bluuebunny/crossref_metadata_2025_split huggingface dataset:
336-OR: Insulin Delivery Modality Does Not Impact Glycemic Change during Physical Activity in Youth with Type 1 Diabetes (T1D)—Results from the Real-World T1DEXI Pediatric Study
Authors: RIDDELL MICHAEL , BERGFORD SIMON , GAL ROBIN L. , PATTON SUSANA R. , CLEMENTS MARK A. , CALHOUN PETER , SHERR JENNIFER ,   T1DEXIP STUDY GROUP
Published: June 2023

Despite its well-established benefits, exercise can cause blood glucose levels to drop precipitously. Factors such as pre-exercise glucose, exercise type and insulin on board (IOB) all appear to influence the magnitude of drop in glucose during exercise, but it is currently unclear if insulin delivery modality (i.e., MDI vs. standard pump vs. closed loop pump) has a clinically significant effect. Data from the Type 1 Diabetes Exercise Initiative Pediatric (T1DEXIP) study allowed us to examine if insulin delivery modality influences the change in glucose during exercise in youth with T1D. Youth (N=248) with T1D ([mean ± SD] age= 14±2 years; T1D duration= 5.4±3.9 years; HbA1c= 7.1±1.3%; BMI percentile= 62±27%; 58% male) wore a continuous glucose monitor (Dexcom G6) and a Garmin, Vivosmart 4 activity monitor while logging meals and activity with the bant smartphone app over a 10-day period. Drop in glucose level during exercise was associated with pre-exercise glucose and IOB (mean change in glucose of 5.7 mg/dL, -15.7 mg/dL, and -26.5 mg/dL for IOB of 0 U/kg, &gt;0 to &lt;0.1 U/kg, and ≥0.1 U/kg, respectively; p&lt;0.001), but did not differ significantly by insulin delivery modality (Figure). Pre-exercise glucose and IOB, but not insulin delivery method, are associated with changes in glucose during exercise in youth with T1D.

Disclosure
M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. S.Bergford: None. R.L.Gal: None. S.R.Patton: None. M.A.Clements: Consultant; Glooko, Inc., Research Support; Dexcom, Inc., Abbott Diabetes. P.Calhoun: None. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Cecelia Health, StartUp Health T1D Moonshot, Consultant; Bigfoot Biomedical, Inc., Insulet Corporation, Medtronic, Lilly, Research Support; Insulet Corporation, Medtronic, NIH - National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF), Speaker's Bureau; Insulet Corporation, Zealand Pharma A/S, Lilly, Medtronic. T1dexip study group: n/a.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust; Dexcom, Inc.
34-OR: Postprandial Glucagon Action in the Human Brain
Authors: WAGNER ROBERT , KULLMANN STEPHANIE , HUMMEL JULIA , VEIT RALF , PRYSTUPA KATSIARYNA , HOSENFELD ELENA , BIRKENFELD ANDREAS L. , HÄRING HANS-ULRICH , PREISSL HUBERT , FRITSCHE ANDREAS , PETER ANDREAS , HENI MARTIN 
Published: June 2023

While elevated fasting glucagon is linked to hyperglycemia, the impact of postprandial changes in glucagon is less clear. Recent findings suggest potential metabolic benefits of rising glucagon after oral glucose intake. In addition to the prominent hepatic action of the hormone, animal data indicate that glucagon signaling in the brain contributes to its effects on whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. We performed oral glucose tolerance tests combined with fMRI to quantify brain activity and connectivity at fasting, 30- and 60-minutes post glucose load in 29 volunteers. In 14 out of 22 volunteers with physiologically suppressed glucagon during OGTT, a second OGTT with low-dose glucagon infusion was performed (0.5 pmol/kg/min). All participants had their first OGTT with intravenous saline infusion. This was compared to 7 participants with endogenous rising glucagon during OGTT. Low-dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during the OGTT significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the regulation of food intake and systemic metabolism (i.e. hypothalamus, nucleus accumbens, midbrain). Postprandial brain responsivity during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underly the promising effects on body weight achieved with upcoming pharmacological multi-agonists that activate the glucagon receptor.

