bluuebunny/crossref_metadata_2025 huggingface dataset:
182-OR: C-Peptide and Metabolic Outcomes in Immunotherapy Studies of New-Onset Type 1 Diabetes
Authors: TAYLOR PETER , COLLINS KIMBERLY S. , KARPEN STEPHEN , ATABAKHSH ELNAZ , AHMED SIMI , MARINAC MARJANA , LATRES ESTHER , LAM ANNA , SENIOR PETER A. , RIGBY MARK , GOTTLIEB PETER , DAYAN COLIN
Published: June 2023

Background: Despite advances in insulin therapy, metabolic outcomes in T1D remain suboptimal. Immunotherapy to preserve beta cell function has enormous potential but the metabolic benefits and the size of trial needed to demonstrate them remain unclear, hindering drug development.

Methods: Our dataset comprised 1315 adults and 1396 children enrolled in 20 immunotherapy intervention trials within 100 days of diagnosis. End points assessed were AUC c-peptide, HbA1c, IDAAC, Beta-2 Score and hypoglycemia. Differences in outcomes between active and control arms in positive and negative studies were assessed using the Wilcoxon rank test.

Results: C-peptide preservation in positive studies resulted in greater improvements in HbA1c within 3 months of beginning therapy. Beyond the initial 3 month “honeymoon” period, 20% greater preservation of C-peptide in active versus placebo subjects was associated with a 0.5% lower HbA1c. Higher initial C-peptide levels and greater C-peptide preservation were associated with better glycemic outcomes.

Sample size for HbA1c, IDAAC, and Beta-2 Score required 2-3 times as many subjects per armto demonstrate a difference at 6 months as compared to C-peptide. Smaller samples sizes were required in children. Longer studies are required to demonstrate durability but not efficacy. Hypoglycaemia rates required substantially larger sample sizes and more than 1 year follow-up.

Conclusion: Immunotherapy to preserve beta cell function is effective at improving metabolic outcomes in new-onset T1D. Beyond the initial 3 month period, improvements in HbA1c are proportional to C-peptide preservation. Early intervention and sustained high C-peptide levels are required for ongoing benefits.

Disclosure

P.Taylor: None. M.Rigby: None. P.Gottlieb: Advisory Panel; ViaCyte, Inc., Board Member; ImmunoMolecular Therapeutics, Research Support; Imcyse, Hemsley Charitable Trust, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Dompé, Nova Pharmaceuticals, Provention Bio, Inc. C.Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc. K.S.Collins: None. S.Karpen: None. E.Atabakhsh: None. S.Ahmed: None. M.Marinac: None. E.Latres: None. A.Lam: None. P.A.Senior: Advisory Panel; Novo Nordisk Canada Inc., Consultant; Novo Nordisk Canada Inc., Bayer Inc., Viatris Inc., Vertex Pharmaceuticals Incorporated, ViaCyte, Inc., Insulet Corporation.

Funding

JDRF; Diabetes UK
186-OR: Genetic Variants That Lower Hemoglobin A1c Independently of Glycemia Are Associated with Higher Diabetic Retinopathy Risk in Diverse Ancestries
Authors: SCHROEDER PHILIP H. , MANDLA RAVI , FLOREZ JOSE C. , MERCADER JOSEP M. , LEONG AARON
Published: June 2023

Introduction: People with type 2 diabetes (T2D) who carry genetic variants that lower hemoglobin A1c (A1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared to those who do not despite achieving similar A1c targets, placing them at greater risk for complications.

Methods: Using data from 39,199 T2D cases of European ancestry (EA) and African ancestry (AA) in UK Biobank and All of Us, we calculated a nonglycemic A1c polygenic score (ngA1cPS) composed of 123 variants previously associated with A1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS with DR (n = 3,859), adjusting for A1c and known DR risk factors (T2D duration, kidney disease, hypertension, lipids, smoking).

Results: Participants at the bottom ngA1cPS quintile showed 25-50% higher DR prevalence vs. the rest despite having lower measured A1c (6.6 vs 6.7%). Odds ratios were 1.28 in EA and 1.37 in AA (Fig. 1). Among carriers of the African-specific G6PD variant rs1050828 known to lower A1c, DR prevalence was 27% higher among those with ngA1cPS below the median vs. above the median.

Conclusions: The aggregate effect of variants that lower A1c independently of glycemia is associated with a higher DR risk in both EA and AA. Genetic effects need to be considered to define personalized A1c targets to improve the outcomes of patients with T2D.

Disclosure

P.H.Schroeder: None. R.Mandla: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. J.M.Mercader: None. A.Leong: Other Relationship; Merck & Co., Inc.

Funding

Doris Duke Charitable Foundation (2020096)
187-LB: Preclinical Biomarkers of Alzheimer's Disease Neuropathology in Young Adults with Youth-Onset Diabetes (YDM)—A Proof-of-Concept Study
Authors: SHAPIRO ALLISON , COUGHLAN CHRISTINA , KIM JEONGCHUL , POTTER HUNTINGTON , BJORNSTAD PETTER , PAULEY MEGHAN E. , RAJIC BENJAMIN S. , TRUONG JENNIFER , GLUECK DEBORAH H. , HARRALL KYLIE K. , BARCUS RICHARD A. , TAN JOSH , BETTCHER BRIANNE , THAKER ASHESH , WALKER KEENAN A. , LIESE ANGELA D. , DABELEA DANA , WHITLOW CHRISTOPHER T.
Published: June 2023

