bluuebunny/crossref_metadata_2025_split huggingface dataset:
222-OR: Metformin Reduces Fasting Glycemia in Well-Controlled Type 2 Diabetes by Promoting Aerobic Glycolysis Independent of Decreasing Endogenous Glucose Production
Authors: SARABHAI THERESIA , LAMOIA TRACI E. , FRIESL SOPHIE , JONUSCHEIT MARC , PETERSEN KITT , SHULMAN GERALD I. , RODEN MICHAEL 
Published: June 2023

It is well established that metformin improves glycemic control in individuals with poorly-controlled type 2 diabetes (T2D) by reducing rates of endogenous glucose production (EGP) mediated by inhibition of hepatic gluconeogenesis. However, the mechanism by which metformin reduces blood glucose levels in well-controlled individuals with T2D is still unknown. To address this question, we examined rates of EGP, lactate turnover and hepatic triglyceride (TAG), ATP and glycogen content in near-normoglycemic individuals with T2D (n=10, HbA1c 7±1%) with (M+; 1000 mg bid x 2 wks) and without (M-; 2 wks) metformin treatment using the PINTA method with [2H7]glucose and [3-13C]lactate tracer infusions in combination with 1H- /31P- /13C- magnetic resonance spectroscopy. Metformin treatment did not affect rates of EGP, but reduced fasting plasma glucose concentrations by 30% (p&lt;0.01 vs. M-), which could be attributed to increased rates of glucose clearance (+18%, p&lt;0.005 vs. M-) resulting in increased lactate production (+14%, p&lt;0.01 vs. M-). These changes were associated with decreased hepatic ATP content (-20%, p&lt;0.05 vs. M-), increased hepatic glycogen content (+40%, p&lt;0.05 vs. M-) and no changes in hepatic TAG content. Conclusion: In contrast to the glucose-lowering effect of metformin in poorly-controlled T2D, which is due to reductions in gluconeogenesis, this study demonstrates that in well-controlled T2D metformin reduces fasting glycemia - independent of reductions in EGP - primarily by increasing rates of aerobic glycolysis as reflected by increased peripheral glucose clearance and lactate production as well as reduced hepatic ATP content, which is consistent with metformin-induced inhibition of mitochondrial electron transport chain activity.

Disclosure
T.Sarabhai: None. T.E.Lamoia: None. S.Friesl: None. M.Jonuscheit: None. K.Petersen: Advisory Panel; Novo Nordisk, Research Support; Merck Sharp & Dohme Corp., Gilead Sciences, Inc. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi.
261-OR: Autonomous Artificial Intelligence (AI) Testing for Diabetic Eye Disease (DED) Closes Care Gap and Improves Health Equity on a Systems Level
Authors: ALVIN LIU T.Y. , HUANG JANE , LEHMANN HAROLD , WOLF RISA M. , CHANNA ROOMASA , ABRÀMOFF MICHAEL D. 
Published: June 2023

We aimed to examine the change in adherence to annual diabetic eye disease (DED) testing in an integrated healthcare system (Johns Hopkins Community Physicians 30+ community based primary care clinics) before and after deployment of autonomous artificial intelligence (AI). Adherence to annual DED testing is defined as completed evaluation by either a human ophthalmology provider, or autonomous AI within a given calendar year. During the COVID pandemic, autonomous AI (IDx-DR, Digital Diagnostics, Coralville, IA) was deployed at multiple clinics, so that by 2021, some clinics had autonomous AI (AI sites), while others did not (non-AI sites). Overall adherence in 2019 (pre-AI) and 2021 (with AI) were compared, and stratified by demographics, using chi-square or Fisher’s exact test. Changes from 2019 to 2021 in odds of adherence within each subgroup were assessed for significant differences by site type (AI vs. non-AI), using logistic regression with a site type-by-time interaction term. From 2019 to 2021, the overall adherence rate increased from 42.6% to 55.5% at AI sites (1949 patients), and increased from 38.0% to 41.0% at non-AI sites (5379 patients). The increase in overall adherence rate at AI sites was significantly greater than that at non-AI sites (p&lt;0.001). Various patient subgroups (M, F, ≥65 yo, &lt;65 yo, Black, White, Medicare/military/commercial insurance) at AI sites demonstrated a significantly greater (p&lt;0.05) compliance rate increase when compared to the same subgroups at non-AI sites. For Black patients, there was no difference in adherence rate between AI sites and non-AI sites (38.5% vs. 37.1%, p=0.45) in 2019, but the difference became significant (p&lt;0.001) in 2021 due to increased adherence at the AI sites (58.0%) vs. 38.8% at non-AI sites. Autonomous AI improved DED testing adherence in a large, diverse patient cohort and decreased disparity in Black patients, a historically-disadvantaged subgroup.

