bluuebunny/crossref_metadata_2025 huggingface dataset:
1241-P: Cross-Sectional Study of the Impact of the COVID-Pandemic on Diabetes Management in Primary Care in Ontario, Canada
Authors: CHENG ALICE Y. , HARRIS STEWART B. , KRAWCHENKO IRIS E. , TYTUS RICHARD , HAHN JINA , LIU AIDEN R. , WANG YANG , GOLDEN SHANE , GOLDENBERG RONALD
Published: May 2022

Background: This study describes the impact of the pandemic on the management of people with type 2 diabetes (PwT2D) in a primary care network with existing virtual care capabilities in Ontario, Canada.

Methods: Using de-identified primary care electronic medical records, PwT2D who had at least one healthcare touchpoint between March 1, 2018 and February 28, 2021 were analyzed by time period (baseline: 2018-19, pre-COVID-19: 2019-20, COVID-19: 2020-21) . The primary outcome measures include the number of people with at least one visit, number of people with vital measurements or lab tests, and the vital or lab results.

Results: The three time periods had a similar average age and gender distribution (Table 1) . Compared to the pre-COVID-period, fewer people had any healthcare touchpoint (17% reduction) . In-person visits were reduced while more people had virtual visits. Fewer people had test results recorded during the COVID-vs. two pre-COVID-time periods, however, average results were similar across all three time periods.

Conclusion: Our study described the immediate impact of the COVID-pandemic on patterns of primary care for PwT2D. While the total number people getting tests remains below pre-pandemic levels, of those who sought care, the mean A1c, LDL-c and eGFR were comparable across the three time periods.

Disclosure

A.Y.Cheng: Advisory Panel; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, HLS Theraoeutics, Insulet Corporation, Janssen Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Sanofi, Board Member; Type 1 Diabetes Think Tank Network, Other Relationship; Diabetes Canada, Speaker's Bureau; Bausch Health, Canada, Merck & Co., Inc. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. I.E.Krawchenko: Speaker's Bureau; Janssen Pharmaceuticals, Inc. R.Tytus: Other Relationship; Banty , Boehringer Ingelheim International GmbH, Canadian Health Research Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. J.Hahn: Employee; Novo Nordisk Canada Inc. A.R.Liu: Employee; Novo Nordisk A/S, Novo Nordisk Canada Inc. Y.Wang: Other Relationship; Novo Nordisk Canada Inc. S.Golden: Other Relationship; Novo Nordisk Canada Inc. R.Goldenberg: Consultant; IQVIA Inc., Speaker's Bureau; Amgen Canada, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi.
1243-P: Who Is Achieving Long-Term Glycemic Control? Ten-Year Trends in 531,995 Indiana Adults
Authors: FU HELEN N. , HANNON TAMARA S. , WEINER MICHAEL , BALIUS PATRICK , WOLFSON JULIAN , SCHLEYER TITUS
Published: May 2022

Despite advances in therapies, many patients with diabetes worldwide are not meeting glycemic control targets. The objective of this study was to characterize adult patients with T2D in Indiana with respect to glycemic control over a 10-year period. We retrospectively analyzed a cohort of 531,995 patients with T2D and generated summary statistics. The success rate for achieving glycemic control (A1c <7 [<65 y/o] or <8 [>=65 y/o]) was defined as (number of A1c tests meeting target) / (number of A1c tests) . Uncontrolled diabetes was defined as (number of A1c tests >8) / (number of A1c tests) . We summarized 1,868,1year-level A1c observations from 20to 2018 by gender, age, and race. In four years within the 10-year period, rates of glycemic control decreased from 68% to 65% with inconsistent year-to-year change of 0.4-1.8%. The rate of uncontrolled diabetes increased from 19% to 23%. Females were more successful than males (67-71% vs. 62-66%) in achieving control.t4 Patients >=65 y/o had the highest success rate (82-88%) , while 49% to 60% of younger patients were controlled. Whites had higher success (67-70%) and less uncontrolled diabetes (17-22%) than other races.t7 Blacks’ rates of success and uncontrolled diabetes were stable at ∼46%t6 and ∼27%, respectively.t7 Black males 18-44 y/o had the lowest success rate (40-45%) . Long-term rates of achieving glycemic control in adults with T2D in Indiana declined over a 10-year period. However, one third to one half of those aged >=65 y/o achieved a high success rate for glycemic control (>80%) . Achieving longitudinal glycemic control is least successful for male blacks aged 18-44. There is a need for diabetes health service research to study population health interventions tailored by age and race.

Disclosure

H.N.Fu: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. M.Weiner: Stock/Shareholder; AbbVie Inc., Accuray, Inc., Allscripts Healthcare Solutions, Amgen Inc., Boston Scientific Corporation, Bristol-Myers Squibb Company, Crispr Therapeutics Ag Com, Express Scripts Hdlg Co, General Electric Co., Globus Med, Inc., IBM, Integer Hldgs Corp Com, Integra Lifesciences Holdings Corp, Johnson & Johnson, Mallinckrodt PLC, Mead Johnson & Company, LLC., Medtronic, Metlife Inc Com, Mylan N.V., Novo Nordisk A/S, Nuvasive, Inc., Orthofix Medical Inc., Perspecta Inc Com, Pfizer Inc., Resmed, Inc., Roche Pharmaceuticals, Seaspine Hldgs, Inc., Senseonics, Stryker Corp., Teva Pharmaceutical Industries Ltd., Varex Imaging Corp., Varian Med Sys, Inc., Walgreens Boots Alliance, Inc. P.Balius: None. J.Wolfson: None. T.Schleyer: None.

