuses on the first-year data since the Imeglimin's (oxidative phosphorylation blocker) launch, examining its utilization in India to assess its initial impact. The primary goals encompass comprehending the patients that benefit most from Imeglimin and determining its role in the present therapeutic scenario.
Methods:A retrospective analysis of 406 T2D patients prescribed Imeglimin was conducted using data from ten diverse centers across India, ensuring a representative sample. Patient profiles, including age, gender, and relevant demographics, were assessed. Prescription patterns were analyzed to glean insights into how Imeglimin is integrated with other diabetic medications, providing insights into its role as monotherapy or combination therapy.
Results:The investigation revealed that Imeglimin was predominantly administered to individuals aged 51-60 (average age of 54.1 years), glycated hemoglobin &gt; 9 (40.8%), and exhibited a male predominance (56.4%). Notably, Imeglimin served as the first-line therapy in 66.4% patients and was frequently prescribed in conjunction with other oral antidiabetic medications (80.3%). Prescription patterns indicated a common combination of Imeglimin with biguanides, followed by dipeptidyl peptidase 4 (DPP-4) inhibitors, with the primary rationale for Imeglimin prescription being the presence of uncontrolled glucose levels.
Conclusion:Imeglimin shows promise as an effective treatment for T2D in the Indian context, showing efficacy across various age groups and particularly in cases of uncontrolled diabetes. Further long-term studies are recommended to assess its efficacy and safety profile over an extended period.

Disclosure
B. Saboo: None. M. Anuj: None. S. Ghosh: None. S.M. Patil: None.
268-OR: Perioperative Fully Closed-Loop vs. Standard Insulin Delivery in Adults Undergoing Major Abdominal Surgery—A Two-Center Randomized Controlled Trial
Authors: KRUTKYTE GABIJA , MARIE CATHERINE GOERG ARNA , GROB CHRISTIAN A. , BELDI GUIDO , SILVIA WENNING ANNA , HOVORKA ROMAN , WILINSKA MALGORZATA E. , HERZIG DAVID , VOGT ANDREAS , GIRARD THIERRY , BALLY LIA 
Published: June 2024

Introduction: Major abdominal surgery predisposes to hyperglycemia due to metabolic stress, inflammation, perioperative nutrition support and medication. The aim of the study was to assess the efficacy of fully closed-loop (FCL) versus usual care (UC) insulin delivery for glycemic management in major abdominal surgery patients.
Methods: In this randomized controlled trial (NCT05392452) we compared perioperative use of the CamAPS HX FCL system (Dexcom G6, YspoPump, SC faster insulin aspart) with UC insulin treatment from admission until hospital discharge (max 20 days) at two tertiary hospitals in Switzerland. The primary endpoint was % time in sensor glucose target range (5.6-10.0mmol/L).
Results: Thirty-seven patients (FCL n=18, UC n=19, 27% female, mean±SD age 66±12 years, BMI 27.8±5.7 kg/m2, HbA1C 6.9±1.0 %) were analyzed. Mean±SD % time in target glucose range (5.6-10.0mmol/L) was 80.1±10.0 % with FCL vs 53.7±19.7 % with UC (p&lt;0.001). Time in hypoglycemia (&lt;3.9mM and &lt;3.0mM) did not differ between groups. Total daily insulin dose was significantly higher in the FCL vs UC group (p&lt;0.001).
Conclusions: Perioperative use of FCL insulin delivery in major abdominal surgery patients with complex medical needs results in significantly better glucose control compared to standard insulin therapy without increasing the risk of hypoglycemia.

Disclosure
G. Krutkyte: None. A. Goerg: None. C.A. Grob: None. G. Beldi: None. A. Wenning: None. R. Hovorka: Other Relationship; CamDiab. Research Support; Abbott, Dexcom, Inc., Ypsomed AG. Speaker's Bureau; Ypsomed AG, Abbott, Novo Nordisk, Novartis Pharmaceuticals Corporation. M.E. Wilinska: Consultant; CamDiab. D. Herzig: Speaker's Bureau; Ypsomed AG. A. Vogt: None. T. Girard: None. L. Bally: None.