Disclosure
T.Liu: None. J.Huang: None. H.Lehmann: None. R.M.Wolf: Research Support; Dexcom, Inc., Boehringer Ingelheim Inc. R.Channa: None. M.D.Abràmoff: Board Member; Digital Diagnostics, Consultant; AbbVie Inc., NovaGo Therapeutics AG, Other Relationship; Digital Diagnostics, Stock/Shareholder; Digital Diagnostics.

Funding
Digital Diagnostics
275-OR: Association between Treatment Adherence and CGM Outcomes in People with T1D Using Smart Insulin Pens in a Real-World Setting
Authors: DANNE THOMAS , HARTVIG NIELS V. , KAAS ANNE , KNUDSEN NIKOLINE N. , MADER JULIA K. 
Published: June 2023

Adherence to insulin therapy can be challenging for individuals with T1D. This analysis explored how adherence to basal and bolus insulin injections influences glycemic outcomes. Data were collected from adults (≥18 years) administering basal insulin (degludec) and bolus insulin (aspart or faster aspart) using smart insulin pens with CGM; data were aggregated in 14-day periods. Treatment adherence was defined as the number of missed basal insulin doses (&gt;40 hrs between doses), flex basal insulin doses (dosing time deviated &gt;±6 hrs from previous day) and missed bolus insulin doses (meals with no bolus dose within -15 to +60 mins from meal onset). Glycemic outcomes included time in range (TIR), time below range, glucose management index (GMI), and coefficient of variation. Multinational data from 403 adults who had 3588 14-day periods with ≥70% CGM coverage were analyzed. Individuals with one missed basal dose per 14-days had a lower TIR (-4.04% [95% CI: -6.83; -1.26]) and higher GMI (0.20% [95% CI: 0.02; 0.38]) than individuals without missed basal doses; flex basal doses were not associated with TIR changes. Missed bolus insulin doses were also associated with lower TIR (Table). These real-world data confirm associations between missed basal and bolus insulin doses and impaired TIR, highlighting a need for digital tools such as smart insulin pens to help individuals manage their diabetes.

Disclosure
T.Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. N.V.Hartvig: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH.

Funding
Novo Nordisk A/S
280-LB: Efficacy of a Respiratory Syncytial Virus (RSV) Prefusion F Protein Vaccine (RSVPreF3 OA) in Older Adults with Preexisting Medical Conditions
Authors: FELDMAN ROBERT G. , ANTONELLI INCALZI RAFFAELE , STEENACKERS KATIE , LEE DONG-GUN , FISSETTE LAURENCE , DAVID MARIE-PIERRE , MARÉCHAL CÉLINE , KOSTANYAN LUSINE , VAN DER WIELEN MARIE , HULSTROEM VERONICA 
Published: June 2023

Background: Adults with diabetes and other conditions are at increased risk of severe RSV disease and hospitalization. In a phase 3 placebo-controlled study (NCT04886596) in adults ≥60 years, RSVPreF3 OA showed 82.6% vaccine efficacy (VE) against RSV-related lower respiratory tract disease (RSV-LRTD) and 71.7% against RSV-related acute respiratory infection (RSV-ARI). We assessed VE among participants with different BMI and with selected pre-existing metabolic or endocrine conditions (eg, diabetes) that increase the risk of severe RSV disease.
Methods: Adults ≥60 years were 1:1 randomized to receive 1 dose of RSVPreF3 OA or placebo before the RSV season. VE against first occurrence of RSV-LRTD and RSV-ARI was calculated for different subgroups (Table).
Results: In total, 24,966 participants received RSVPreF3 OA (12,467) or placebo (12,499). Of these, 25.7% (RSVPreF3 OA) and 25.9% (placebo) had ≥1 metabolic or endocrine condition (22.9% diabetes). Mean BMI in both groups was 29.1 kg/m2. In participants with overweight/obesity, VE was 85.6% (RSV-LRTD) and 76.3% (RSV-ARI). In those with ≥1 metabolic or endocrine condition, VE was 100% (RSV-LRTD) and 79.4% (RSV-ARI) (Table).
Conclusion: RSVPreF3 OA is highly efficacious against RSV-LRTD and RSV-ARI in adults ≥60 years with overweight/obesity and in those with ≥1 metabolic or endocrine condition.