Funding

T15LM012502, UL1TR002529, the Lilly Endowment
1255-P: IA-2A Autoantibody Titers Predict Subsequent Divergence between Nonprogressors (NP) and Progressors (P) to Type 1 Diabetes with Similar Degree of Initial Metabolic Abnormality
Authors: SIMS EMILY K. , CUTHBERTSON DAVID D. , JACOBSEN LAURA M. , ISMAIL HEBA M. , NATHAN BRANDON M. , REDONDO MARIA J. , SOSENKO JAY
Published: May 2022

Even after stratification based on established risk factors, the progression to T1D is variable. Thus, we aimed to examine differences in metabolic patterns of change between NP and P to T1D, and identify non-metabolic factors contributing to the differences. Specifically, we analyzed OGTT and autoantibody (Aab) data from children <18 yrs participating in Diabetes Prevention Trial-Type 1 (DPT-1) or TrialNet Pathway to Prevention (PTP) , with “baseline” DPT-1 Risk Scores (DPTRS) at initial testing in the abnormal range of 6.50 to <7.50. No difference in AUC ratio (AUC C-peptide/AUC glucose) was present between P (n=85) and NP (n=161) in DPT-1 or between P (n=171) and NP (n=332) in PTP at baseline. However, during follow-up we found that by the first 6-month OGTT the AUC ratio had diverged, with lower AUC ratio in P both in DPT-1 (p=0.05) and PTP (p<0.001) , adjusting for baseline age, BMI, DPTRS, and AUC ratio. Moreover, in yearly change from baseline to last OGTT (before diagnosis in P) , AUC ratio decreased in P (p<0.001) and increased in NP (p<0.01) in DPT-1 and PTP. In assessments of factors relating to this divergence we observed that despite their metabolic similarity, at baseline P had higher harmonized IA-2A Aab positivity (70.8 vs. 49.1%, p<0.001) and titers (median 194 vs. 3, p<0.001) in PTP (not harmonized in DPT-1) . Based on this, we compared P with NP for yearly changes in IA-2A from baseline to the last visit, with adjustment for baseline values. P had a greater increase in IA-2A titer over time (p=0.025) . Furthermore, T1D progression was associated with yearly increases in IA-2A titer (HR: 1.006, 95%CI: 1.003, 1.009; p<0.001) .

In conclusion, when NP and P have a similar degree of metabolic abnormality, IA-2A titers are greater in P. Moreover, as AUC ratio declines in P and improves in NP, IA-2A titers increase more in P than in NP. These findings suggest that IA-2A is a sensitive indicator of active β-cell pathology.

Disclosure

E.K.Sims: Other Relationship; Medscape, Patent. D.D.Cuthbertson: None. L.M.Jacobsen: None. H.M.Ismail: n/a. B.M.Nathan: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. J.Sosenko: None.
1259-P: Using Simplification Strategies for Older Adults with Type 1 Diabetes
Authors: MUNSHI MEDHA , SLYNE CHRISTINE , HURLBERT REBECCA , TOSCHI ELENA
Published: May 2022

Objective: Simplification of insulin regimen algorithms for older adults with type 2 diabetes have been established and recommended as the standard of care. However, simplification of insulin regimens in older adults with type 1 diabetes (T1D) has not been described.

Methods: Community-living older adults ≥65 years with T1D were randomized to assess the impact of technology use, combined with geriatric specific interventions to reduce the risk of hypoglycemia (Clinicaltrials.gov NCT03078491) . We developed simplification strategies as part of a geriatric intervention program. Glycemic parameters and quality of life measures were evaluated at baseline and 6-months after enrollment.

Results: Thirty-four out of forty-one older adults (83%) with T1D (age 71±4 years, T1D duration 41±16 years, 36% with cognitive dysfunction, 22% living alone) in the subpopulation from the intervention arm were considered appropriate for simplification. We identified four procedures for simplification.1) Liberalization of goals for A1C and/or pump and CGM targets were recommended for 16/34 (47%) participants;2) Fixed-dose boluses for routinely eaten meals, especially at breakfast and lunch, were recommended for 24/34 (71%) participants;3) Avoiding multiple correction doses was recommended for to 25/34 (74%) participants; and4) Proactive adjustment to boluses, rather than constantly reacting to hyper- and hypoglycemia was recommended to 13/34 (38%) . The change in glycemic metrics from baseline to 6-months post-enrollment showed a decreased percent of hypoglycemia (6% vs. 2%; p<0.0001) and decreased glycemic variability (coefficient of variation (%)) (41% vs. 35%, p=0.0001) . A1c and time-in-range remained stable (7.5% vs. 7.6%: 56% vs. 57%, respectively) .

Conclusions: In this study, simplification procedures for insulin regimens in older adults with T1D were developed. Simplification of regimens did not contribute to worsening of glycemic parameters. Prospective studies are needed to confirm our findings.

Disclosure

M.Munshi: Consultant; Sanofi. C.Slyne: None. R.Hurlbert: None. E.Toschi: Consultant; Medtronic.

Funding

This research was supported by an NIH DP3 Grant (1DP3DK112214-01) and an NIH P30 Grant (P30DK036836) . Continuous glucose monitoring materials were partially suppliedby Dexcom.
126-LB: Type 2 Diabetes Mellitus (T2DM) Has Greater Adverse Effect on Mortality in Females than Males—Results of 10-Year Cohort Study
Authors: HEALD ADRIAN H. , STEDMAN MICHAEL , LAING IAN , ROBINSON ADAM , RAYMAN GERRY , WHYTE MARTIN B.
Published: May 2022

Females are more prone to obesity than males. This may lead to different outcomes. We studied if sex differences were seen in mortality outcomes in a longitudinal T2D cohort study.

Data from a regional UK database (Salford) was taken between 2010-2020. Standardised Mortality Ratio (SMR) was established from actual versus expected deaths calculated from national annual statistics for mortality rate by sex and age. The SMR was then calculated for by each sex, year, age group, HbA1c level, and diabetes medication as taken by a patient in previous years.