Adult-onset diabetes increases one's risk for Alzheimer's disease and its related dementias (AD/ADRD). However, little is known about the risk for AD/ADRD in young adults with YDM. The current study quantified preclinical plasma and imaging biomarkers of AD/ADRD in a subset of young adults with YDM from the SEARCH for Diabetes in Youth study cohort (type 1 diabetes [T1D], n=20; type 2 diabetes [T2D], n=21; mean [SD], age=27.4 years [2.2], diabetes duration=13.6 years [2.4], 59% female). Plasma biomarkers were assayed from stored samples at two timepoints: within 1-year of YDM diagnosis (baseline) and in young adulthood via the Quanterix Simoa platform including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), amyloid beta (Aβ)40, and Aβ42. Seven participants from the SEARCH subset (T1D=6, T2D=1; age=30.7 years [2.4], 87% female) and four age-similar controls (age=26.5 years [4.4], 50% female) underwent [18F]PI-2620 tau positron emission tomography (PET) to quantify brain tau density. Tau standardized uptake value ratios (SUVRs) with partial volume correction were derived in AD/ADRD sensitive brain regions. From baseline to young adulthood, plasma pTau181 significantly increased in both YDM-T1D and YDM-T2D (mean change=9.5 pg/mL [3.8] and 12.4 pg/mL [6.3], respectively; p<0.001). Average tau SUVRs in the middle temporal poles (SUVR=1.26 [0.14] vs 1.17 [0.04]) and parahippocampal gyri (SUVR=1.01 [0.33] vs 0.92 [0.05]) were greater in YDM vs. controls. However, these differences were not statistically significant. Our preliminary results suggest that YDM may increase the risk of AD/ADRD via accelerated accumulation of soluble phosphorylated tau. Additional measurement of AD/ADRD neuropathology, including amyloid PET scans, is currently underway to further understand the trajectory of preclinical AD/ADRD pathology in YDM.

Disclosure

A. Shapiro: None. K. K. Harrall: None. R. A. Barcus: None. J. Tan: None. B. Bettcher: None. A. Thaker: None. K. A. Walker: None. A. D. Liese: None. D. Dabelea: None. C. T. Whitlow: Consultant; Biogen, Genentech, Inc. C. Coughlan: None. J. Kim: None. H. Potter: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. M. E. Pauley: None. B. S. Rajic: None. J. Truong: None. D. H. Glueck: None.

Funding

American College of Radiology
187-OR: Circulating MicroRNAs Predict Weight Loss in Participants from the Diabetes Prevention Program
Authors: GONG XINGYUE , LEWIS KIMBERLY A. , FLOREZ JOSE C. , AOUIZERAT BRADLEY , KANAYA ALKA M. , ZHANG LI , FLOWERS ELENA
Published: June 2023

Introduction: Weight loss is an important strategy for prevention of type 2 diabetes (T2D). Circulating microRNAs (miRs) are emerging as promising biomarkers of risk for T2D and responses to risk reduction interventions. The purpose of this study was to determine whether baseline microRNAs predict weight loss in a subset of participants in the Diabetes Prevention Program (DPP).

Methods: This study was a secondary analysis of a subset of participants from DPP (n=150, equally stratified by trial arm (intensive lifestyle, metformin, and placebo)). MiRs (58 total) were measured in banked plasma from the baseline timepoint using a custom Fireplex assay. Lasso was used to apply shrinkage for feature selection to identify a composite score of optimal miR predictors and logistic regression was used to model >7% weight loss after 2 years.

Results: Five miRs (miR-122, miR-151a, miR-192, miR-197, miR-23b) were identified as the optimal predictors of weight loss using Lasso. After adjustment for significant covariates (age, gender, race or ethnicity, and trial arm), the odds ratio of composite score for >7% weight loss was 3.16 (95% confidence interval (CI) 1.62, 6.18; p<0.001). There was no significant interaction between the composite score and the trial arms (p=0.239), where odds ratio of composite score in the metformin arm, the intensive lifestyle arm and placebo are 1.16, 4.67, 2.42, respectively. Five-fold cross validation showed an accuracy score of 80%. The area under the receiver operating characteristic curve for >7% weight loss after 2-years was 0.85.

Conclusions: MiRs are significant predictors of weight loss for prevention of T2D. Future directions include external validation in order to determine whether this risk score may have clinical utility, and functional analysis of the potential genes and pathways targeted by the miRs that were included in the risk score.

Disclosure

X.Gong: None. K.A.Lewis: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. B.Aouizerat: None. A.M.Kanaya: None. L.Zhang: None. E.Flowers: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124228, X01DK115999)
19-LB: Metabolomics and Continuous Glucose Monitoring Analyses during the Perioperative Period of Coronary Artery Bypass Graft Surgery
Authors: GUERRERO ARROYO LIZDA I. , ZAHEDI TAJRISHI FARBOD , SAM VARGHESE JITHIN , PEREZ-GUZMAN MIREYA , ABRAHAM AMALIA , SMITH MATTHEW R. , PASQUEL FRANCISCO J.
Published: June 2023

Hyperglycemia is common after Coronary Artery Bypass Graft (CABG) surgery. Many patients with stress hyperglycemia experience poor outcomes after surgery. The metabolic pathways associated with glycemic control during this period remain unknown. We used prospective observational data from 17 patients without diabetes who underwent CABG surgery and wore blinded Dexcom G6 pro devices during the perioperative period to explore associations with changes in the metabolome. We estimated the percentage time spent in the target range (70-140 mg/dL) using CGM values calibrated to point-of-care measurements. We categorized patients according to time spent (≥70 or <70%) in the target range. Nine participants spent >70% of time in the target range, while eight participants spent <70% of time in the target range. Metabolic pathways were identified from HILIC positive and Reverse Phase C18 analysis, with metabolites mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG) human pathways using mummichog. Baseline characteristics were similar between groups. Acylcarnitines and microbiome-related metabolites (e.g. 2-Dehydro-3-deoxy-D-gluconate 6-phosphate) were associated with worse glycemic control in the perioperative period, Figure. Metabolomics analysis suggests microbiome interactions and lipid pathways are associated with glycemic control after CABG surgery.

