bluuebunny/crossref_metadata_2025_split huggingface dataset:
320-OR: Pyruvate Kinase M2 (PKM2) Activation in the Podocyte Prevented Subset Differentiation of Glomerular Cells Induced by Diabetes
Authors: FU JIALIN , LI QIAN , PARK KYOUNGMIN , SHINJO TAKANORI , HUANG QIAN , WU I-HSIEN , KING GEORGE L. 
Published: June 2024

Pyruvate kinase M2 (PKM2) activation in the glomeruli has been reported as a potential protective factor against diabetic nephropathy (DN). We have previously found that systemic or local activation of PKM2 in the podocyte could reversed mitochondrial dysfunction, glomerular metabolism and pathology in diabetic mice, partially via its regulation of paracrine action of vascular endothelial growth factor (VEGF) against the toxicity of hyperglycemia. To further investigate the protective function of PKM2 in glomerular cell differentiation and gene expressions induced by diabetes, unbiased single-cell RNA sequencing (scRNA-seq) was performed using glomerular cells from mice with PKM2-specific overexpression in podocytes (PPKM2Tg) or WT mice, with or without 7 months of diabetes. High-qualitied glomerular cells (N=87,283) were isolated and sequenced, with &gt; 98% from glomeruli, including 43% endothelial cells (EC), 31% podocytes, 14% mesangial cells (MC), 2% of parietal epithelial cells (PEC), 8% immune cells (macrophages, B cells, T cells, NK cells and neutrophils). Diabetes increased macrophage and B cell numbers from 2.2% to 4.8% and 0.35% to 1%, respectively. Although diabetes or PKM2 overexpression did not change the percentage of EC, MC and podocytes, phenotype switch occurred within subsets of these cells. Diabetes increased podocyte subsets enriched for stressed proteins, while decreased subsets enriched for ECM production and CDC42 GTPase cycle, which were involved in cytoskeleton and foot process formation. These phenotype switches induced by diabetes were reversed in PPKM2Tg mice. Further, MC subset with high expression of mitochondrial electron transport chain and TCA cycle, and EC subset with anti-inflammatory phenotype were reduced by diabetes and restored in PPKM2Tg mice. Thus, PKM2 overexpression in the podocyte changed the energy metabolism and differentiation of subsets of podocyte, MC and EC to protect from DN.

Disclosure
J. Fu: None. Q. Li: None. K. Park: None. T. Shinjo: None. Q. Huang: None. I. Wu: None. G.L. King: None.
321-OR: Haptoglobin (Hp) Levels and Phenotype Are Unrelated to Severe Retinopathy in Type 2 Diabetes, but Lower Hp Reductions by Fenofibrate Are Associated with Greater Retinopathy Benefit—A FIELD Trial Study
Authors: LEUNG ONG KWOK , JANUSZEWSKI ANDRZEJ S. , FRANCIS HABIB , MANGANI ABUBAKAR SIDDIQ O. , O'CONNELL RACHEL L. , JENKINS ALICIA , KEECH ANTHONY C. 
Published: June 2024

Background: The abundant plasma protein Hp has anti-oxidant and anti-inflammatory effects. Its genotype/phenotype modulates chronic diabetes complication risk and fenofibrate benefit on coronary artery and kidney disease in type 2 diabetes (T2D). It is unknown whether Hp phenotype and level are associated with risk of sight-threatening diabetic retinopathy (STDR) and fenofibrate benefit. Fenofibrate reduced STDR risk by 31% in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.
Methods: Hp phenotype and level were measured in 8047 FIELD subjects at baseline and randomization (after a 16-week run-in with fenofibrate in the last 6-weeks).
Results: There were 307 on-trial STDR events over 5 years. Hp phenotype and baseline levels were not related to STDR risk. Fenofibrate benefit on STDR risk appeared greater for the Hp 2-1/2-2 phenotypes, but p for heterogeneity was &gt;0.05 (Table 1). During run-in fenofibrate reduced Hp level by 20.7%, p&lt;0.001. Fenofibrate benefit was greatest in those with the lowest tertile of baseline Hp levels as well as among those in whom Hp levels decreased least with treatment.
Conclusion: Whilst baseline Hp levels and phenotype are not strongly related to STDR risk in T2D Hp levels and phenotype identify subjects more likely to benefit from fenofibrate.