We included 9,558 patients with 88,102 patient years and 2,909 recorded deaths against 1,851 expected, SMR men 1.46 and women 1.72 (18% higher than men) . SMR increased slightly over time (Figure 1a) . SMR in younger females (<75 years) was higher than older females (Figure 1b) . SMR in females with high HbA1c (>86mmol/mol) was higher (Figure 1c) than lower HbA1c. Patients currently on insulin and GLP1 had much higher SMR than oral alone (Figure 1d) .SMR analysis of the oral drug use had SGLT2i 1.28; metformin 1.50; thiazolinedione 1.61; DPP4i 1.74; sulphonylurea 1.78. Note that average age and HbA1c varied across therapies.

Diabetes has greater impact on women’s mortality than men for both age, and HbA1c. Indication bias will impact drug choice but lower SMR with SGLT2i and higher with sulphonylureas concords with trial data. Despite newer therapies, SMR for diabetes has not improved over time.

Disclosure

A. H. Heald: None. M. Stedman: None. I. Laing: None. A. Robinson: None. G. Rayman: None. M. B. Whyte: Consultant; AstraZeneca, Research Support; AstraZeneca, Sanofi.
1260-P: Gut Microbiome and Metabolic Activity in Type 1 Diabetes—An Analysis Based on the Presence of GADA
Authors: YUE TONG , ZHENG XUEYING , LIU ZIYU , DING YU , WEI JIANG W. , XU WEN , WENG JIANPING , LUO SIHUI
Published: May 2022

Background: Type 1 diabetes (T1D) progression is affected by the level of circulating glutamic acid decarboxylase antibody (GADA) , a main manifestation of islet autoimmunity. The gut microbiome and serum metabolites may contribute to islet autoimmunity in patients with T1D.

Methods: We used radiobinding assay to measure GADA titers and identify the GADA+ ones (n=49) in 1T1D patients. The gut microbiome was assessed by 16S rRNA gene sequencing, and the serum metabolites were analysed with GC/MS.

Results: T1D patients with and without GADA exhibited compositional and functional changes in the gut microbiome. Profiles in patients with GADA were distinct, with a significant increase in the abundances of Alistipes, Ruminococcus, Prevotella, Dialister, and marked depletion of Bacteroides, Bifidobacterium, Roseburia. For the untargeted serum metabolites, compared with those of GADA-, there were 54 significantly different metabolites with tryptophan metabolism: phenylalanine, and tyrosine and tryptophan biosynthesis decreased in patients with GADA. In addition, patients with GADA had elevated concentrations of Indole-3-acetic-acid, a marker of intestinal inflammation and epithelial damage. Co-occurrence network analysis revealed that gut microbiome disturbances affected tryptophan metabolism, suggesting that disturbed gut microbiome may mediate T1D immunotypes. Tryptophan metabolism may mediate inflammation in the pathogenesis and pathophysiology of T1D.

Conclusion: These findings suggest that metabolites produced by the patients with GADA gut microbiota could cause damage to intestinal and systemic homeostasis and could be targeted for preventing the development of T1D.

Disclosure

T.Yue: None. X.Zheng: None. Z.Liu: None. Y.Ding: None. J.W.Wei: None. W.Xu: None. J.Weng: None. S.Luo: None.

Funding

the National Key r&D Program (2017YFC1309600) the Anhui Provincial Natural science foundation (006212943003)
1267-P: Fine-Mapping Type 1 Diabetes Risk at the MHC Locus
Authors: MCGRAIL CAROLYN , CHIOU JOSHUA , BENAGLIO PAOLA , GAULTON KYLE J.
Published: May 2022

The Major Histocompatibility Complex (MHC) locus regulates the adaptive immune response and self-recognition and is the largest contributor to genetic risk of type 1 diabetes (T1D) . Protein-coding alleles in MHC class II and class I genes have long been known to contribute substantial T1D risk, yet whether additional variants affect T1D risk at this locus particularly in the non-coding genome has not been exhaustively evaluated. We therefore performed high-resolution fine-mapping of the MHC locus to identify additional coding and non-coding variants that contribute to T1D risk. We imputed genotypes for 39,270 samples from six European or American cohorts of T1D cases and controls into the T1DGC reference panel using SNP2HLA. We then performed two analyses to fine-map causal variants, first, stepwise conditional analysis using Firth bias-corrected logistic likelihood ratio test and second, iterative Bayesian stepwise selection analysis using the Sum of Single Effects (SuSiE) method. We identified 33 signals in stepwise conditional analysis with p<1×10-6 and 30 signals in SuSiE, where the results were highly concordant between methods. Both methods identified the known high-risk amino acid residue 57 of HLA-DQB1 as the top signal, as well as most known and several novel protein-coding risk and protective alleles in MHC class I and II genes. In addition, we identified multiple signals where the likely causal variant was non-coding and not linked to a protein-coding variant, including those that mapped to the LST1, HLA-DRA and NOTCH4 genes. We further annotated these non-coding signals using accessible chromatin, and several likely causal variants mapped in immune cell and/or pancreatic islet accessible chromatin. In ongoing analyses, we are replicating these signals in independent cohorts and performing molecular validation studies of their regulatory effects in relevant cell types. In total, high-resolution fine-mapping of the MHC locus identified additional T1D risk including in the non-coding genome.

Disclosure

C.Mcgrail: None. J.Chiou: Employee; Pfizer Inc. P.Benaglio: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated.