Disclosure

L. I. Guerrero arroyo: None. F. Zahedi tajrishi: None. J. Varghese: None. M. Perez-guzman: None. A. Abraham: None. M. R. Smith: None. F. J. Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies.

Funding

National Institutes of Health (K23GM128221); Dexcom, Inc.
190-LB: Differences in Postprandial and Counterregulatory Glucagon Excursions in Healthy Relatives to Type 1 Diabetes with Different Number of Islet Autoantibodies
Authors: IGBE TOBORE , MONTASER ESLAM , BRETON MARC D. , BROWN SUE A. , DEBOER MARK D. , MCCALL ANTHONY L. , KOVATCHEV BORIS , FARHY LEON
Published: June 2023

Background and aims: Early changes in glucagon during the progression to type 1 diabetes (T1D) are not well understood. We investigate whether the glucagon responses to a mixed meal and hypoglycemia depend on the number of islet autoantibodies (Ab) in individuals at risk for T1D.

Methods: Sixty healthy relatives of T1D with mean±SD age of 23.7±10.7 years, HbA1c of 5.3±0.3%, and BMI of 23.8±5.6 kg/m2 and zero (N=21), one (N=18), and ≥2 (N=21) Ab, were enrolled in an ancillary study from the NIH-funded TrialNet Pathway to Prevention study. Participants underwent a clinical test consisting of a mixed meal tolerance test (MMTT) followed by insulin-induced hypoglycemia. Glucagon was measured from -30 to 120 min around the MMTT and 0 to 40 min during hypoglycemia to estimate the Ab group differences in the meal and counter-regulatory glucagon responses assessed via the glucagon incremental area under the curve (iAUC).

Results: There were significant differences in the net iAUC of the glucagon responses to the MMTT (p=0.024), while the group difference in the glucagon counter-regulation estimated via the total AUC approached significance (p=0.08).

Conclusion: The study suggests that the glucagon responses to a meal and possibly, hypoglycemia, may be altered during the very early stages of the progression to T1D.

Disclosure

T. Igbe: None. E. Montaser: None. M. D. Breton: Consultant; Dexcom, Inc. Research Support; Dexcom, Inc. Consultant; Tandem Diabetes Care, Inc. Research Support; Tandem Diabetes Care, Inc., Novo Nordisk. Consultant; Roche Diabetes Care, Sanofi, Arecor. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. M. D. DeBoer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. A. L. McCall: None. B. Kovatchev: Speaker's Bureau; Tandem Diabetes Care, Inc. Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc. Other Relationship; Dexcom, Inc., Johnson & Johnson Medical Devices Companies, Novo Nordisk, Sanofi. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106907); Commonwealth Research Commercialization Fund (MF20-007-LS); The Leona M. and Harry B. Helmsley Charitable Trust (2204-05134); JDRF (2-SRA-2022-1260-S-B)
195-LB: Type 2 Diabetes Data Quality in the All of Us Dataset
Authors: SULIEMAN LINA , GIANNINI JOHN , DEDE YILDIRIM ELIF , OSTCHEGA YECHIAM , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA
Published: June 2023

Data quality significantly impacts the reproducibility and validity of clinical research. The All of Us Research Program aims to collect biomedical data from one million or more participants, with the goal of enabling discoveries and improving targeted management of diseases like type 2 diabetes (T2D). All of Us data include whole genome sequences (WGS), electronic health records (EHRs), device measurements of physical activity, physical measures, and surveys available for analysis on the Researcher Workbench. The program's Spring 2023 curated data release makes All of Us the world's largest, most diverse genomic dataset of its kind available for broad research use, including 413,457 participants among which 60.4% are female, 44.6% are non-white.

To ensure maximum utility of this dataset for T2D researchers, we set out to quantify the data quality among participants who have T2D diagnosis codes in their EHRs. We identified the measurements and laboratory tests (hemoglobin A1C, height, weight, body mass index), medications (Insulin and non-insulin), and procedures commonly used in T2D research. We quantified data fitness using five dimensions of quality: completeness, concordance (i.e., agreement), conformance to data standards, plausibility, and temporality.

Among 287,012 participants who shared EHRs, 40,093 (14%) had T2D diagnosis codes where the mean age at first diagnosis was 56. Regarding measurements, 68% had A1C, 89% had height, and 70% had weight recorded in their EHR. For plausibility, 99.7% of weights, 99.9% of heights, and 99.3% of BMI were valid, and 97% of heights and weights have high concordance values. For medications, 99.7% of T2D participants had T2D medications, and 47.6% were prescribed after T2D diagnosis. Of these T2D participants, 69% have WGS or array data available.

Our analysis shows that the All of Us dataset offers a valuable and high-quality dataset for T2D phenotyping and diagnosis research. Our quality report and code will be available for replication and reuse by researchers with the upcoming release.

Disclosure

L. Sulieman: None. J. Giannini: None. E. Dede yildirim: None. Y. Ostchega: None. E. Ochsenfaber: None. L. Berman: None. A. Ramirez: n/a.
196-OR: The Long-Chain Fatty-Acid Receptor FFA4 Stimulates Insulin Secretion via Inhibition of Somatostatin Release from the Delta Cell
Authors: REININGER LAURA , ETHIER MÉLANIE , TREMBLAY CAROLINE , GHISLAIN JULIEN , HUISING MARK , POITOUT VINCENT , FLISHER MARCUS
Published: June 2023