Disclosure
R. G. Feldman: Research Support; GSK, Speaker's Bureau; Amgen Inc., GSK. V. Hulstroem: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. R. Antonelli incalzi: None. K. Steenackers: Employee; Johnson & Johnson Medical Devices Companies. D. Lee: None. L. Fissette: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. M. David: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. C. Maréchal: Employee; GlaxoSmithKline plc., Stock/Shareholder; GlaxoSmithKline plc. L. Kostanyan: None. M. Van der wielen: Employee; GlaxoSmithKline plc.

Funding
GlaxoSmithKline Biologicals SA
289-OR: Defining Pathway-Selective Insulin Resistance in Type 2 Diabetes Using iPS Cell-Derived Hepatocytes
Authors: GATTU ARIJEET , KROOK ANNA , ZIERATH JULEEN R. , MANN MATTHIAS , RONALD KAHN C. 
Published: June 2023

Hepatic insulin resistance is central to type 2 diabetes (T2D), fatty liver disease, and metabolic syndrome. To identify the fundamental, cell-autonomous defects underlying hepatic insulin resistance in T2D, we have used inducible human pluripotent stem (iPS) cells derived from 16 individuals with and without T2D differentiated to hepatocytes (iHeps) and studied in vitro. Consistent with pathway selective insulin resistance, we find that insulin failed to suppress gene expression of critical gluconeogenic enzymes (PCK1, G6PC) but continued to stimulate increased expression of the lipogenic enzymes, fatty acid synthase and acetyl Co-A carboxylase 1 in T2D iHeps. iHeps from T2D also displayed reduced insulin receptor tyrosine phosphorylation and reduced phosphorylation through the IRS/Akt pathway. Global phosphoproteomics in control and T2D iHeps identified 378 unique phosphosites regulated by insulin, and many dysregulated phosphosites within the classical insulin signaling pathway (IRS, AKT1/2, GSK3, FOXO1, RPS6KB1, TSC2) and components of gene transcription regulation, membrane trafficking, Rho-GTPases, vesicle transport. Using a kinome-wide data set created with synthetic peptide libraries to profile almost all functional known human serine/threonine kinases, we found the alterations in insulin signaling mapped to AKT, P70S6K, P90S6K, RSK, PKCτ, and SGK kinases. Thus, iHeps from T2D patients show pathway-selective insulin resistance with a loss of suppression of gluconeogenesis by insulin yet persistent activation of lipogenesis, even in vitro, in the absence of any circulating factor exposure. T2D iHeps also show a dysregulated phosphorylation network that provides new clues to the kinases whose action is altered in T2D and hepatic insulin resistance.

Disclosure
A.Gattu: None. A.Krook: None. J.R.Zierath: None. M.Mann: None. C.Kahn: None.

Funding
National Institutes of Health (T32DK007260-46)
29-OR: Diabetic Wound Keratinocytes Induce Macrophage JMJD3–Mediated Nlrp3 Expression
Authors: WOLF-FORTUNE SONYA , MOON JADIE , JOSHI AMRITA , MAZUMDER PURBA , BARRETT EMILY , MANGUM KEVIN D. , GALLAGHER KATHERINE 
Published: June 2023