Disclosure
K. Ong: None. A.S. Januszewski: None. H. Francis: None. A.O. Mangani: None. R.L. O'Connell: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. A.C. Keech: Research Support; Abbott, Amgen Inc., Bayer Inc., Kowa Company, Ltd., Mylan. Speaker's Bureau; Novartis Pharmaceuticals Corporation. Research Support; Novartis Pharmaceuticals Corporation, Sanofi, Viatris Inc.

Funding
Laboratoires Fournier, Dijon, France and the National Health and Medical Research Council of Australia (NHMRC) (457103, 1024105, 1037786, 1105467)
325-OR: Enhancing Physical Activity Engagement among Individuals with Type 1 Diabetes—Exploring Perceived Barriers in the Era of New Technologies
Authors: GUÉDET CAPUCINE , TAGOUGUI SEMAH , MESSIER VIRGINIE , BOUDREAU VALERIE , BRAZEAU ANNE-SOPHIE , RABASA-LHORET RÉMI P.R. 
Published: June 2024

Background: Physical activity benefits people with type 1 diabetes (PwT1D); however, PwT1D appear less active than their nondiabetic peers. This study seeks to investigate the potential of diabetes technologies in mitigating perceived barriers to physical activity in type 1 diabetes (T1D).
Methods: A cross-sectional study with participants from the BETTER registry (age&gt; 14 years) who completed BAPAD-1 (Barriers to Physical Activity in T1D) questionnaire. A significant barrier is defined by score &gt; 5 to BAPAD-1 items. Four groups were defined according to the participants' treatment and blood glucose monitoring mode: Multiple daily injections (MDI) without continuous glucose monitoring (CGM), MDI with CGM, pump with CGM, and those using an automated insulin delivery system (AID).
Results: Among 1019 eligible participants, the main perceived barrier is the fear of hypoglycemia. The mean BAPAD-1 score is similar for all groups. A higher proportion of individuals using AID systems reported significant barriers for items fear of hypoglycemia and loss of control over their diabetes compared to the No-CGM-MDI (+20% both), CGM-MDI (+7% and +10%), and CGM+Pump (+9% and +7%).
Conclusion: Barriers to physical activity for PwT1D are not reduced by diabetes technologies. Some barriers are even perceived as more important for people using CGM, pump, and AID systems.

Disclosure
C. Guédet: None. S. Tagougui: None. V. Messier: None. V. Boudreau: None. A. Brazeau: Other Relationship; Dexcom, Inc. Research Support; Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF), Diabète québec, Fonds de recherche du Québec en Santé. R.P.R. Rabasa-Lhoret: Other Relationship; Abbott, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc. Research Support; Diabetes Canada. Other Relationship; Eli Lilly and Company. Research Support; Cystic Fibrosis Canada, Canadian Institutes of Health Research, FFRD - Fondation Francophone pour la Recherche du Diabète. Other Relationship; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Other Relationship; Novo Nordisk, GlaxoSmithKline plc. Consultant; HLS Therapeutics Inc., Insulet Corporation. Speaker's Bureau; CPD Networks. Other Relationship; Medtronic. Consultant; Pfizer Inc. Speaker's Bureau; Tandem Diabetes Care, Inc. Other Relationship; Sanofi. Speaker's Bureau; Vertex Pharmaceuticals Incorporated. Research Support; SFD - Société Francophone du Diabète.
338-OR: Regulation of Pancreatic Beta-Cell Survival and Function during Aging
Authors: PARK JIMIN , HUANG MENGHAO , LIANG JINGRU , CHARLIE DONG X. 
Published: June 2024