The long-chain fatty-acid receptor FFA4 exerts beneficial effects on glucose homeostasis and insulin secretion and is considered a potential therapeutic target for type 2 diabetes. FFA4 is expressed in islets, but its precise mechanism of action remains unknown. Previous studies from our group suggest that FFA4 is expressed in delta cells and regulates somatostatin secretion. The objective of this study was to test the hypothesis that FFA4 agonists indirectly stimulate insulin secretion via inhibition of somatostatin release. In 1-h static incubations of isolated, wild-type mouse islets, the FFA4 agonist CpdA dose-dependently potentiated glucose-induced insulin secretion from 2.2±0.2 to 3.4±0.2 % of insulin content at the concentration of 50 μM (n=8; p<0.001), and simultaneously decreased somatostatin secretion from 28.4±2.1 to 10.5±0.9 pM (n=8; p<0.0001). No effect of CpdA on insulin or somatostatin secretion was observed in islets from mice that do not express somatostatin (insulin: 3.2±0.1 vs 2.9±0.4, n=6, NS; somatostatin: 11.4±1.2 vs 11.9±1.2, n=6, NS). No sex differences were observed. Likewise, in delta-cell deficient islets isolated from diphtheria toxin-treated male mice expressing the diphtheria toxin receptor under the somatostatin promoter, no effect of CpdA was observed on insulin or somatostatin release (insulin: 4.9±0.9 vs 4.1±0.8, n=3, NS; somatostatin: 10.1±4.9 vs 9.2±5.3, n=6, NS). We conclude that FFA4 stimulation of insulin secretion is exclusively mediated by inhibition of somatostatin secretion from delta cells.

Disclosure

L.Reininger: None. M.Ethier: None. C.Tremblay: None. J.Ghislain: None. M.Huising: Consultant; AstraZeneca, Research Support; Crinetics Pharmaceuticals, Inc. V.Poitout: Consultant; AstraZeneca. M.Flisher: None.

Funding

National Institutes of Health (R01DK132597)
197-LB: Capillary Islet Autoantibody Testing at the Preschool Vaccination Is a Feasible and Acceptable Method to Screen Children for Type 1 Diabetes
Authors: SCUDDER CLAIRE , BOWEN-MORRIS JANE , EVANS PHILIP H. , JONES SARAH C. , THOMAS NICHOLAS P.B. , FOX ROBIN , TODD JOHN , GREENFIELD SHEILA , DAYAN COLIN , TOWNSON JULIA , BESSER RACHEL
Published: June 2023

Background: Islet autoantibody screening for type 1 diabetes (T1D) reduces life-threatening diabetic ketoacidosis, hospitalization and identifies individuals eligible for future preventative treatments. 3.5-4 years has been indicated as an optimal time to screen younger children for T1D at a single-time point. We therefore assessed the feasibility and acceptability of screening at this age, to align with the pre-school vaccination visit, in a first of its kind, proof-of-concept study in the UK.

Methods: Children attending routine pre-school vaccinations (n= 63; median age 3.5y (IQR 3.4-3.6, range 3.1-5.1y), 26 (41.3%) male) provided capillary blood samples which were posted for IAA, GADA, IA-2A and ZnT8A analysis. Serum volumes >60µL were tested using Radiobinding assay (RBA), and <60µL by Luciferase Immunoprecipitation Systems (LIPS) assay. Acceptability was assessed using open question postcards, and semi structured interviews.

Results: There was 97% (61/63 samples) success in sample analysis, with median serum collected 100µL (IQR 80-155) and 83% (52/63)>60µL. One participant screened and confirmed positive by RBA for IAA.

Participants (n=15 interviews, n=31 postcards) were uniformly positive about screening aligning to the vaccination programme, citing that they may have been less likely to take part had screening been a separate visit. Themes identified included being prepared in the event of a T1D diagnosis, feeling reassured by a negative test result, and the long-term benefit of screening outweighing short-term upset. Parents reported that the volume of blood was higher, and collection time longer than expected.

Conclusions: Capillary islet autoantibody testing is a feasible and acceptable method to screen children for T1D. Aligning sample collection to the pre-school vaccination was not a deterrent to vaccination. The approach of combining screening with a routine health visit may enable uptake and could be cost saving.

Disclosure

C. Scudder: None. J. Townson: None. R. Besser: Consultant; Provention Bio, Inc. J. Bowen-morris: None. P. H. Evans: None. S. C. Jones: None. N. P. B. Thomas: None. R. Fox: None. J. Todd: Advisory Panel; GlaxoSmithKline plc., Precion, Qlife, Vesalius Therapeutics. S. Greenfield: None. C. Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc.

Funding

National Institute for Health Research (203948)
199-LB: Mitochondrial Diabetes (MD) in the University of Chicago Monogenic Diabetes Registry
Authors: BOWDEN TIANA L. , KANDASAMY BALAMURUGAN , LETOURNEAU-FREIBERG LISA R. , RODRIGUEZ KAREN , MCCULLOUGH MICHAEL , GREELEY SIRI ATMA W. , PHILIPSON LOUIS H.
Published: June 2023

Mitochondrial diabetes (MD) results from pathogenic variants in mitochondrial (MT) genes. MT disease is associated with neuromuscular disease. MD may occur either alone or with other conditions. The most common MD genetic variant is MT-TL1 m.3243 A>G, associated with Maternally Inherited Diabetes and Deafness and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes. The incidence, variability and optimum treatment are uncertain. We describe clinical characteristics of participants in the Univ. of Chicago Monogenic Diabetes Registry with MD variants. Participants enrolled in the Univ. of Chicago Monogenic Diabetes Registry (IRB 6858,15617B). Clinical and genetic information was collected. As of February 2023, 18 participants from 13 families had a known MT variant. Clinical characteristics are in Table 1. Clinicians should consider MD when the patient is negative for T1D antibodies, is non-obese, has high frequency bilateral hearing loss, and has a strong maternal family history of diabetes. However, the features are variable and can include multiple organs and tissues. Genetic testing panels should include MT variants because MD can be misdiagnosed and the prevalence is uncertain. Clinical phenotypes are heterogenous among family members. Cascade testing and screening for related conditions is encouraged. Our data shows that MD is misdiagnosed as T1 or T2DM (16/16).