Funding

National Institutes of Health (DK120429) National Institutes of Health (DK122607)
1270-P: ICA1 Is Differentially Methylated and Expressed in Familial Type 1 Diabetes
Authors: DASHTI MOHAMMED H. , NIZAM RASHEEBA , HEBBAR PRASHANTHA , JACOB SINDHU , JOHN SUMI E. , CHANNANATH ARSHAD M. , ALKANDARI HESSA , THANGAVEL ALPHONSE T. , ALMULLA FAHD
Published: May 2022

There has recently been a growing interest in examining the role of epigenetic modifications, such as DNA methylation, in the etiology of type 1 diabetes (T1D) . This study aimed to delineate differences in methylation patterns between T1D-affected and healthy individuals by examining the genome-wide methylation of individuals from three Arab families from Kuwait with T1D-affected mono-/dizygotic twins and non-twinned siblings. Bisulfite sequencing of DNA from the peripheral blood of affected and healthy individuals from each of the three families was performed. Methylation profiles of the affected individuals were compared to those of healthy individuals. The principal component analysis on methylation profiling based on base-pair resolution clustered the T1D-affected twins together family-wide. Sites/regions that were differentially methylated between T1D and healthy samples harbored 84 genes, of which 18 were known to be differentially methylated in T1D individuals compared to healthy individuals in publicly available gene expression data resources. We further validated two of the 18 genes—namely ICA1 and DRAM1 that were hypermethylated in T1D samples compared to healthy samples—for upregulation in T1D samples from an extended study cohort of familial T1D. The ICA1 is well-known to have a role in the development of autoimmune beta-cell destruction.

Disclosure

M.H.Dashti: None. R.Nizam: None. P.Hebbar: None. S.Jacob: None. S.E.John: None. A.M.Channanath: None. H.Alkandari: None. A.T.Thangavel: None. F.Almulla: None.

Funding

Kuwait Foundation for Advancement in Sciences funding RA-2014-024
1273-P: The Interplay between Polygenic and Rare HNF1A Variant Risk in Type 2 Diabetes
Authors: STALBOW LAUREN , PREUSS MICHAEL H. , CHAMI NATHALIE , SMIT ROELOF A.J. , LOOS RUTH J.
Published: May 2022

Rare variants in HNF1A, a pancreatic beta cell transcription factor, have been shown to be associated with T2D and monogenic diabetes. Here, we examine the effect of functionally validated rare (MAF<1%) nonsynonymous variants (RNVs) in a functional domain of HNF1A on T2D risk, and whether their effect is influenced by an overall genetic susceptibility to T2D.

Using exome sequencing data of 3,443 African ancestry (AA) and 157,182 European ancestry (EA) individuals in the UK Biobank and 5,018 AA, 5,6EA and 7,1Hispanic-Latino Ancestry (HA) individuals in the BioMe Biobank, we identified 132 AA, 287 EA, and 64 HA RNV carriers (NRNVs= 30) of HNF1A variants that impair protein function ≤ 60%. T2D Polygenic Risk Scores (PRSs) were built using either trans-ethnic or EA GWAS summary statistics and standardized per ancestry. We tested the association between RNV carrier status and the PRS with T2D risk, and meta-analyzed the ancestry-specific results.

Carrying any of the HNF1A RNV mutations was associated with a 1.5 increase in the odds of T2D in the EA, albeit non-significantly (P=0.06) , but not in the AA (OR=1.1, P=0.6) or HA (OR=1 , P=1) . We then restricted analyses to RNVs within a functional domain, which results in more pronounced effects in the AA (OR=1.5, P=0.07) and EA (OR=1.9, P=0.002) but not in the HA (OR=0.8, P=0.5) . Per SD increase in the PRS, there is a significant 1.7, 1.6 and 2.1 higher odds of T2D in AA, EA and HA individuals, respectively. Even though we observed no interaction between the PRS and HNF1A RNVs (P >; 0.05) , the association between RNVs and T2D was more pronounced among EA individuals with a high PRS. Functional domain carriers (NEA = 50) in the top PRS quintile had a 3.6 (P=0.0008) higher odds of T2D as compared to non-carriers in the same quintile.

Our study shows the value of large biobanks in studying rare variants, the importance of variant selection, and the need to include non-European ancestry populations. We demonstrate the utility of combining rare and common variant risks to better assess T2D risk.

Disclosure

L.Stalbow: None. M.H.Preuss: None. N.Chami: None. R.A.J.Smit: None. R.J.Loos: None.
1277-P: Spatial Whole Transcriptome Profiling of the Human Pancreas Uncovers Unique Insights into Histological Structures
Authors: YANG WEI , HOGAN MEGHAN F. , LIANG YAN , BEECHEM JOSEPH M.
Published: May 2022

Understanding the physiology of the pancreas and pathology that occurs during diabetes requires knowing transcriptional patterns driving biological activity within the functional structures of the tissue. Previous technologies have not enabled spatially resolved high plex profiling to elucidate these biological pathways. Using the unique ability of GeoMx® Digital Spatial Profiler to resolve functional units within FFPE tissue in situ, we provide whole transcriptome expression data from islets, acini, and ducts from four pancreata of nondiabetes patients.

On average, 6000-8000 genes were detected from functional groups within each histological structure. Data were validated against the independent Human Protein Atlas, with ∼90% concordance between RNA expression and known protein localization. Deconvolution based on single-cell RNASeq enabled calculation of the proportion of distinct cell types within each structure, confirming cell composition. For example, while ductal components consist of small islands punctuating the acini, over 3000 genes were identified to be highly specific to each structure (FDR < 0.05) , and enriched for pathways related to focal adhesion, ECM structure, and diabetic disease processes. Within islets, we identified >300 genes with differences between α- and β-cells (FDR < 0.2) . Functional characterization confirmed enrichment of insulin biosynthesis and secretion pathways, with genes such as insulin, glucagon, and IAPP expression captured accurately with a single assay. Determination of expression in four individual pancreas samples identified variation between tissues, which may be central to health and disease processes.