Introduction & Objective: Type 2 diabetes is often associated with pancreatic beta cell impairment or failure. However, it is poorly understood how beta cells are adapted or maladapted to both intrinsic and extrinsic stresses during aging. The objective of this work is to investigate the role of SIRT6, an NAD-dependent deacetylase, in the regulation of beta cells during aging.
Methods: Both gain-of-function and loss-of-function approaches were used to illustrate the function of SIRT6 in the regulation of beta cell survival and function in cell and animal models. Glucose tolerance and insulin secretion analyses were performed to assess the underlying pathophysiology. Immunofluorescence microscopy was performed to illustrate cell survival or death. RNA-seq analysis was performed to profile transcriptomic changes.
Results: We performed glucose tolerance tests in beta cell-specific Sirt6 knockout and transgenic mice at young and old ages. Our results show a strong beneficial effect of Sirt6 on systemic glucose tolerance in the transgenic mice and deteriorated glucose tolerance in the knockout mice compared to wild-type mice of young and old ages. Our RNA-seq and imaging data reveal a key role of Sirt6 in the protection against beta cell senescence and death. Among numerous potential target genes of Sirt6, we evaluated RRAD and GEM like GTPase 2 (REM2, an endogenous inhibitor of high-voltage-activated calcium channels) as a key downstream player. Indeed, knockdown or knockout of Rem2 in beta cells significantly improve Sirt6 deficiency-induced cellular senescence and death. Additionally, beta cell-specific Rem2 knockout mice exhibit improved glucose tolerance.
Conclusion: This study demonstrates that SIRT6 is a critical regulator of beta cell survival and function during aging. Boosting SIRT6 levels and/or activities could be a strategy for maintaining healthy beta cells into the late ages.

Disclosure
J. Park: None. M. Huang: None. J. Liang: None. X. Dong: None.

Funding
National Institute on Aging (R21AG072288)
342-OR: Systemic Identification of Functionally Conserved lncRNA Metabolic Regulators between Humans and Mice
Authors: JIANG CHENGFEI , LI ZHE , MA YONGHE , CAO HAIMING 
Published: June 2024

Mounting genetic and clinical evidence supports the critical role of human long non-coding RNA metabolic regulators (hLMRs) in metabolic homeostasis. Yet, most human lncRNAs are non-conserved, hindering their functional characterization for clinical translation in a physiological context. In this study, we investigated the hypothesis that non-conserved hLMRs and mLMRs may have shared functions, forming functionally conserved LMRs (fcLMRs), which could define the physiological role of hLMRs in mice. To test this hypothesis, we have developed a sequence-independent strategy to select fcLMRs and validated their functional similarity in vivo. Knocking down mLMRs in mouse livers demonstrated that concurrent hLMR expression rescued their functions, confirming the pipeline's effectiveness. Using fcLMR1 (h/mLMR1) as an example, we further demonstrated that h/mLMR1 share similar in vivo metabolic function via a conserved docking mechanism. Specifically, both h/mLMR1 robustly regulated triglyceride levels through modulating the expression of a similar set of lipogenic genes in mice. Mechanistically, h/mLMR1 binds to PABPC1 via a short motif on either lncRNA that have divergent sequences but similar structures. The h/mLMR1-PABPC1 interaction inhibits protein translation, which subsequently activates an amino acid-mTOR-SREBP1 axis to regulate lipogenic gene expression. In light of the elevated expression of h/mLMR1 in humans and mice with hepatic steatosis, the PABPC1-binding motif on hLMR1 represents a potential non-conserved human drug target whose function can be fully validated in a physiologically relevant setting before any clinical studies. Hence our study indicates that fcLMRs represent a novel and prevalent biological phenomenon, and deep phenotyping of genetic mLMR mouse models constitutes a powerful approach to understand the pathophysiological role of hLMRs before translating them to actionable drug targets in humans.