Disclosure

T. L. Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B. Kandasamy: None. L. R. Letourneau-freiberg: None. K. Rodriguez: None. M. Mccullough: None. S. W. Greeley: None. L. H. Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation.

Funding

National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
199-OR: Optogenetic Control of Pancreatic Delta Cells Reveals Their Central Role in Hormone Release from Pancreatic Islets
Authors: DOU HAIQIANG , MIRANDA CAROLINE A. , TOLÖ JOHAN , ZHANG QUAN , RORSMAN PATRIK
Published: June 2023

Diabetes mellitus is a metabolic disorder resulting from insufficient insulin release and associated with dysregulation of glucagon secretion. Somatostatin secreted from pancreatic δ-cells is a strong paracrine factor for both insulin and glucagon secretion in islets. Here, we developed an optogenetic approach, through specific expressing light-sensitive channels/pumps in δ-cells, to investigate the paracrine control of hormone release from islets. We generated mouse models that express either a light-sensitive cation channel, channelrhodopsin-2 (ChR2), or a chloride pump, halorhodopsin (HR), specifically in the pancreatic δ-cells (SST-ChR2 and SST-HR mouse). Their specific expression was confirmed by immunostaining. Optoactivation of ChR2 at 1mM glucose rapidly depolarized δ-cells by 37mV (n=5) and stimulated electrical activity and somatostatin release. At high glucose or tolbutamide, light activation of HR repolarized δ-cells by 15 mV (n=3), suppressing action potentials. Optoactivation of SST-ChR2 δ-cells suppressed, after a variable delay depending on the distance from δ-cells, action potential firing in neighbouring α-cells, inhibited exocytosis by 30% (n=5) and glucagon secretion by 55% at 1mM glucose (n=7). In a subset (35%) α-cells with no spontaneous action potentials, opto-inhibition of SST-HR δ-cells caused a 9mV depolarization (n=7) and induced action potential firing, which may account for the stimulation of glucagon secretion. Neither optoactivation, nor opto-inhibition of δ-cells affected insulin secretion at hypo- and hyperglycaemia. However, at normoglycaemia (6 mM glucose), optoactivation of δ-cells depolarized neighbouring β-cells (via gap-junctions) and evoked action potential firing, leading to a paradoxical 160% stimulation of insulin secretion (n=9). We conclude that δ-cells play a central role in the regulation of both insulin and glucagon release but that the effects are more complex than appreciated to date.

Disclosure

H.Dou: None. C.A.Miranda: None. J.Tolö: None. Q.Zhang: None. P.Rorsman: None.

Funding

Swedish Research Council
200-LB: Benefit of Dual Therapy with GLP-1 RA and SGLT2i on Cardiovascular Outcomes in Type 2 Diabetes
Authors: ZAREINI BOCHRA , GERDS THOMAS A. , SØRENSEN KATHRINE K. , CLEMMENSEN KIM K.B. , KVIST KAJSA , DAVID JENS-PETER , TORP-PEDERSEN CHRISTIAN
Published: June 2023

Background: Evidence on the cardiovascular benefit of dual glucagon like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapy is lacking.

Aim: To compare the benefit of dual GLP-1 RA and SGLT2i therapy to other dual type 2 diabetes therapies with respect to heart failure and major cardiovascular adverse events (MACE).

Methods: From 2010-2021 patients from the Danish nationwide registries were followed from start of dual second-line type 2 diabetes treatment. Primary outcome was heart failure, and secondary outcomes were MACE and all-cause death. The estimated risk following 1 of 4 dual therapy combinations was determined using a longitudinal causal inference framework assuming all patients followed one dual therapy for 5 years.

Results: A total of 87,201 persons were included (GLP-1 RA and SGLT2i: 14,831, GLP-1 RA and DPP4/SU/TZD: 20,417, SGLT2i and DPP4/SU/TZD: 22,803, dual DPP4/SU/TZD: 29,150). The 5-year risk ratio (95% CI) of dual GLP-1 RA and SGLT2i therapy compared to reference (dual DPP4/SU/TZD) for heart failure was: 0.93 (0.87;1.00), for MACE: 0.91 (0.87;0.95) and for all cause death: 0.78 (0.74;0.82), see Figure.

Conclusion: Dual therapy with GLP-1 RA and SGLT2i showed a benefit on heart failure compared to other dual therapies. Dual therapy with GLP-1 RA and SGLT2i showed a benefit on MACE and all-cause death compared to the reference treatment.

Disclosure

B. Zareini: None. T. A. Gerds: None. K. K. Sørensen: None. K. K. B. Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. K. Kvist: Employee; Novo Nordisk A/S. J. David: Employee; Novo Nordisk A/S, Sanofi. C. Torp-pedersen: Research Support; Novo Nordisk, Bayer Inc.
201-OR: Characterization of Type 1 Diabetes (T1D) Endotypes
Authors: BEDRAT AMINA , PANT TARUN , JIA SHUANG , ROETHLE MARK , TRUCHAN NATHAN A. , CABRERA SUSANNE M. , CHEN YI-GUANG , LIN CHIEN-WEI , HESSNER MARTIN
Published: June 2023