Disclosure
R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.Peter: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. S.Kullmann: None. J.Hummel: None. R.Veit: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. E.Hosenfeld: None. A.L.Birkenfeld: None. H.Häring: None. H.Preissl: None.
350-OR: Transcriptomics Identification of a-Cell Subpopulations in Human Islets Using Integrated scRNA-seq and snRNA-seq
Authors: KANG RANDY , LEE JUNGEUN , GARCIA-OCANA ADOLFO , LU GEMING 
Published: June 2023

Loss of β cells leads to diabetes. α cells are refractory to spontaneous conversion to β cells, but a small percentage are reprogrammed to β cells with acute β cell loss. β cell heterogeneity and identification of β cell subpopulations and their transcriptomic profiles have been reported. However, α cell subpopulations in the human islet have not been clearly defined yet. Moreover, whether specific human α cell subpopulations can potentially evolve into β cells is unknown. Here, we integrated scRNA- and snRNA-seq data of human islets from 3 adult healthy donors to determine α cell subpopulations and their transcriptomic profiles. We extracted the α cell cluster (7,535 cells) and using Louvain resolution 0.8, we identified 5 subclusters: 1) α cells (GCGhigh/TTRhigh/PTPRT high); 2) αβ-Transition-1 (αβ-Tr1) cells; 3) αβ-Tr2 cells; 4) αβ1 cells (GCGhigh/INSlow/IAPPlow); and 5) αβ2 cells (GCGlow/INShigh/IAPPhigh). To investigate the transcriptomics connectivity among clusters, we performed RNA velocity and Partition-based Graph Abstraction (PAGA) analyses. PAGA showed that αβ-Tr1 cells (15.3% of cells) are the root subcluster from where α cells and αβ-Tr2 cells are formed, suggesting a precursor nature. αβ-Tr2 cells are the origin of αβ1 and αβ2 cells. We next projected this finding into the pseudotime algorithm and analyzed gene expression gradients in the trajectories. Interestingly, the αβ-Tr1/αβ-Tr2/αβ2 cells trajectory showed a gradual increase in the expression of β cell genes (INS, ZNF385D, CASR, MAFA) while decreasing expression of ribosomal genes, GCG and MALAT1. Single cell pathway analysis with escape package showed that αβ-Tr1 cells are enriched in ribosome and translation gene pathways and that αβ-Tr2 cells are enriched in transdifferentiation genes INSM1, PDX1 and SMAD3. In summary, these studies identified 5 α cell subpopulations with different transcriptomic profiles and highlight the potential plasticity of αβ-Tr cells to generate αβ cells.

Disclosure
R.Kang: None. J.Lee: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.Lu: None.
411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease
Authors: NADKARNI GIRISH N. , FLEMING FERGUS , DONOVAN MICHAEL J. , COCA STEVEN 
Published: June 2023

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR&lt;15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors.

Disclosure
G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix.

Funding
Renalytix
438-P: Very-Low-Dose Metformin Can Safely Improve Glycemic Control in Type 2 Diabetic Patients Receiving Maintenance Hemodialysis (HD)
Authors: FUNAKOSHI SATOSHI 
Published: June 2023