In conclusion, whole transcriptome data for spatial gene expression profiles of structures of the non-diseased pancreas are publicly available and can be used as standards to inform future profiling studies in normal and diseased tissue.

FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.

Disclosure

W.Yang: None. M.F.Hogan: Employee; NanoString. Y.Liang: None. J.M.Beechem: None.
1278-P: The Tale of Caveolin 1 rs1997623 Variant in Obesity and Metabolic Syndrome
Authors: MADHOUN ASHRAF AL , HADDAD DANIA , KOCHUMON SHIHAB P. , NIZAM RASHEEBA , JACOB SINDHU , SINDHU SARDAR T. , AHMAD RASHEED , ALMULLA FAHD
Published: May 2022

We Have previously established that caveolin-1 (CAV1) rs1997623 C/A variant is associated with metabolic syndrome in obese children (PMID: 30622557) and adults (ADA 82) . Here, we evaluated the functional role of the identified variant in association with obesity. Sequence analysis revealed that the variant is located at CAV1 regulatory region and creates a site for EBF Transcription Factor 1 (EBF1) . DNA fragment (240pb) flanking the variant was cloned upstream luciferase reporter gene. Wildtype, CAV1-C-Luc, and the generated mutant, CAV1-A-Luc, were individually transfected into pre-adipocytes. CAV1-A-luc significantly upregulated Luciferase activity indicating a prospective functional role of CAV1-A allele in CAV1 regulation. The reporter gene activity was differential regulated in lean versus obese pre-adipocytes. Co-transfections with EBF1 construct resulted in a significant upregulation in CAV1-A Luc activity, particularly in pre-adipocytes from obese individuals. The role of EBF1 was further evaluated in vivo using ChIP assays. PCR analysis using specific primers flanking the CAV1 variant and anti-bodies against EBF1 showed a significant elevated enrichment of chromatins from obese individuals, which was also associated with an enrichment for H3K27ac at the same locus, indicating active transcription. Moreover, CAV1 expression was differentially regulated in response to EBF1 siRNA/overexpression in pre-adipocytes harboring CAV1 A/A or A/C alleles relative to that with C/C allele. Furthermore, a significant reduction of DNA methylation at the variant locus was observed particularly in preadipocytes with A/A alleles. Finally, RNA isolated from adipose tissue of lean and obese individuals showed a significant correlation between CAV1 and cytokines transcripts in healthy obese individuals, at least in part, is due to CAV1 rs1997623 variant as verified by sequence analysis. Taken together, our study delineates the role of CAV1 rs1997623 variant in the context of obesity and MetS.

Disclosure

A.Al madhoun: None. D.Haddad: None. S.P.Kochumon: None. R.Nizam: None. S.Jacob: None. S.T.Sindhu: None. R.Ahmad: None. F.Almulla: None.

Funding

Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007
1286-P: Plasma-Induced Signatures Measured at Type 1 Diabetes (T1D) Onset Correlate with Post-onset Beta-Cell Function
Authors: BEDRAT AMINA , JIA SHUANG , ROETHLE MARK , DEW KRISTEN , CABRERA SUSANNE M. , LIN CHIEN-WEI , HESSNER MARTIN
Published: May 2022

Significant phenotypic diversity exists among T1D patients, supporting the existence of distinct disease endotypes (e.g. duration of the post-onset partial remission period) . To broaden our understanding of T1D heterogeneity and its relationship to disease progression and therapeutic responsiveness, we studied 566 new onset T1D patients (241 females, 325 males; mean age 16.5 +/- 8.2 years) that had participated in TrialNet clinical trials: TN02/MMF DZB; TN05/anti-CD20; TN08/GAD-alum; TN09/CTLA4-Ig; TN14/Canakinumab; and TN19/ATG-GCSF. Baseline samples were analyzed with a sensitive bioassay, where subject plasma is used to induce transcription in a well-controlled peripheral blood mononuclear cell population. The response was measured with a microarray, data were normalized, and transcripts exhibiting the highest median absolute deviation within each trial were identified. Weighted gene correlation network analysis was used to cluster patterns of variation into modules of co-expressed transcripts. Co-expression networks were correlated with clinical data collected over the 24-months following clinical onset. In the placebo arms of all 6 trials, we identified modules that significantly correlated with post-onset C-peptide AUC, post-onset insulin dose, Insulin-Dose Adjusted A1c, and/or the rate of C-peptide decline. This suggests that the baseline analyses identified modules that differentiated subjects in terms of post-onset beta-cell function, supporting the existence of T1D endotypes. While TN02, TN08, and TN14 did not show overall efficacy in slowing post-onset C-peptide decline, the module correlations with phenotypes related to beta-cell function were fewer in number and of lesser statistical significance in the treatment arms of all 6 trials. This suggests that there was greater beta-cell function in the treatment arms of all trials, and that varying degrees of immunomodulation had occurred even in those trials that did not show efficacy.

Disclosure

A.Bedrat: None. S.Jia: None. M.Roethle: None. K.Dew: None. S.M.Cabrera: None. C.Lin: None. M.Hessner: None.