To better understand how T1D heterogeneity relates to disease progression and therapeutic responsiveness, we studied 566 recent onset subjects (mean age at onset: 16.5 +/- 8.2) that had participated in the following TrialNet trials: MMF-DZB, anti-CD20; GAD-alum; CTLA4-Ig; Canakinumab; and ATG-GCSF. Our analysis began with a bioassay where plasma collected pre-intervention and within 100 days of diagnosis was used to induce transcription in a well-controlled peripheral blood mononuclear cell population. Microarray analysis identified 2,854 transcripts exhibiting high variation in at least 5 out of 6 trials. Hierarchical clustering and principal component analysis of these transcripts concordantly divided the participants into 2 major groups: Group 1 and Group 2. Analysis of post-baseline samples found group assignments conserved over time. Proportional analyses of the 406 subjects aged <18 years found Groups 1 and 2 distinct: subjects aged >14years segregated within Group 2 (39.9% vs 29.3%, p=0.03); subjects possessing neutral/low-risk HLA haplotypes segregated within Group 1 (20.5% vs 11.8%, p=0.04); placebo arm participants with the most rapid C-peptide rate of decline (<-0.15) segregated within Group 1 (20.3% vs 7.1%, p=0.04); and the subjects most responsive to anti-CD20 (p=0.01) and ATG-GCSF (p=0.07) segregated within Group 1. A local validation cohort (n=66, mean age at onset: 11.1 +/- 4.0) was analyzed by plasma induced transcription. A Random Forest model, which utilized the TrialNet data as a training set, was used to assign the local subjects to Group 1 or 2 (ROC: AUC=0.95; p=7.7E-9). Consistent with pathway analysis of the TrialNet transcriptomic data, ELISA analysis identified elevated plasma IFNγ, TNFα, IL-1β, IL-6, IL-12p70 levels (p<0.05) in Group 1. Flow cytometry measured higher percentages CD4+ CD45RO+ memory T cells (among total CD4 T cells, p=0.01) in Group 1. These analyses support the existence of two major T1D endotypes that exhibit differing immune phenotypes and therapeutic responsiveness.

Disclosure

A.Bedrat: None. T.Pant: None. S.Jia: None. M.Roethle: None. N.A.Truchan: None. S.M.Cabrera: Research Support; Abbott Diabetes. Y.Chen: None. C.Lin: None. M.Hessner: None.

Funding

National Institutes of Health (R01DK121528)
202-LB: Association between Diabetes and the Vaginal Microbiota
Authors: ROBBINS SARAH J. , BROTMAN REBECCA M. , MILLER RYAN S. , BEITELSHEES AMBER L. , SHARDELL MICHELLE , RAVEL JACQUES , TAYLOR SIMEON I.
Published: June 2023

Type 2 diabetes is a known risk factor for urinary tract infection and vulvovaginal candidiasis, and this risk is modulated in part by vaginal microbiota. We sought to assess the associations between diabetes and the vaginal microbiota, specifically whether diabetes may reduce vaginal Lactobacillus spp., which produce lactic acid and protect the urogenital tract. This study included 811 participants (2,301 person-visits) aged 35-60 recruited to a 2-year observational cohort with mid-vaginal sampling every 6 months. Diabetes was defined as self-reported diabetes medications, history, or serum glycated albumin (GA) levels >16.5% (HbA1c not available). Vaginal microbiota was characterized by 16S rRNA gene sequencing and clustered into community state types (CSTs) by VALENCIA, a nearest centroid algorithm based on a reference dataset. Mixed-effects multinomial logistic regression with bootstrapping was used to assess the association between case status and CSTs. Among diabetes cases (n=45, 130 person-visits), 45% had L. crispatus, L. jensenii, L. gasseri-dominated (CST I/II/V), 12% had L. iners-dominated (CST III) and 43% had low-Lactobacillus (CST IV) microbiota. Diabetes cases had reduced odds of L. iners-dominated CST III (aOR: 0.54, 95% CI: 0.31-0.81) than controls (12% vs 24%) and no association with low-Lactobacillus CST IV (aOR=01.05, 95% CI: 0.76-1.44) compared to Lactobacillus-dominated CST I/II/V in a model adjusted for menopause status and race. Estimates were similar when only GA was used for a diabetes case definition on a subset (1,001 person-visits). The results suggest diabetes is associated with reduced L. iners dominance. Diabetes cases had even frequencies of low-Lactobacillus or the optimal Lactobacillus-dominated CSTs. L. iners is metabolically distinct from other lactobacilli, producing only L-lactic acid (not the more protective D-lactic acid), and is associated with increased reproductive tract infection risk. This data informs how diabetes may affect the vaginal microenvironment.

Disclosure

S. J. Robbins: None. R. M. Brotman: None. R. S. Miller: None. A. L. Beitelshees: None. M. Shardell: None. J. Ravel: None. S. I. Taylor: Consultant; Ionis Pharmaceuticals.

Funding

National Institute of Allergy and Infectious Diseases (F31-AI164859)
204-LB: Application of a Data Quality Framework to Diabetic Retinopathy in the All of Us Dataset
Authors: GIANNINI JOHN , OSTCHEGA YECHIAM , VOLYNSKI MICHAEL , SULIEMAN LINA , DEDE YILDIRIM ELIF , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA
Published: June 2023

Diabetic retinopathy (DR) is the leading cause of preventable vision impairment and blindness among adults with diabetes. The All of Us Research Program aims to collect biomedical data (electronic health records (EHR), surveys, biospecimens, physiological measures, and digital health technology such as wearable devices) from one million or more participants, with the goal of improving targeted management of diseases like diabetes and DR. Because issues such as data entry and record harmonization may affect the usability of these types of data, this study examines the quality and validity of All of Us data to inform fitness for research use. This study's primary objective was to examine the quality of the EHR data as it relates to the diagnosis, treatment, and procedures related to DR. Adults were selected for inclusion if their EHR data contained one of five ICD10CM codes that are associated with DR from type 2 diabetes. Demographics, measurements, eye care procedures, and medications are analyzed using a framework of five data quality dimensions (DQDs): completeness, concordance, conformance, plausibility, and temporality. After the Spring 2023 update, the database contains over 413,000 consented participants sharing EHRs, with nearly 49,000 participants with a type 2 diagnosis (excluding type 1) and 3,600 participants with a related DR diagnosis (prevalence of 0.87%). The DR cohort was 50% female, compared to all participants at 60%. In participant EHRs, over 99% contained physical measurements (height, weight, blood pressure), 79% contained codes for blood glucose lowering drugs (excluding insulin), and 47% contained a relevant eye care procedure. 73% of participant EHRs contained a plausible diagnosis series (type 2 diabetes before DR), with a median elapsed time of 2.1 years. This exploration of EHR data using DQDs affirms the validity and trustworthiness of All of Us program data, which forms a valuable dataset for future DR research.