Objective: Use of metformin in patients with impaired renal function is controversial as it may increase the risk of lactic acidosis. To evaluate metformin with appropriate dose reduction can safely improve glycemic control in patients with type 2 diabetes (T2D) on HD.
Methods: In six relatively poor-controlled HD patients with T2D (av. BMI=29.7±5.9, glycoalbumin: GA&gt;27%) treated with insulin degludec (8-35 units/day) + dulaglutide (0.75mg/week), low-dose metformin (250-500mg/day) was added on. From starting of metformin administration serum lactate level and pH were monitored biweekly in all patients. Glycemic control was assessed by CGM and the mean amplitude of glycemic excursions (MAGE) was calculated before and 4 weeks after.
Results As shown in figure (each color represents the average glycemic profile of one patient), glycemic control was improved by low-dose metformin as average MAGE was significantly decreased from 128.4+69.1 mg/dL to 83.4+43.3 mg/dL (p&lt;0.05) without episode of hypoglycemia. Average GA was significantly reduced from 32.0% to 22.62% (p&lt;0.01), whereas serum pH and lactate stayed stable up to 3 months.
Conclusion More than 90% of metformin or lactate is cleared, and acid-base balance is adjusted by a single hemodialysis session. Unlike pre-HD patients with impaired renal function, in patients on maintenance HD metformin is potentially safe and useful in controlling plasma glucose level when the dose is appropriately reduced.

Disclosure
S.Funakoshi: None.
452-P: Risk of Cardiovascular Disease according to Baseline LDL Cholesterol Level in Different Age Groups among 2 Million Diabetes Patients
Authors: LEE WON-YOUNG , RHEE EUN-JUNG , HAN KYUNGDO 
Published: June 2023

Background: In the population with diabetes mellitus (DM), the impact of age on the association between low density lipoprotein-cholesterol (LDL-C) level and cardiovascular disease (CVD) risk is unclear. Therefore, we conducted a cohort study to elucidate the relationship.
Methods: We assessed the 2009-2012 Korean National Health Screening and the National Health Insurance Service record, with follow up to primary outcome (myocardial infarction [MI] or stroke) or December 2018. Participants with a history of MI and stroke were excluded. Finally, 2,227,394 participants with DM were included. Participants were categorized based on baseline LDL-C level and age. Cox proportional hazard modeling was conducted with confounding factor adjustment. CVD risk of age &lt;40, LDL-C &lt;70mg/dL were set as a reference. In each age group, LDL-C &lt;70mg/dL was set as a reference and subgroup analysis was done.
Results: The cut-off LDL-C value for increased MI risk were different in each age group (&lt;40 year old, LDL-C ≥160mg/dL, HR 2.03, 95% CI 1.644-2.506; 40-49 year old, LDL-C &lt;115 mg/dL, HR 1.245, 1.04-1.489; 50-59 year old, LDL-C &lt;115 mg/dL, HR 1.21, 1.014-1.445; 60-69 year old, LDL-C &lt;145mg/dL, HR 1.229, 1.022-1.479; ≥70year old group, LDL-C &lt;100mg/dL, HR 1.238, 1.018-1.504). The cut-off LDL-C value for increased stroke risk were different in each age subgroup (&lt;40 year old, LDL-C ≥160mg/dL, HR 1.395, 1.094-1.779; 40-49 year old, LDL-C &lt;145 mg/dL, HR 1.13, 1.019-1.253; 50-59 year old, HR 1.079, 1.008-1.154, 60-69 year old, LDL-C &lt;130mg/dL, HR 1.07, 1.022-1.119; ≥70year old; LDL-C &lt;115mg/dL, HR 1.064, 1.019-1.112)
Conclusions: The impact of LDL-C on the risk of CVD varies according to the age of DM population.

Disclosure
W.Lee: None. E.Rhee: None. K.Han: None.
455-P: Waist–to–Body-Mass-Index Ratio Independently from Type 2 Diabetes Predicts MACE in Patients with Cardiovascular Disease
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , PLATTNER THOMAS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2023

Waist circumference reflect central fat accumulation and is an important additive information to BMI. The Waist Circumference-to-Body-Mass-Ratio (W/BMI-Ratio) has been suggested to provide additional information on cardiovascular event risk. Its power to predict cardiovascular events in patients with established cardiovascular disease is not known and is addressed in the present study. We prospectively recorded cardiovascular events in 1833 patients with angiographically verified coronary artery disease or sonographically proven peripheral artery disease. The mean follow-up time was 9.4±5.1 years. At baseline, there was no significant difference in the W/BMI-Ratio between patients with and those without T2DM (3.6±0.3 vs. 3.6±0.3; p=0.465). Prospectively, the W/BMI-Ratio significantly predicted the incidence of MACE (n=716) both univariately (standardized HR 1.46 [1.18-1.80], p&lt;0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR=1.29 [1.02±1.63], p=0.032); HRs were 1.29 [1.02±1.85], p=0.013 in patients without diabetes and 1.08 [0.98-1.21], p=0.138 in those with diabetes, with a non-significant p for interaction W/BMI-Ratio x diabetes status. We conclude that the W/BMI-Ratio independently from diabetes status is a predictor for MACE in patients with established cardiovascular disease.