Funding
Helmut Horten FoundationScherbarth Foundation and intramural grants of the Department of Anaesthesiology and Pain Medicine, University Hospital BernSwiss Foundation for Anaesthesiology and Intensive CareClinic for Anaesthesiology, University Hospital BaselFreiwillige Akademische Gesellschaft Basel
27-PUB: A Systematic Review on the Theranostic Potential of Iron in Diabetes
Authors: PRADIPKUMAR THAKER SHIVAM , SHREYANSH SHREYANSH , MONAPPA VIDYA 
Published: June 2024

Background:Iron is an element now synonymous with inflammatory diseases, but in recent years it has shown potential in the pathophysiology of Diabetes. This review aims to cohesively analyze the association of serum iron in Diabetes and evaluate its clinical theranostic potential.
Method:Literature was obtained from PubMed, Embase, and Clinical Key. The search included Keywords,‘“DIABET” AND IRON’.
Result:21 papers were included in the review. Hemochromatosis is an established cause of type-1 and 2 diabetes. In recent years, several studies have found an increase in serum ferritin levels(Mean: 27.6%; Median: 11.9%) among diabetics, not associated with hemochromatosis. This can serve as a predictive marker for the development of microvascular complications in diabetes. The authors suggest this phenomenon may be the result of 2 mechanisms;(1) Hepcidin upregulation, and (2) Mild hemolysis due to increased osmotic fragility with HbA1c. The increased ferritin is associated with insulin resistance which may be attributed to ROS-induced mitochondrial fission. The authors suggest another cause may be apoferritin which stimulates PI3K, causing PDK1 activation and GLUT-4 translocation. This translocation is reduced with increased serum ferritin. Several animal studies have shown substantial improvement in glucose metabolism amongst diabetic mice on iron chelation therapy. Additionally, improved wound healing and nephropathy were found to be significant. Fernández-Real JM, et. al. in 2002, found that Phlebotomy(450mL ) increased insulin sensitivity amongst high ferritin (human)diabetics by 80.6 ± 43.2% from baseline at 4 months(P=0.0049). Iron chelation therapy is a promising potential adjuvant in high ferritin diabetes with microvascular complications, but adequate human trials have yet to be done.
Conclusion:In consideration of the available data, the authors believe that iron and iron chelation may serve an important low-cost effective role in the monitoring and therapeutics of diabetes.

Disclosure
S. Thaker: None. S. Shreyansh: None. V. Monappa: None.
277-OR: Whole-Genome Sequencing Identifies a Rare Noncoding Variant Proximal to METRN Associated with HbA1c Levels
Authors: HAWKES GARETH , PATEL KASHYAP A. , BARROSO INÊS , FRAYLING TIMOTHY M. , MANNING ALISA , WEEDON MICHAEL N. 
Published: June 2024

Introduction & Objective: Hundreds of common genetic variants have been associated with type 2 diabetes and glycated haemoglobin (HbA1c). However, the vast majority of these variants lie in regions of the genome which are not protein coding, making it difficult to identify biological pathways. We aimed to identify rare non-coding variants to aid in pinpointing causal genes and variants.
Methods: We performed a whole-genome sequencing association analysis of non-coding variation in 200,000 UK Biobank participants. We stratified our analysis by three genetically-inferred ancestries: European-like (EUR), African-like (AFR) and South Asian-like (SAS).
Results: We identified 4 rare (MAF&lt;0.1%) variants associated with HbA1c, downstream of the haemoglobin alpha gene-cluster based on an analysis of EUR-like participants. In our analysis of 3,184 AFR-like individuals, only one variant (16:715289:T:C) showed evidence of replication. This likely-causal variant lies in the first element of the kozak sequence of meteorin (METRN), and was associated with substantially increased HbA1c levels (beta = 4.87mmol/mol [3.54, 6.21], P = 8.14e-13). We observed no evidence of association with common blood cell traits, circulating glucose, or haemoglobin. We replicated our result in the recently released additional 300,000 UKB WGS samples (beta = 6.02mmol/mol [4.83, 7.20], P = 2.93e-17). We attempted to replicate our findings in All of Us (N = 250,000), but found that the allele was substantially less frequent than in UKB (MAF = 3.7e-6 vs. 1.9e-4). The alternate allele was not present in individuals in TOPMed with HbA1c measures.
Conclusion: Our results suggest that this variant may be a founder effect in the UK population acting through an alteration of glucose uptake to red blood cells. Identification of a novel variant in only 200k individuals with whole-genome sequences suggests a high yield of novel variants and biological pathways from upcoming releases of millions whole-genomes.