Disclosure

J. Giannini: None. Y. Ostchega: None. M. Volynski: None. L. Sulieman: None. E. Dede Yildirim: None. E. Ochsenfaber: None. L. Berman: None.

Funding

National Institutes of Health
206-OR: A Human Gut Commensal, Parabacteroides distasonis, Stimulates an Inflammatory Response Specific to the Pancreas but Not to the Intestines, and Induces Type 1 Diabetes
Authors: GIRDHAR KHYATI , RAISINGANI AMOL , ALTINDIS EMRAH
Published: June 2023

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic β-cells, resulting in insulin deficiency and hyperglycemia. Previous studies have shown that the gut microbiome is associated with the development and incidence of diabetes, however, the main trigger of T1D is unknown. Insulin protein epitopes are the primary targets of the T-cells, stimulating an autoimmune response against β-cells. We previously identified and characterized a bacterial peptide mimic of insulin B-chain 9-23 epitope (insB:9-23) in P. distasonis, a human gut commensal. This bacterial mimic, hprt4-18, is identified in the N-terminal of the hypoxanthine-guanine phosphoribosyltransferase protein. It activates both human T-cell clones and nonobese diabetic (NOD) mice T-cell hybridomas specific to insB:9-23. Reanalysis of DIABIMMUNE data confirms that exposure to hprt-4:18 in the first three years of life increases the risk of seropositivity. The colonization of female NOD mice's gut microbiome with P. distasonis accelerated the infiltration of T-cells into the islets and increased the incidence of T1D. In addition, P. distasonis colonization increased splenic CD4+ and CD8+ T-cells and decreased FoxP3+ Treg cells. Because the first interaction between the host immune system and gut microbes occurs in the intestines, we determined the direct effects of P. distasonis colonization on intestinal intraepithelial lymphocyte (IELs) composition. Notably, P. distasonis colonization decreased CD4+, CD4+ CD62L+ (Naïve), CD8+CD44+ (Effector), CD4+CD44+CD62L+ (Central) T-cell and B-cell populations. Taken together, these results support our molecular mimicry mechanism hypothesis as P. distasonis decrease inflammation in the intestines, however, induce an autoimmune response specific to pancreatic β-cells resulting in accelerated diabetes incidence in female NOD mice.

Disclosure

K.Girdhar: None. A.Raisingani: None. E.Altindis: None.

Funding

JDRF T1D (5112731); Mathers Foundation
21-OR: Insulin and Glucagon Regulate a Novel Bidirectional Long Noncoding RNA/Protein-Coding Gene Pair That Control Cell Sensitivity to Metabolic Stress
Authors: LIU XIANGYU , RONALD KAHN C.
Published: June 2023

An imbalance of glucagon and insulin actions in type 2 diabetes (T2D) results in the dysregulation of glucose and lipid metabolism and metabolic stress throughout the body. Integrating gene expression data in multiple models of T2D and metabolic syndromes, we have identified a novel gene pair, that share the same bidirectional promoter, are coordinately upregulated by glucagon and downregulated by insulin in the liver in a variety of physiological and pathophysiological states. This gene pair consists of the long non-coding (lnc) RNA Gm15663 and the protein coding gene Tmtc2, an important regulator of endoplasmic reticulum (ER) Ca2+ flux. Gm15663/Tmtc2 are also upregulated when glucagon predominates insulin, such as during fasting, after high-fat or western diet and in ob/ob mice. Conversely, Gm15663/Tmtc2 are downregulated during feeding, when insulin predominates glucagon. This transcriptional regulation is mediated in part by the transcription factor Foxo1. Foxo1 binds with two promoter-distal enhancers, creating a spatial chromatin looping interaction with Gm15663/Tmtc2 promoter, which is involved in transcriptional regulation of this gene pair. Knockdown of Tmtc2 in hepatocytes results in a higher cytosolic Ca2+ level and lower ER Ca2+ level. This renders the cell more sensitive to both metabolic and ER stress, and impairs cell respiration, which is in part mediated by the increased cytosolic Ca2+ level and the activation of CaM kinase II (CamKII). In a unique mechanism, Gm15663 and Tmtc2 also cis-regulate the transcription of each other to maintain the homeostasis of their own expression levels. Thus, Gm15663/Tmtc2 gene pair are dynamically regulated by glucagon and insulin and serve as novel regulators of cell sensitivity to metabolic stress. This gene pair is also linked to a common subtype of T2D in GWAS studies, making them potential targets to treat or modify the development of T2D in these individuals.

Disclosure

X.Liu: None. C.Kahn: None.
211-LB: Risk of Type 2 Diabetes in Young Adults with Psychiatric Disorders
Authors: LEE MIN-KYUNG , OH HYUNJYUNG , HONG OAK-KEE , HAN KYUNGDO
Published: June 2023

Objective: The study of the association between type 2 diabetes (T2D) and psychiatric disorders can provide significant implications for the early detection and timely intervention of T2D. As T2D is increasingly prevalent in young adults, we explores whether young adults with psychiatric disorders have higher risk of developing T2D than those without the disorders.