Funding

National Institutes of Health (R01DK121528)
129-LB: The Impact of a Passive Alert on Screening for Euglycemic Diabetic Ketoacidosis in Hospitalized Patients Using an Sodium–Glucose Cotransporter 2 Inhibitor
Authors: SOLIMAN DIANA , MUSSER R. CLAYTON , JACKSON JASON P. , GERMAN JASHALYNN , CARLSON SCOTT , ODONNELL KATHRYN H. , SETJI TRACY
Published: May 2022

The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors has recently been associated with euglycemic diabetic ketoacidosis (euDKA) . The absence of hyperglycemia can delay recognition of euDKA. We aimed to increase screening rates for euDKA by implementing a passive alert to providers in the EHR (built as a BestPractice Advisory [BPA] on the Epic Storyboard) if an emergency department or hospitalized patient taking an SGLT2 inhibitor was at risk for euDKA. Criteria were blood glucose <250 mg/dL, SGLT2 inhibitor on the home medication list or initiated in the hospital, lack of an insulin infusion, and one of the following labs indicating acidosis: 1) anion gap >12 with serum bicarbonate <18 mmol/L, 2) urine ketones ≥ 3+, or 3) serum ketones ≥ 2 mmol/L. We conducted a retrospective review of the alert from implementation on 5/15/2021 until 12/13/2021. Of the 76 patients who triggered the alert, 13 (18%) had euDKA confirmed and 5 (7%) may have had it but were not evaluated for it. The alert introduced in the electronic health record successfully identified patients taking an SGLT2 inhibitor who were at risk for euDKA and may serve as a safety net to reduce delayed recognition of this serious condition.

Disclosure

D. Soliman: None. R. Musser: None. J. P. Jackson: None. J. German: None. S. Carlson: None. K. H. Odonnell: None. T. Setji: None.
129-OR: Catastrophic Health Expenditures: A Disproportionate Risk in Uninsured Ethnic Minorities with Diabetes
Authors: LINDE SEBASTIAN , EGEDE LEONARD E.
Published: May 2022

Background: Chargemaster prices are the list prices that providers and health systems assign to each of their medical services in the US. These charges are often several factors of magnitude higher than those extended to individuals with either private or public insurance, however, these list prices are billed in full to uninsured patients, putting them at increased risk of catastrophic medical expenditures (CHE) .

Methods: We perform a retrospective observational study on a nationally representative cohort of adult patients from the Medical Expenditure Panel Survey for the years 2002-2017. Using logistic regression models we estimate the risk of CHE across insurance status, diabetes diagnosis and explore disparity gaps across race/ethnicity.

Results: Our fully adjusted results show that the relative odds of having CHE if uninsured is 5.9 (p<0.01) compared to if insured, and 1.1 (p<0.01) for patients with a diabetes diagnosis (compared to those without one) . We note significant interactions between insurance status and diabetes diagnosis, with uninsured patients with a diabetes diagnosis being 9.5 (p<0.01) more likely to experience CHE than insured patients without a diabetes diagnosis. In terms of racial/ethnic disparities, we find that among the uninsured, non-Hispanic blacks are 13% (p<0.05) , and Hispanics 14.2% (p<0.05) , more likely to experience CHE than non-Hispanic whites. Among uninsured patients with diabetes, we further find that Hispanic patients are 39.3% (p<0.05) more likely to have CHE than non-Hispanic white patients.

Conclusions: Our findings indicate that uninsured patients with diabetes are at significantly elevated risks for CHE. These risks are further found to be disproportionately higher among uninsured racial/ethnic minorities, suggesting that CHE may present a channel through which structural economic and health disparities are perpetuated.

Disclosure

S.Linde: None. L.E.Egede: None.

Funding

National Institute of Diabetes and Digestive Kidney Disease (K24DK093699, R01DK118038, R01DK120861, PI: Egede) National Institute for Minority Health and Health Disparities (R01MD013826, PI: Egede/Walker)
1303-P: Decreased Hepatic HMGB1 in Type 2 Diabetes Increases Mitochondrial Glucose Uptake by Regulating Insulin/AKT Signaling
Authors: LIU ZEYU , KALTENMEIER CHRISTOF , MOTA ALVIDREZ ROBERTO I.
Published: May 2022

Introduction: High Mobility Group Box-1 (HMGB1) is strongly associated with Type 2 Diabetes (T2D) and hepatocyte function. HMGB1 can regulate mitochondrial function under high glucose conditions. Our group has shown that knockdown of HMGB1 reduces hyperglycemia with decrease insulin activity. We want to further understand the role of HMGB1 in hepatocyte mitochondrial function and the insulin/AKT signaling, a vital pathway in glucose hemostasis. We hypothesize that by decreasing HMGB1, hepatocytes increase glucose uptake by regulating mitochondrial function with more effective Insulin/AKT signaling.

Methods: Primary hepatocytes and liver lysates were isolated from inducible HMGB1 KO (iHMGB1 KO) and HMGB1 Flox (wildtype) mice after Tamoxifen and Streptozotocin IP injections for HMGB1 knockout and T2D-10-weeks development. HMGB1 knockdown and insulin/AKT signaling were assessed by RT-PCR and immunoblot. Flow cytometry was performed on primary hepatocyte cell suspension for mitochondrial function/mass (TMRE, Mitotracker) and glucose uptake (NDBG) cellular markers.

Results: Liver lysates showed significant decreased expression/activity of HMGB1, Insulin Receptor-B, phosphorylated AKT, PDK and SIRT3 in iHMGB1 KO T2D mice. A counter regulator of metabolic and glucose activity, phosphorylated PDH, was found increased in iHMGB1 KO mice. Flow cytometry of isolated hepatocytes showed that iHMGB1 KO T2D animals had significantly less mitochondrial mass and functioning mitochondria, however showed increased glucose uptake.

Conclusion: We found a potential mechanism by which HMGB1 regulates glucose uptake by regulating mitochondrial function and mass potentially by regulating the effectiveness of the Insulin/Akt signaling in T2D. Future studies will be directed to test glucose transport/metabolism in HMGB1 KO hepatocytes guided by more effective Insulin activity in the mediation of mitochondria function at the different stages of T2D progression.

Disclosure

Z.Liu: None. C.Kaltenmeier: None. R.I.Mota alvidrez: None.