Disclosure
G. Hawkes: None. K.A. Patel: None. I. Barroso: Stock/Shareholder; GlaxoSmithKline plc, NeoGenomics (NASDAQ: NEO). T.M. Frayling: None. A. Manning: None. M.N. Weedon: None.

Funding
Innovative Medicines Initiative 2 Joint Undertaking (875534)
280-OR: Manganese Regulates Hepatic Insulin Sensitivity and Glucose Tolerance
Authors: GAMARRA JENNIFER , XIE YUKE , HIGUCHI SEI , HAEUSLER REBECCA 
Published: June 2024

Introduction & Objective: Metals are known to be necessary for cellular processes such as signal transduction and in protein conformation, though the characterization of which proteins bind metals is incomplete. Manganese (Mn) is known to be required for life but is one of the least understood metals. We aim to: (i) determine the mechanisms that regulate Mn and (ii) the molecular targets of Mn.
Methods: We used a mouse model of Mn excess that depletes the Mn efflux transporter, Slc30a10, from the liver and intestine (Slc30a10Tbg,Vil). We conducted metabolic studies on mice kept on a standard chow diet or fed a high-fat diet for eight weeks. We used primary hepatocytes treated with Mn ex vivo to perform glucose production assays and assess the phosphorylation cascade in the insulin signaling pathway.
Results: We found that Slc30a10Tbg,Vil mice have a significant improvement in glucose tolerance on a standard chow diet and are protected from impaired glucose tolerance when put on a high-fat diet. We treated hepatocytes with Mn ex vivo and found a significant reduction in glucose production. These data were associated with increased phosphorylation of Akt targets without increased phosphorylation of Akt itself. Using knockout and inhibitor approaches, we found that Mn acts downstream of both insulin receptor and PI3 kinase, suggesting that Mn acts directly on Akt. Fasting and refeeding studies on wildtype mice found Slc30a10 is low during fasting and increases rapidly after refeeding.
Conclusions: These data suggest Mn acts directly on Akt to sensitize hepatocytes to insulin. Further, our finding that Slc30a10 is regulated nutritionally suggests the possibility that controlled access to Mn may be a physiological mechanism to regulate Akt activity. These results highlight a novel role of Mn in the insulin signaling pathway and shed light on how Mn homeostasis is regulated in the liver.

Disclosure
J. Gamarra: None. Y. Xie: None. S. Higuchi: None. R. Haeusler: None.
296-OR: Glucagon and Insulin Cross Talk Regulates Hepatic Glycogen Metabolism
Authors: CAPOZZI MEGAN , BOUSLOV DAVID , SARGSYAN ASHOT , CAMPBELL JONATHAN 
Published: June 2024

The fed state is often defined with a glucose-centric focus, where elevated glycemia stimulates insulin and reduces glucagon secretion. However, protein-containing meals that better reflect normal nutrition increase glucagon secretion, producing elevations in both hormones. Glucagon and insulin have opposing effects on hepatic glycogen; glucagon promotes glycogenolysis while insulin promotes storage. Yet, most work in this area has focused on the individual rather than combined actions of these hormones. The purpose of this study was to determine the effect of combined insulin and glucagon on postprandial hepatic glycogen metabolism. We hypothesized that their combined actions increase glycogen flux to enable storage of meal nutrients.
Glucagon and/or insulin were injected into 5-hr fasted wild-type mice to determine the individual versus combined actions on hepatic glycogen content. Next, glucose alone versus a mixed-nutrient meal was gavaged with matching carbohydrate loads, using a 13C6-glucose tracer to assess incorporation of meal-derived glucose into glycogen. Finally, a mixed-nutrient meal with tracer was given to proglucagon null mice (Gcg-/-) to determine the effect on glycogen metabolism.
Glucagon or insulin alone did not alter hepatic glycogen levels, however the combination of both hormones enhanced glycogenolysis. Meal-derived glucose incorporated into hepatic glycogen was higher after a mixed-nutrient meal compared to oral glucose alone. Gcg-/- mice stored significantly less meal-derived glucose as glycogen versus controls.
Our results suggest that the combined actions of glucagon and insulin enhance hepatic glycogen turnover due to both enhanced glycogenolysis and storage of meal-derived glucose as glycogen. These actions enable the liver to have greater metabolic flexibility for nutrient storage in the postprandial state. This may have implications for disease states such as diabetes or metabolic-associated steatotic liver disease, where hormone action is altered.