Research Design and Methods: We used the data collected by the South Korean National Health Insurance Service between 2009 and 2012. The nationwide population-based cohort study uses the sample data from 97% of South Korean population. Among 6,891,399 participants aged 20-39 year, we excluded 287,406 subjects with missing data and 146,002 subjects who had history of T2D were excluded. The five psychiatric disorders were evaluated, namely, schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. The primary outcome was newly diagnosed T2D during the follow-up period of 7.59 years.

Results: The cumulative incidences of T2D were significantly different between individuals with and without psychiatric disorders (log-rank test, P < .01). Incidence rates of T2D for individuals with and without a psychiatric disorder were 2.889 and 2.564 per 1,000 person-years. Individuals with a psychiatric disorder showed a higher risk of T2D than those without it (adjusted hazard ratio [aHR], 1.195: 95% CI, 1.174-1.217). The aHRs for T2D in individuals with schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder were 2.04 (95% CI, 1.826-2.28), 1.991 (95% CI, 1.726-2.115), 1.241 (95% CI, 1.202-1.282), 1.133 (95% CI, 1.108-1.159), and 1.308 (95% CI, 1.267-1.35), respectively.

Conclusions: In this large-scale prospective cohort study of young adults, all five psychiatric disorders were significantly associated with an increased risk of developing T2D. We observed that young adults with schizophrenia and bipolar disorder have a higher risk of T2D.

Disclosure

M. Lee: None. H. Oh: None. O. Hong: None. K. Han: None.

Funding

National Research Foundation of Korea (2022R1F1A061069)
211-OR: Dual Amylin and Calcitonin Receptor Agonists Increase Mitochondrial Respiratory Capacity in Adipose Tissues of Obese Rat
Authors: PETERSEN EMILIE A. , BLOM IDA , MELANDER SIMONE A. , KARSDAL MORTEN A. , LARSEN STEEN , HENRIKSEN KIM , LARSEN ANNA T.
Published: June 2023

Dual amylin and calcitonin receptor agonists (DACRAs) are potential therapeutic candidates for treatment of obesity. Preclinical studies have shown favorable effects of DACRAs on appetite regulation contributing to a reduction in body weight. Interestingly, the DACRA-induced effects on weight loss are superior to the effects of a suppressed food intake, suggesting an effect on energy expenditure potentially by targeting the mitochondria.

We investigated the effects of long-term treatment with a class of DACRAs, namely KBPs, on body weight, food intake and mitochondrial respiratory capacity (MRC) in Sprague-Dawley rats fed a high-fat diet and treated s.c. with KBPs for 8 weeks. Moreover, a pair-fed (PF) group was used to examine food intake-independent effects of KBPs on MRC. At study end, MRC was analyzed in perirenal (pAT) and inguinal (iAT) adipose tissue using high resolution respirometry.

Expectedly, KBP treatment significantly reduced body weight compared to PF and vehicle. PF was successfully KBP-matched in terms of accumulated food intake and the food intake was significantly lower than that of vehicle-treated rats. Coupled and uncoupled MRC supported by complex I+II substrates and fatty acids were significantly greater in iAT and pAT after KBP treatment indicating effects on both carbohydrate and lipid metabolism. Additionally, an increased oligomycin-induced leak-respiration was found to be independent of food intake in iAT. Further analysis will shed light on whether these changes in MRC are a result of an increased mitochondrial content or of the respiratory capacity of each mitochondrion.

In conclusion, treatment with KBPs in obese rats is associated with an increased MRC in pAT and iAT and elicits effects additional to those obtained by diet-induced weight loss. This highlights DACRAs’ potential as anti-obesity agents with possible benefits on energy expenditure as a contributing cause to the DACRA-induced weight loss.

Disclosure

E.A.Petersen: Employee; Nordic Bioscience A/S. I.Blom: None. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. S.Larsen: None. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. A.T.Larsen: Employee; Nordic Bioscience A/S.

Funding

Innovation Fund Denmark
213-LB: Impact of Alpha- and Beta-Cell Dysfunction on the Longitudinal Progression to Type 2 Diabetes
Authors: SUBRAMANIAN VIJAYA , SHERMAN ARTHUR
Published: June 2023

T2D results from glucotoxicity-driven impairment of insulin secretion which limits compensation for increased insulin demand. Increased demand results from insulin resistance and elevated hepatic glucose production (HGP). Increased HGP can result either from insulin resistance or alpha-cell dysregulation leading to hyperglucagonemia.

Objectives: To investigate with a mathematical model whether increased HGP and progression to T2D could result from impaired glucagon secretion in addition to insulin resistance. Toward this end, we developed a realistic model of beta-cell growth, death and function and interfaced it with a previously validated model of glucose-insulin-glucagon dynamics.

Methods: A previously published model of longitudinal progression to T2D over years was extended to include glucagon dynamics. The beta cell mass/function equation was parametrized by interfacing with results from a previously published paper on modeling isoglycemic, intravenous glucose infusion tests to obtain snapshots of the metabolic state. The range of parameters observed in the cohort studied cover the gamut from normal, insulin sensitive to normal, insulin resistant to T2D patients, and was used to calibrate the model. The influence of insulin resistance and impaired glucagon secretion as they develop over time was included in the combined model to see how they impact the balance between enhanced and impaired beta-cell function and mass.

Results and Conclusion: When only insulin sensitivity was allowed to decrease, the normal subjects did not transition to T2D. This was because the glucose levels were not elevated sufficiently to upset the balance between enhancement and impairment and lead to a catastrophic decline in insulin secretion. Including time-dependent impairment of glucagon suppression, in addition to declining insulin sensitivity, was sufficient to lead to the significant imbalance required to progress to T2D diabetes. Thus, both appear to be required.

Disclosure

V. Subramanian: None. A. Sherman: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK131328)