Disclosure
A.Mader: None. C.H.Saely: None. L.Sprenger: None. A.Vonbank: None. B.Larcher: None. M.Maechler: None. T.Plattner: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None.
456-P: Ceramide- and Phosphatidylcholine-Based Coronary Event Risk Tests 1 and 2 (CERT1, CERT2) Predict Both Type 2 Diabetes and Chronic Kidney Disease
Authors: PLATTNER THOMAS , SAELY CHRISTOPH H. , MUENDLEIN AXEL , VONBANK ALEXANDER , MADER ARTHUR , SPRENGER LUKAS , MAECHLER MAXIMILIAN , LARCHER BARBARA , DREXEL HEINZ , LEIHERER ANDREAS 
Published: June 2023

The ceramide- and phosphatidylcholine-based scores CERT1 and CERT2 are predictors for cardiovascular events. The presence of chronic kidney disease (CKD) indicates a high risk of cardiovascular events, particularly in patients who also have type 2 diabetes (T2DM). However, little is known about the associations between T2DM, CKD and CERT1 or CERT2. Therefore, we determined CKD status (eGFR &lt;60 ml/min. 1,73 m2 or albuminuria with an albumin/creatinine ratio &gt;30 mg/g) and analyzed CERT1/2 in 945 high-risk patients, of whom 259 had T2DM. T2DM was diagnosed using ADA criteria. Both CERT1 and CERT2 were significantly higher in patients with T2DM than in nondiabetic subjects (4.5±3.4 vs. 3.5±2.9;p&lt;0.001 and 5.9±2.6 vs. 5.2±2.3; p&lt;0.001, respectively). Further, CERT1 and CERT2 predicted T2DM after adjusting for age, sex, smoking, BMI, LDL-C, HDL-C, with ORs of 1.10 [1.05-1.15]; p&lt;0.001 and 1.10 [1.03-1.17]; p=0.004, respectively. CKD was present in 52.5% of our patients with T2DM and in 30.3% of nondiabetic subjects (p&lt;0.001). CERT1 predicted the risk of CKD in patients with T2DM as well as in patients who did not have T2DM (with ORs of 1.11 [1.03-1.20]; p=0.005 and 1.10 [1.04-1.17]; p=0.001; respectively), as did CERT2 (ORs 1.16 [1.05-1.29]; p=0.005 and 1.14 [1.06-1.24]; p&lt;0.001; respectively). We conclude that CERT1 and CERT2 are strong and significant predictors of T2DM as well as of CKD.

Disclosure
T. Plattner: None. C.H. Saely: None. A. Muendlein: None. A. Vonbank: None. A. Mader: None. L. Sprenger: None. M. Maechler: None. B. Larcher: None. H. Drexel: None. A. Leiherer: None.
475-P: Intermittent Hypoxia Increased the Expression of Intercellular Adhesion Molecule-1 and Endothelial Cell–Specific Molecule-1 in Vascular Endothelial Cells via the Downregulation of MicroRNA-181a1
Authors: TAKASAWA SHIN , MAKINO MAI , YAMAUCHI AKIYO , SAKURAMOTO-TSUCHIDA SUMIYO , TAKEDA YOSHINORI , UCHIYAMA TOMOKO , SHOBATAKE RYOGO 
Published: June 2023