Disclosure
C. Jiang: None. Z. Li: None. Y. Ma: None. H. Cao: None.
343-OR: Identifying Nogo-B Receptor as a Resilience Factor in Preventing Obesity-Associated Type 2 Diabetes
Authors: SARIF MOHIUDDIN MOHAMMAD , HU WENQUAN , BARUA RASHU , TIRUMALASETTY MUNICHANDRA B. , CHOUBEY MAYANK , MIAO QING 
Published: June 2024

Obesity is a well-known risk factor for type 2 diabetes (T2D), with over 90% of T2D patients being overweight or obese. However, only approximately 30% of obese individuals develop T2D, suggesting the existence of resilience factors in non-T2D obese individuals that protect against obesity-related T2D. Our research aimed to identify these protective factors by comparing gene expression profiles between obese T2D patients and obese individuals without T2D. Our findings suggest that the Nogo-B receptor (NgBR) may be a key resilience factor in preventing obesity-induced T2D. We observed that obesity-induced loss of NgBR in the liver disrupts the regulation of hepatic gluconeogenesis and insulin sensitivity. This was further supported by decreased NgBR expression in the livers of diabetic mice and T2D obese patients, compared to non-T2D obese and lean subjects. NgBR hepatocyte-specific knockout mice exhibited a moderate increase in blood glucose levels, which was significantly augmented by high-fat diet (HFD) feeding to T2D levels. Our data demonstrated that NgBR plays a crucial, previously unrecognized role in maintaining AMPK activation. NgBR binds to the farnesylated form of liver kinase B1 (LKB1), a key regulator of AMPK. The depletion of NgBR in hepatocytes disrupts the localization of LKB1 in the plasma membrane, impairing AMPK activation, a critical signal for adiponectin-mediated insulin sensitivity. The loss of NgBR in the obese liver disrupts adiponectin-dependent regulation of hepatic gluconeogenesis and insulin sensitivity. NgBR hepatocyte-specific knockout mice display many prediabetes characteristics and are more susceptible to HFD-induced T2D onset.
In conclusion, our findings indicate that NgBR is a critical resilience factor necessary for maintaining hepatic gluconeogenesis regulation and preventing insulin resistance in obesity-associated T2D.

Disclosure
M. Mohiuddin: None. W. Hu: None. R. Barua: None. M.B. Tirumalasetty: None. M. Choubey: None. Q. Miao: None.

Funding
NIDDK (DK132056, DK112971)
347-OR: Plasma Lipidome in People with Insulin-Sensitive and Insulin-Resistant Obesity
Authors: PETERSEN MAX C. , SMITH GORDON I. , ARMANDO AARON , QUEHENBERGER OSWALD , DENNIS EDWARD A. , KLEIN SAMUEL 
Published: June 2024

Insulin-resistant glucose metabolism is common in obesity. However, some people with obesity are insulin-sensitive. It is not clear whether obesity and insulin sensitivity have independent effects on the plasma lipidome. We evaluated plasma complex lipids (including phospholipids, glycerolipids, sphingolipids, acylcarnitines, and cholesteryl esters) by using UPLC-MS/MS and assessed insulin sensitivity as the glucose disposal rate (GDR) per kg fat-free mass divided by plasma insulin concentration during a hyperinsulinemic-euglycemic clamp procedure in 14 adults with insulin-sensitive obesity [ISO, GDR 99.0 ± 8.1 (mg/kg FFM/min)/(µU/mL), 14 adults with insulin-resistant obesity [IRO, GDR (31.8 ± 1.7 mg/kg FFM/min)/(µU/mL)], and 14 adults who were insulin sensitive and lean [ISL, GDR (101.3 ± 5.5 mg/kg FFM/min)/(µU/mL)]. The ISO and IRO groups were matched on age, sex, and body mass index. A total of 780 lipid species in 15 classes were identified. No plasma lipids were significantly different between the ISL and ISO groups, but 52 lipids were significantly different between the ISO and MUO groups (≥1.25 fold-change and false discovery rate &lt;0.05). For all lipid classes, total concentration (sum of species) was not different between the ISL and ISO groups, whereas phosphatidylethanolamine, phosphatidylglycerol, triglyceride, and diacylglycerol (DAG) concentrations were greater and alkyl-phosphatidylcholine (PC) concentration was lower in the IRO than the ISO group (all P &lt; 0.05). The ten lipid species most strongly correlated with insulin resistance included six DAGs, three sphingomyelins, and one ceramide species (r = -0.55 to -0.66, all P &lt;0.0005). The ten lipids most correlated with insulin sensitivity included five lyso-PC, three alkyl-PC, and two plasmenyl-PC species (r = 0.58 to 0.70, all P &lt;0.0001). These results indicate that insulin resistance, rather than obesity per se, is associated with alterations in the plasma lipidome.