Disclosure
M. Capozzi: None. D. Bouslov: None. A. Sargsyan: Employee; AstraZeneca. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc. Advisory Panel; Structure Therapeutics, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK129417)
33-PUB: Triple-Arm, Prospective, Multicentre, Randomized, Open-Label, Active-Controlled Study to Assess Effect on FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg Compared with FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg and FDC of Linagliptin 5 mg+ Empagliflozin 25 mg on 24-Hour Glucose Profile Assessed by Continuous Glucose Monitoring (CGM) in Indian Patients of Type 2 Diabetes Mellitus In Real-World Setting (AMPLIFY-TIR STUDY)—Interim Report
Authors: BARKATE HANMANT V. , PETARE ANUP U. , BHUSHAN SUMIT , CHOUDHARI SANJAY Y. , BRID MANASI , PATIL SAIPRASAD 
Published: June 2024

Introduction & Objective: Fixed dose combination (FDC) of Teneligliptin 20 mg + Dapagliflozin 10 mg has been recently approved in India for treatment of T2DM. Study was designed to compare effect of FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg (Arm A) with FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg (Arm B) & FDC of Linagliptin 5 mg + Empagliflozin 25 mg (Arm C) with parameters derived from CGM in Indian T2DM
Results: Present interim analysis report of 50 T2DM patients shows changes in CGM parameters when compared as intergroup between FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg, FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg & FDC of Linagliptin 5 mg + Empagliflozin 25 mg at end of phase II as non-significant (p&gt;0.05). Significant improvement seen in intragroup from Pre-treatment to End of phase II in all efficacy parameter. No serious adverse event reported.
Conclusion: FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg, Sitagliptin 100 mg + Dapagliflozin 10 mg & FDC of Linagliptin 5 mg + Empagliflozin 25 mg had significant improvement in CGM & Glycemic parameters.

Disclosure
H.V. Barkate: Employee; Glenmark Pharmaceuticals. A.U. Petare: Employee; Glenmark Pharmaceuticals. S. Bhushan: None. S.Y. Choudhari: Employee; Glenmark Pharmaceuticals, Sun Pharmaceutical Industries Ltd. M. Brid: None. S. Patil: Employee; Glenmark Pharmaceuticals.
334-OR: Allogeneic Neo-Islets Reduce Insulin Need by up to 1.2 U/kg bw in Autoimmune Type 1 Diabetes Dogs over Three Years without Requiring Antirejection Drugs, Enough to Meet Human Type 1 Diabetes Mellitus Needs
Authors: GOOCH ANNA , WESTENFELDER CHRISTOF 
Published: June 2024

The spontaneously diabetic dog is ideal to test therapies intended for humans with T1DM. Neither insulin treated dogs nor humans spontaneously revert. Both have islet autoantibodies, shortened life expectancy, end-organ damage, while dogs need more insulin (humans: 0.5-1; dogs: 1-4 U/kg/day). We tested Neo Islets (NIs), 3-D organoids made of culture expanded islet cells and Mesenchymal Stem Cells in 9 spontaneously DM pet dogs. NI dose = 2x10e5 per kg bw, given i.p. to sedated dogs under ultrasound guidance. Follow up: Blood Glucose Levels monitored with continuous monitors. Insulin needs were recorded, and late follow-up levels of serum Creatinine, BUN and proteinuria were monitored. Each dog served as its own control. UA, full chemistries, lipids, CBC were assessed at baseline, monthly for 3 months, and biannually for 3 years. Results in Figure.

Allogeneic NI treatment is safe and effective (3 year follow up). T1DM dogs require significantly more insulin per kg bw than T1DM humans. Since NIs can produce up to 1.2 U/kg bwt and are dosed on a per kg bw basis, this implies that NIs would be curative for T1DM in humans while not needing anti-rejection drugs, thereby readily exceeding the therapeutic potency of other current biotherapies.