Macrophage (Mφ) plasticity is critical for normal wound repair; however, type 2 diabetic (T2D) wound Mφs display a delayed chronic inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome gene expression and activation in Mφs contributes to impaired wound healing in T2D and is induced by diabetic wound environment factors, yet the molecular mechanisms regulating this are unclear. Our lab has shown that keratinocytes, structural cells in the skin, regulate skin inflammation and Mφ phenotype during wound healing by preferentially producing proinflammatory cytokines. Thus, this project explores the molecular mechanisms by which keratinocytes drive increased Nlrp3 expression in diabetic wound Mφs. Here, we found that Nlrp3 expression is increased in diabetic wound Mφs late post-injury, and this can be induced by stimulation of normal wound Mφs with diabetic wound keratinocyte supernatant. Further, we found that stimulation of Mφs with diabetic wound keratinocyte supernatant resulted in decreased H3K27me3 deposition at the Nlrp3 promoter. Using genetically engineered mice (Jmjd3 fl/fl lyz2cre), we demonstrate that JMJD3, a demethylase specific for H3K27, controls Mφ-mediated Nlrp3 expression and inflammasome activation during wound healing. Importantly, we show that diabetic wound keratinocytes induce Jmjd3 expression in Mφs via IL1 receptor and MyD88 upstream signaling. Interestingly, we found that IL1α is increased in human and murine wound diabetic keratinocytes compared to nondiabetic controls and stimulation of Mφs with IL1α increases Nlrp3 expression via a H3K27me3/JMJD3-mediated mechanism. Thus, our data suggest a role for keratinocyte IL1α in driving increased Nlrp3 expression in chronic diabetic wound Mφs via JMJD3. Continued investigation into the dysregulation of the keratinocyte-Mφ axis in diabetic wounds is key to developing novel treatments for non-healing wounds in T2D patients.

Disclosure
S. Wolf-Fortune: None. J. Moon: None. A. Joshi: None. P. Mazumder: None. E. Barrett: None. K.D. Mangum: None. K. Gallagher: None.

Funding
National Institutes of Health (1K99DK133828-01, P30DK089503, R01HL137919, R01DK124290, R01HL15627401, R01DK127531)
294-OR: Hepatic Integrin ß1 Subunit Is Required for Liver Insulin Resistance but Not Fatty Liver in Diet-Induced Obese Mice
Authors: TREFTS ELIJAH , GHOSHAL KAKALI , DO ALLISON V. , GUERIN AMANDA , GUAN CHRISTOPHER , BRACY DEANNA , LANTIER LOUISE , ZENT ROY , POZZI AMBRA , WASSERMAN DAVID H. 
Published: June 2023

Obesity can lead to liver fibrosis and a selective insulin resistance whereby insulin-stimulated lipogenesis is maintained and liver triglycerides (TG) are elevated, while insulin suppression of liver glucose production (Ra) is impaired. The hypothesis that extracellular matrix (ECM) proteins of the fibrotic liver signal via integrin receptors contributing to hepatic insulin resistance was tested. Integrins consist of an α subunit that confers ligand specificity and a β subunit that interacts with adhesion proteins that transmit signals that lead to adaptations in cell function. The integrin β1 subunit is the primary isoform in the liver. Lean and diet-induced obese (DIO) C57Bl/6J mice with hepatocyte-specific deletion of the integrin β1 subunit (hitgβ1) knockout (KO) and wild type littermates (WT) were studied. Insulin clamps were performed in hitgβ1 KO and WT mice. Ra and glucose utilization (Rd) were measured before and during clamps. Metabolism in lean mice was unaffected by hitgβ1 KO. DIO WT mice were resistant to insulin suppression of Ra and had elevated liver TG. This insulin resistance to suppression of Ra was completely alleviated in DIO hitgβ1 KO mice. However, liver TG remained elevated. Alleviation of hepatic insulin resistance in DIO hitgβ1 KO mice was reflected by a greater activation of the insulin signaling pathway in hepatocytes. In contrast, impaired response of enzymes that participate in cytoskeletal organization and mitochondrial oxidation were observed in DIO hitgβ1 KO mice. It is postulated that impaired cytoskeletal organization decreases mitochondrial oxidation through effects on mitochondrial interactions. Impaired oxidation may contribute to the elevated TG that is present despite the improvement in insulin action. In conclusion, the hitgβ1 subunit contributes to selective hepatic insulin resistance in DIO mice. These data provide a mechanistic basis for an ECM - integrin receptor - insulin resistance axis in DIO mice.

Disclosure
E.Trefts: None. D.H.Wasserman: None. K.Ghoshal: None. A.V.Do: None. A.Guerin: None. C.Guan: None. D.Bracy: None. L.Lantier: None. R.Zent: None. A.Pozzi: None.