Funding

This work was funded by department of surgery support for RIMA
1305-P: Insulin Receptor Condensates in Insulin Sensitivity and Resistance
Authors: DALL’AGNESE ALESSANDRA , PLATT JESSE , LEE TONG IHN , JEPPESEN JACOB F. , YOUNG RICHARD A.
Published: May 2022

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We have found that IR is incorporated into biomolecular condensates during the response to insulin stimulation and that the activity of IR in these condensates is altered in insulin resistance. In normal cells, insulin stimulation results in accumulation of IR in bodies that display dynamic molecular characteristics expected of liquid-like condensates. In insulin-resistant cells, both IR accumulation in condensates and the normal dynamic behavior of these condensates are reduced, suggesting a physico-mechanical link between insulin response and the dynamic molecular behavior of IR condensates. The observed defects in IR condensate behaviors are caused, at least in part, by an increase in oxidative stress in insulin-resistant cells, which is known to interfere with normal condensate dynamics. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue accumulation and dynamic behavior of IR condensates. This rescue corresponds with metformin’s effect of reducing the levels of reactive oxygen species. The observation that IR is incorporated into biomolecular condensates during the response to insulin stimulation, and evidence that changes in the physico-mechanical features of IR condensates contribute to insulin resistance, have implications for improved therapeutic approaches for patients.

Disclosure

A.Dall’agnese: Consultant; Dewpoint Therapeutics. J.Platt: None. T.Lee: None. J.F.Jeppesen: Employee; Novo Nordisk A/S. R.A.Young: Research Support; Novo Nordisk.
1317-P: Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuronal Cells via MicroRNA-Mediated Mechanism
Authors: TAKASAWA SHIN , SHOBATAKE RYOGO , TAKEDA YOSHINORI , UCHIYAMA TOMOKO , YAMAUCHI AKIYO , MAKINO MAI , ASAI KEITO , OTA HIROYO
Published: May 2022

Sleep apnea syndrome (SAS) , characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) , is a risk factor for hypertension and insulin resistance. We have reported correlation between IH and insulin resistance. However, why hypertension is induced by IH has been elusive. Here, we investigated the effect of IH on the expression of catecholamine metabolizing enzymes using in vitro IH system. Human and mouse neuronal cells, NB-1 and Neuro-2a, were exposed to IH (70 cycles of 5 min hypoxia [1% O2] and min normoxia [21% O2]) or normoxia for 24 hours. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in both NB-1 (P=0.0271 and P<0.0001, respectively) and Neuro-2a (P=0.0135 and P=0.0341, respectively) . Western blot showed that the expression of DBH and PNMT in the NB-1 cells significantly increased by IH (P=0.0296 and P=0.0007, respectively) . We next prepared reporter plasmids containing human DBH (-1018˜+10) and PNMT (-600˜+67) upstream of luciferase reporter gene and transfected them into NB-1 cells. The promoter activities of these genes were not increased by IH. Target mRNA search of microRNA (miR) s using MicroRNA.org program revealed that the mRNAs have a potential target sequence for miR-375. The miR-375 level of IH-treated cells was significantly decreased than that of normoxia-treated cells (P=0.0222) . To clarify the role of miR-375, miR-375 mimic and non-specific control RNA (miR-375 mimic NC) were introduced into NB-1 cells. The IH-induced up-regulation of mRNAs of DBH and PNMT was abolished by introduction of miR-375 mimic but not by miR-375 mimic NC. Theses results strongly suggest that IH stress down-regulates the miR-375 in neuronal cells, resulting in the increased levels of DBH and PNMT via the inhibition of the miR-375-mediated mRNA degradation, leading SAS patients to hypertension.

Disclosure

S.Takasawa: None. R.Shobatake: None. Y.Takeda: None. T.Uchiyama: None. A.Yamauchi: None. M.Makino: None. K.Asai: None. H.Ota: None.
1321-P: Reproductive Experience Impairs Warm Sensing in Female Mice
Authors: ZHANG NAN , HE YANLIN , XU YONG
Published: May 2022

The maternal body experiences drastic alterations in energy balance during pregnancy and lactation, but little is known about the long-term metabolic changes after this reproductive experience. Here we systemically compared the metabolic phenotypes in reproductive experienced (RE) female mice vs. virgin females, and found that RE mice showed a chronic hypothermia when housed at the room temperature (24°C) . In a warm sensing test, virgin females show clear preference to 30 °C ambient temperature vs. the room temperature, while RE mice lose this preference. In a cold sensing test, both virgin and RE females showed similar preference to the room temperature vs. 15 °C ambient temperature. Immunofluorescence staining revealed that expression of estrogen receptor alpha (ERα) in the medial preoptic area (MPA) was significantly decreased in the RE mice compared to virgins. Electrophysiological recordings demonstrated that the warm-sensing property of ERα neurons in the MPA were impaired in RE mice. Our results indicate that reproductive experience impairs the thermoregulation in female mice, associated with defective warm sensing of ERα neurons in the MPA.

Disclosure

N.Zhang: None. Y.He: None. Y.Xu: None.
1327-P: Loss of Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion in Diet-Induced Hyperglycemia
Authors: ABI RAAD SARAH , SALEH MOHAMED , GITTES GEORGE
Published: May 2022