Sleep apnea syndrome (SAS), which is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for vascular dysfunction, as well as hypertension, and insulin resistance/Type 2 diabetes. We have reported correlations between IH and insulin resistance/Type 2 diabetes, and hypertension. However, the question of why vascular dysfunction is induced by IH has remained unanswered. Here, we investigated the effects of IH on the expression of endothelial inflammatory transcripts such as intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8, C-C motif chemokine ligand 5 (CCL5), endothelial nitric oxide synthase (NOS3), vascular cell adhesion molecule-1 (VCAM-1), endothelial cell specific molecule 1 (ESM1), and endothelin-1 (EDN-1) using an in vitro IH system. Human and mouse vascular endothelial cells (HUEhT-1 and UV2) were exposed to IH or normoxia for 24 hours. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of ICAM-1 and ESM1 in both HUEhT-1 (P=0.0436 and P=0.0145, respectively) and UV2 cells (P&lt;0.0001 and P=0.0422, respectively). ELISA showed that ICAM-1 and ESM1 were significantly increased (P=0.0105 and P&lt;0.0001, respectively) in the UV2 cell medium by IH. Reporter assays revealed that the promoter activities of ICAM-1 and ESM1 were not increased by IH. The microRNA (miR)-181a1 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells (P=0.0374). The IH-induced upregulation of ICAM-1 and ESM1 was abolished by the introduction of miR-181a1 mimic, indicating that IH stress increased levels of ICAM-1 and ESM1 via the inhibition of miR-181a1-mediated mRNA degradation, leading SAS patients to develop atherosclerosis.

Disclosure
S.Takasawa: None. M.Makino: None. A.Yamauchi: None. S.Sakuramoto-tsuchida: None. Y.Takeda: None. T.Uchiyama: None. R.Shobatake: None.
485-P: Proteomic Analysis Reveals Different Therapeutic Mechanisms for Diabetic Neuropathy between DPP-4 Inhibitor and SGLT2 Inhibitor
Authors: TAKEUCHI YUKI , OSONOI SHO , SASAKI TAKANORI , MIZUKAMI HIROKI 
Published: June 2023

Aim: Diabetic neuropathy (DN) is the most prevalent complication with microangiopathy in diabetes. Although, DN would decrease quality of life, currently there is no radical treatment for DN. DPP-4 inhibitor (DP4i) and SGLT-2 inhibitor (SG2i) have been experimentally shown to possibly ameliorate DN. However, the difference in the mechanism between two agents has not been clarified so far. In this study, we performed proteomic analysis of the sciatic nerve (SN) and dorsal root ganglion (DRG) of Goto-Kakizaki rats (GK), a model of lean type 2 diabetes, treated with DP4i and/or SG2i.
Methods: Male GK and control Wister rats (W) were used. Since 5 weeks of age, GK rats were treated with 10mg/day DP4i (Te), 10mg/ day SG2i (Ca), and DP4i + SG2i (CaTe) until 29 weeks of age. Thermal perception was evaluated by tail flick test. At the end of experiment, SN, DRG, and skin tissue were dissected. Proteomic analysis was performed with SN and DRG tissues by mass spectrometry. In the skin, fluorescent immunostaining with anti-PGP 9.5 antibody was performed for the assessment of intraepidermal nerve density (IENFD).
Results: Tail flick test and IENFD were significantly decreased in GK compared to W (p&lt;0.05), and significantly improved in Te, Ca, and CaTe (p&lt;0.05, p&lt;0.05 and p&lt;0.01 vs GK, respectively). Proteomic analysis for SN showed only two pathways changed in Te, whereas seven and six pathways changed in the Ca and CaTe, respectively. Conversely, in the DRG, only two pathways changed in Ca, whereas the five and seven pathways changed in Te and CaTe, respectively.
Conclusion: Our results suggest that the DP4i and SG2i act on the different sites of peripheral nervous system with different mechanism. Combining these two agents possibly have complementary effects on DPN treatment.

Disclosure
Y.Takeuchi: None. S.Osonoi: None. T.Sasaki: None. H.Mizukami: None.

Funding
Mitsubishi Tanabe Pharma Corporation