Funding
National Institutes of Health (DK050277, DK054902, DK059637)
295-OR: Mechanisms of Antigen-Specific Immunotherapy following Tolerance Induction to a CD4 Hybrid Insulin Peptide Epitope and the Impact on CD8 T Cell Dysfunction
Authors: DILISIO JAMES E. , BAKER ROCKY L. , HASKINS KATHRYN M. 
Published: June 2023

Type 1 diabetes is the culmination of T cell mediated autoimmunity resulting in the destruction of insulin-producing beta cells. Islet-derived hybrid insulin peptides (HIPs), recognized by autoreactive CD4 T cells, are likely dominant T cell epitopes in the NOD mouse model of autoimmune diabetes. The 2.5HIP is formed by the fusion of a fragment of insulin C-peptide with a natural cleavage product of chromogranin A, generating a neoepitope. When the 2.5HIP was delivered as an immunotherapy on tolerance inducing PLG-nanoparticles, islet grafts functioned longer in transplanted, diabetic NOD mice. Tolerance induction to this single neoepitope induced dysfunctional cytokine production in autoreactive CD4 and CD8 T cells specific for other known islet antigens. Here we used both prediabetic NOD mice and diabetic transplant recipients to examine mechanisms of peripheral tolerance induction to a HIP. Using the Tiger IL10-GFP reporter mouse, we observed a substantial increase in the proportion of (CD25+) Treg and (CD25-) Tr1 2.5HIP tetramer+ CD4 T cells that expressed IL10 in the islets, spleen, and draining lymph node of 2.5HIP nanoparticle treated mice. Autoreactive, IGRP tetramer+ CD8 T cells displayed a trafficking defect and accumulated in secondary lymphoid tissue with a concomitant reduction within islets. The proportion of cytolytic, CX3CR1+ IGRP tetramer+ CD8 T cells that infiltrated islets was also reduced. IL10 generated by both Treg and Tr1 2.5HIP tet+ T cells may directly suppress IGRP tetramer+ CD8 T cells or suppress an intermediate cell type such as a dendritic cell, causing CD8 T cell dysfunction. Examining how antigen-specific immunotherapies suppress multiple autoreactive T cells specificities may help inform future therapies without the need for immunosuppression.

Disclosure
J.E.Dilisio: None. R.L.Baker: None. K.M.Haskins: None.

Funding
National Institutes of Health (5T32DK120520-03, 2R01DK081166-11); JDRF (2-SRA-2020-907-S-B)
328-OR: Effect of Unblinded vs. Blinded Dexcom G6 CGM Wear in Outpatients with Type 2 Diabetes—Real-World Data
Authors: HICKS CHRISTIAN , ZHOU TERESA , MENON SIDDHARTH , CRAWFORD MARGARET A. , CHERÑAVVSKY DANIEL R. , RATERMAN DANIEL , SMITH NICOLE , TRESSLER MICHELLE , WELSH JOHN , SINGH HARSIMRAN 
Published: June 2023

Recent studies have demonstrated the value of CGM in optimizing Type 2 diabetes (T2D) management. There is an interesting debate in the literature examining the value of unblinded vs blinded wear of CGM, which is especially relevant in T2D management. We sought to understand the glycemic effects of transitioning from unblinded to blinded CGM wear in a small cohort of T2D outpatients from a community hospital. Participants (n=46) wore unblinded Dexcom G6 sensors for 90 days. After a 90-day washout period, they wore blinded G6 sensors for 10 days. They then completed surveys regarding device acceptability and behavioral changes attributable to CGM wear. Paired t-tests were used to compare unblinded vs. blinded intervals. Median (IQR) age was 59 (54-63) years and 72% were CGM naïve. Median (IQR) baseline A1C was 7.4% (6.7-8.5). Twenty-one participants completed the program in full. The post-washout mean TIR was 15 percentage points lower than during rt-CGM use (Table), attributable to more time in hyperglycemia. Most participants reported that CGM was helpful in making dietary decisions. In adults with T2D, discontinuation of CGM is associated with worsening of glycemic control. Ongoing access to CGM data is likely necessary to maintain good control in T2D. Further research with large and diverse T2D samples is needed to understand how CGM impacts patient behavior and how to sustain long-term improvements.

Disclosure
C.Hicks: Employee; Dexcom, Inc. H.Singh: Employee; Tandem Diabetes Care, Inc., Dexcom, Inc. T.Zhou: Employee; Pfizer Inc. S.Menon: Employee; Dexcom, Inc. M.A.Crawford: Employee; Dexcom, Inc. D.R.Cherñavvsky: None. D.Raterman: None. N.Smith: None. M.Tressler: Employee; Dexcom, Inc. J.Welsh: Employee; Dexcom, Inc.

Funding
Dexcom, Inc.