There are two intra-pancreatic axes of communication between the endocrine and exocrine pancreas (insular-acinar & acinar-insular axes) yet the study of the endocrine and exocrine pancreas have generally been conducted separately. We previously showed that loss of acinar cells improved glucose homeostasis in wild type mice. Here, we examined the effect of loss of acinar cells on diet-induced hyperglycemia.We used a genetic mouse model (ElaCreERT2; R26DTR) , wherein diphtheria toxin (DT) ablates acinar cells, allowing for the study of β-cell function in the absence of acinar cells. We included 3 groups [ElaCreERT2; R26DTR + high fat diet (HFD) ], [R26DTR + HFD], and [R26DTR + regular diet (RD) ]. These groups were on their respective diets for 12 weeks, then underwent glucose tolerance testing (GTT) and glucose stimulated insulin secretion (GSIS) after DT injection. Four days post-DT, the ElaCreERT2; R26DTR+HFD mice had a significantly improved glucose tolerance compared to R26DTR + HFD (AUC p=0.0003) . Importantly, the ElaCreERT2; R26DTR + HFD were not different from R26DTR+RD, indicating complete reversal of the hyperglycemia. GSIS done during GTT showed significantly lower insulin secretion in ElaCreERT2; R26DTR + HFD compared to R26DTR + HFD (AUC p=0.0388) , but similar to R26DTR+ RD, again indicating normalization. Islets were isolated from the 3 groups for in vitro GSIS, which showed no difference in the insulin secretion between ElaCreERT2; R26DTR + HFD and R26DTR + RD, but both had increased insulin secretion compared to R26DTR + HFD. Four weeks post-DT, when full regeneration of acinar cells from duct cells takes place, repeat GTT in the same animals showed that HFD groups had worse glucose tolerance compared to the RD group, suggesting that it was specifically the loss of the acinar cells that improved glucose tolerance. We conclude that the acute ablation of exocrine pancreas improves glucose tolerance and reverses HFD-induced hyperglycemia by enhancing insulin secretion.

Disclosure

S.Abi raad: None. M.Saleh: None. G.Gittes: None.
1328-P: COVID Associated Insulitis in Type 1 Diabetes
Authors: UWAIFO GABRIEL I.
Published: May 2022

Recent reports suggest a potential relationship between COVID-and onset of diabetes (DM) . We present the case of a 35 yr old female with type 1 DM (T1DM) who following COVID-pneumonia (COVP) developed worsening insulitis suggesting a potential direct effect of COVID-on beta cell function. The patient is a 35 yr old Caucasian female with T1DM first diagnosed 5 yrs ago. She had some residual beta cell secretory function with fasting C-peptide; 0.51 (0-8-3.85ng/ml) . She also has hemochromatosis, thyroiditis with thyroid nodular disease and +ve history of T1DM in her older brother and maternal cousin. Since diagnosis she has been on insulin pump therapy and a CGMS device with excellent glycemic control and HBA1c of 6.7-7.1. She had not received the COVID-vaccine and had COVP in July 2021 requiring inpatient care but not intubation. She received oral steroids and Remdesivir with salutary response. She has not had post-acute sequelae of SARS-CoV (PASC) but ˜ 2 months post discharge had acute thyroiditis with no thyroid abscess, elevated sed rate, leucocytosis and peak thyroglobulin; 158 (3-40ng/ml) . Since discharge she noted persistent global hyperglycemia requiring increased basal and bolus insulin therapy with peak HBA1c of 8.3. Further evaluation showed active insulitis with reduced C-peptide 0.and increase in islet related antibodies compared to titers obtained at the time of initial diagnosis 5 yrs prior. The clinical presentation of our patient suggests a potential role of COVID-in inducing insulitis with significant implications for at risk patients including T1DM patients with preserved islet function but also type 2 DM and LADA patients. This case provides another compelling reason for advocating COVID-vaccination in at risk patients. The duration of this effect on islet function and whether beta cell functional recovery is possible over time remains to be seen. The insulitis manifests with worsening glycemic profiles as well as possibly impacting islet mediated counterregulatory glycemic responses.

Disclosure

G.I.Uwaifo: None.
133-OR: Increasing Economic Returns of Structured Lifestyle Intervention Associated with Rising Costs of Treating Diabetes: 2010–2018
Authors: HUANG WENXI , GUAN DAWEI , NIU SHU , ALI MOHAMMED K. , ZHANG YONGKANG , GUO JINGCHUAN , SHAO HUI
Published: May 2022

The medical costs of treating type 2 diabetes (T2D) can be considered a counterfactual to measure the value for preventing T2D. This study examined changes in the cost-effectiveness of the structured lifestyle intervention (SLI) to prevent T2D, attributable to the sharp increase in the costs of T2D between 20 and 2018. We developed a patient-level discrete-time microsimulation model for diabetes progression and mortality in people eligible for SLI as specified in the National Diabetes Prevention Program (NDPP) using data from the 2009-20 National Health and Nutrition Examination Survey (NHANES) with linked National Death Index, and published literature. We used the Medical Expenditure Panel Survey to develop a health utility equation (2018 data) and two cost equations (20 and 2018 data) . We simulated the long-term health and economic consequences of SLI using the simulation model based on 20 and 2018 cost equations, respectively. We took a payers’ perspective, and all costs were standardized to 2018 USD. The incremental net benefit (INB) was estimated using a $50,000/QALY. The SLI achieved cost-saving over a 20-year time horizon in a scenario using 2010’s costs but only 9 years under 2018’s costs. Based on 20 costs, SLI costs below $997 and $2,153 would make the SLI cost-saving and cost-effective, respectively, over a 20-year window. Based on 2018 costs, if SLI costs were below $1,479 and $2,635, respectively, it would be cost-saving and cost-effective over 20 years. Subgroup analysis suggested the SLI was more cost-effective in the Hispanic adults (INB:$5,383) than non-Hispanic white (INB: $2,192) and black (INB:$2,364) adults. From 20 to 2018, the increasing medical costs for treating T2D has led to a higher likelihood and shorter time horizon for SLI to be cost-saving. This suggests that payers can raise reimbursements for SLI programs to make the adoption of these programs more feasible for delivery systems while maintaining economic value.

Disclosure

W.Huang: None. D.Guan: None. S.Niu: None. M.K.Ali: Advisory Panel; Bayer AG, Research Support; Merck & Co., Inc. Y.Zhang: None. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.