Disclosure
M.C. Petersen: None. G.I. Smith: None. A. Armando: None. O. Quehenberger: None. E.A. Dennis: None. S. Klein: Consultant; Alnylam Pharmaceuticals, Inc. Advisory Panel; Altimmune Inc., Merck Sharp & Dohme Corp.

Funding
National Institutes of Health (KL2TR002346)
35-PUB: Glycemic Control and Quality of Life in Patients with Type 1 Diabetes from Brazil Treated with Automated Insulin Delivery Systems
Authors: DA SILVA MESSIAS LARYSSA , VENTURA GABRIELLA L. , DANTAS MARIA EDUARDA P. , DANTAS JOANA R. , SOUTO DÉBORA L. , DE LOURDES MACHADO MARIA , OLIVEIRA TÁSSIA , SANTOS EDSON P. , SOARES THIAGO M. , ZAJDENVERG LENITA , RODACKI MELANIE 
Published: June 2024

Automated insulin delivery systems (AID) such as AAPS or Medtronic's 780G™ pump may reduce the burden of decision-making for patients with type 1 diabetes (T1D). This study aims to compare quality of life (QOL) and glycemic control between patients with T1D that receive AID systems and other treatments in the Brazilian population.This was a study that included T1D patients reached through an online survey via social media. Remote data was collected with an AirTable form, including questions about education, glucose control and QOL questionnaire (DQOL-Brazil).The study groups comprised 228 patients with a mean age and disease duration of 30.4 ± 11.4 and 13.5 ± 10.7 years, respectively. They were divided in groups: 78 with automation (Group A) and 150 without automation (Group B). Group A had a higher proportion of patients or caregivers with higher education (p &lt; 0.01; 74.7 vs 48% and 88.9 vs 51.5%, respectively), lower A1c (6.6± 0.8% vs 7.5± 2.3%; p&lt;0.001), more A1c &lt; 7% (65.8 vs 56.1%; p &lt; 0.001), lower severe hypoglycemic events in a year (0.5 ± 1.1 vs 1.8 ± 1.9; p &lt; 0.001) and better DQOL scores (93.1 ± 27.4 vs 120.8 ± 28.7; p&lt; 0.001) than group B. Weekly mean reported hypoglycemia rates were similar between groups (3.51 ± 2.09 in A vs 3.4 ± 1.9 in B; p=0.73). More patients in group A reported being moderately of very satisfied with time spent to manage diabetes (52.6 vs 12.7%; p&lt;0.001) and being moderately/very happy with current treatment (67.9 vs 18%; p &lt; 0.001) than in group B. Similar results were seen when only patients using sensors were included, except for the difference in A1c (6.6 ± 0,8% vs 7.1 ± 1.7%; p=0.12) and % A1c &lt; 7% (66.7 vs 54.3; p=0.13), which did not persist.In this sample, patients with T1D and AID had better QOL and glycemic control, with a lower rate of severe hypoglycemia than others. Although A1c did not differ between patients who did not use AID systems but had sensors and those in AID systems, differences in QOL and hypoglycemia rates were still seen.

Disclosure
L. Messias: None. G.L. Ventura: None. M.P. Dantas: None. J.R. Dantas: None. D.L. Souto: None. M. Machado: None. T. Oliveira: None. E.P. Santos: None. T.M. Soares: None. L. Zajdenverg: None. M. Rodacki: None.
363-OR: Matrix Metalloprotease-2 as a Novel Regulator of Glucose Utilization by Adipocytes and High-Fat Diet-Induced Glucose Intolerance
Authors: LEMPICKI MELISSA D. , GARRIGUES RYAN J. , GARCIA BRANDON , MEHER AKSHAYA K. 
Published: June 2024