Disclosure
A. Gooch: Employee; SymbioCellTech, LLC. Board Member; SymbioCellTech, LLC. Stock/Shareholder; SymbioCellTech, LLC. C. Westenfelder: None.
337-OR: ADA Presidents' Select Abstract: The LonP1 Protease Maintains Pancreatic ß-Cell Survival by Governing Mitochondrial Protein Folding
Authors: LI JIN , ZHU JIE , RECK EMMA C. , WALKER EMILY M. , SOLEIMANPOUR SCOTT 
Published: June 2024

Accumulating evidence indicates that type 2 diabetes (T2D) is a protein misfolding disease. LonP1 is an essential mitochondrial protease that mediates mitochondrial proteostasis through clearance of unfolded or misfolded proteins, but its role in β-cells is unknown. We generated mice bearing β-cell specific deletion of LonP1 (β-LonP1KO) and found that LonP1 deletion led to progressively impaired glucose tolerance with age and decreased glucose-stimulated insulin release (GSIS). LonP1 deficiency also induced β-cell apoptosis resulting in the loss of β-cell mass. In the mitochondria, β-LonP1KO mice exhibited diminished mitochondrial respiration, abnormal mitochondrial ultrastructure, reduced mitochondrial mass, and elevated ROS levels. An accumulation of misfolded mitochondrial proteins, defect of OXPHOS complex assembly, and/or induction of ROS could be primary triggers driving mitochondrial dysfunction and β-cell apoptosis in β-LonP1KO islets. Interestingly, β-cell specific overexpression of the antioxidant enzyme catalase targeted to mitochondria exerted only a modest, transient protective effect on glucose tolerance and β-cell mass in β-LonP1KO mice yet did not relieve accumulation of misfolded mitochondrial proteins, suggesting ROS alone could not account for the phenotype in LonP1-deficient mice. Concordantly, a similar effect of anti-oxidants on β-cell survival and mitochondrial protein misfolding was observed in human islets in the context of LonP1-deficiency. Thus, the LonP1 protease is vital for β-cell survival and mass by governing mitochondrial protein folding, which could be a potential therapeutic target to prevent β-cell failure during the development of T2D.

Disclosure
J. Li: None. J. Zhu: None. E.C. Reck: None. E.M. Walker: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd.
361-OR: A Multiomics Approach to Identify Genes Important for the Regulation of Antidiabetic and Anti-inflammatory Lipids
Authors: SANTORO ANNA , KELLER MARK , CHEN ZHENLONG , ATTIE ALAN D. , SIEGEL DIONICIO , CHURCHILL GARY A. , SAGHATELIAN ALAN , KAHN BARBARA B. 
Published: June 2024

Introduction: Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are signaling lipids with beneficial metabolic effects. Serum and adipose tissue (AT) PAHSA levels correlate highly with insulin sensitivity in people. PAHSAs enhance insulin sensitivity in diabetic mice. Thus, low PAHSA levels could contribute to the etiology of insulin resistance and T2D. PAHSAs are regulated by synthesis, degradation and incorporation into other lipids. We aimed to identify candidate enzymes that regulate PAHSAs using genetic mouse models in which large changes in PAHSAs are associated with major changes in glucose tolerance and/or insulin sensitivity.
Methods: AT PAHSA levels are increased in mice with Adipose-specific Glucose Transporter 4 overexpression (AG4OX) which induces expression of the lipogenic transcription factor, Carbohydrate-response element-binding protein (ChREBP). Thus, we performed lipidomics and bulk RNA sequencing in perigonadal AT from wildtype, AG4OX, ChREBP knockout and AG4OX crossed to ChREBP KO which reverses the massive elevation of PAHSAs in AG4OX. We also measured PAHSAs in 8 genetically inbred mouse strains. We merged these datasets to identify genes strongly associated with PAHSAs in both models. A subsequent GWAS query for lipid-related SNPs delivered a discrete number of genes to validate as important PAHSA regulators.
Results: All PAHSA regioisomers increase in AT with upregulation of glucose transport and decrease with ChREBP downregulation. PAHSA levels are higher in insulin-sensitive genetic strains. Many genes that strongly associate with 9-PAHSA belong to lipid metabolism pathways. Our single-gene queries in human GWAS support a role for 27 genes in the regulation of lipid metabolism in humans and, potentially, in PAHSA regulation.
Conclusions: These studies provide novel insights into the metabolic pathways and enzymatic machinery responsible for PAHSA metabolism, which may be targeted to prevent or treat T2D in humans.

Disclosure
A. Santoro: None. M. Keller: None. Z. Chen: None. A.D. Attie: None. D. Siegel: None. G.A. Churchill: None. A. Saghatelian: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc.

Funding
K01 DK128075 (Anna Santoro), NIH P30 DK135043 (Barbara B. Kahn), NIH R01 DK106210 (Barbara B. Kahn and Alan Saghatelian), and JPB foundation (Barbara B. Kahn)