Obesity and its related comorbidities, such as glucose intolerance and hyperglycemia, pose risks for type 2 diabetes. Studies on the murine models of high-fat diet (HFD)-induced obesity revealed that glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorption of excess glucose and maintenance of whole-body glucose homeostasis. Matrix metalloproteases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, surprisingly, it is unknown if MMPs can directly cleave GLUT4 on adipocyte surface and impair glucose absorption. To determine the highly active MMP expressed in the WAT during obesity, we placed male C57BL/6J mice on an HFD for 5, 9, and 11 weeks or on a standard chow diet, examined the development of hyperglycemia, inflammation, and MMP activity in the gonadal WAT using gelatin zymography. Flow cytometry studies on gonadal WAT confirmed an increase in inflammatory immune cell infiltration, and RT-PCR analysis confirmed elevated TNF-α in late stages of obesity. Zymography identified MMP2 as the highly active MMP in the WAT after HFD. Next, we used the Seahorse extracellular flux analyzer to determine the metabolic fitness of differentiating 3T3-L1 adipocytes after treatment with MMP2 for 2 hours. Glycolysis stress tests revealed MMP2, even at 200 ng/ml, attenuated glucose utilization, as indicated by 30% decreased basal glycolysis, 50% decrease in glycolytic capacity, and blunted glycolytic reserve. Further, in silico structural analysis using AlphaFold identified a potential MMP2 cleavage site on the extracellular domain of both murine and human GLUT4. This encouraged us to hypothesize that MMP2 reduces glucose utilization in differentiating adipocytes by cleaving GLUT4 extracellular domains. This is a novel mechanism that may add to insulin resistance to promote hyperglycemia and suggests inhibition of MMP2 would promote healthy obesity.

Disclosure
M.D. Lempicki: None. R.J. Garrigues: None. B. Garcia: None. A.K. Meher: None.
380-P: Safety of SGLT2 Inhibitors in People with Diabetes With or Without Background Insulin—Data from DAR Global Survey
Authors: ABDELGADIR ELAMIN I.E. , HASSANEIN MOHAMED 
Published: June 2024

Introduction: A considerable number of studies have assessed the safety of Ramadan fasting in people with diabetes mellitus. This global survey from various region in the middle east and north Africa is tailored to fill further gaps in safety of SGLT2i during Ramadan fasting.
Methods: The participating countries from 5 geographical regions were as follows: Southeast Asia, Gulf nations, Maghreb countries, Middle East and Turkey. All participating physicians interviewed people with diabetes who intended to fast Ramadan, the biometric and biochemical data was extracted from the electronic medical files
Results: The overall survey population was 5865 people with T2D on oral injectable. Out of those patients 2379 were on SGLT2i plus other hypoglycaemic agents. 705 were on GLT2i without Sulfonylurea (SU) or insulin, 927 were on SGLT2i and insulin but without SU, and 169 patients were on combination of theSGLT2i, SU, and insulin. Only 5.4 % did break their fast in the SGLT2i group compared to 13.6% in the triple combination. Hypoglycemia was least encountered in the SGLT2i (8%), 16.4% in the dual combination, and 20.9% in the triple combination therapy. Majority of hypoglycemia episodes were between 3 pm and Maghrib time (estimated 6-8 PM) in the SGLT2i group (72.5%), while in the group with insulin and/or SU had hypoglycemia predominance from 12 mid-day till maghrib. In terms of emergency room attendance due to hypoglycemia doubled when insulin was added and increased to 3.5 folds when both insulin and SU was added to SGLT2i (3.4 and 6.9%, respectively compared to 1.9% in the SGLT2i group).
Conclusion: In this study, SGLT2i without insulin and/or SU is associated with less hypoglycemia, less days with broken fasting due to diabetes related complications. The emergency room attendance increased up to 3.5 folds when Insulin and/or SU to SGLT2i.

Disclosure
E.I.E. Abdelgadir: None. M. Hassanein: Research Support; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Abbott, Boehringer-Ingelheim, Medtronic. Advisory Panel; Eli Lilly and Company.