bluuebunny/crossref_metadata_2025 huggingface dataset:
1439-P: Vitamin D Intake and Risk of Islet Autoimmunity (IA) and Type 1 Diabetes (T1D)
Authors: NORRIS JILL M. , CLASEN JOANNA L. , LIU XIANG , UUSITALO ULLA , ANDRÉN ARONSSON CARIN , HUMMEL SANDRA , YANG JIMIN , REWERS MARIAN , MCINDOE RICHARD , HAGOPIAN WILLIAM , ZIEGLER ANETTE-GABRIELE , LERNMARK ÅKE , TOPPARI JORMA , RICH STEPHEN S. , ONENGUT-GUMUSCU SUNA , PARIKH HEMANG M. , ERLUND IRIS A.M. , AKOLKAR BEENA , KRISCHER JEFFREY , VIRTANEN SUVI
Published: June 2024

Objective: We studied if vitamin D intake was associated with risk of IA or progression to T1D and whether single nucleotide polymorphisms (SNP) in vitamin D metabolism genes modify the effect of intake on risk.

Methods: We followed 7,520 high risk children from birth until development of IA, defined as persistent GAD65 (GADA), insulin (IAA) and/or IA-2 autoantibodies, and until progression to T1D. Vitamin D intake from foods and supplements was estimated with 3 day food records collected quarterly in the first year and then semi-annually to age 10. We analyzed vitamin D per energy intake in time-dependent Cox proportional hazards models, adjusting for country, sex, T1D family history, HLA, energy, ancestry and seroconversion age (for progression analysis). We tested interactions between intake and 18 SNPs in GC, CYP2R1, CYP24A1, DHCR7 and VDR on risk of IA and progression to T1D using a false discovery rate of <0.05 for significance.

Results: Higher vitamin D intake was associated with increased risk of GADA-first, only in those with 2 minor alleles in a SNP in CYP24A1 (which inactivates vitamin D) (Figure). Higher vitamin D intake at seroconversion was associated with decreased risk of progression from IA to T1D, only in those with no minor alleles in SNPs in GC (vitamin D binding protein gene) and VDR (vitamin D receptor gene).

Conclusion: Vitamin D intake may have differing effects on risk of IA and T1D, depending on variants in vitamin D genes.

Disclosure

J.M. Norris: None. J.L. Clasen: None. X. Liu: None. U. Uusitalo: None. C. Andrén Aronsson: None. S. Hummel: None. J. Yang: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. R. McIndoe: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. A. Ziegler: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. J. Toppari: None. S.S. Rich: None. S. Onengut-Gumuscu: None. H.M. Parikh: None. I.A.M. Erlund: None. B. Akolkar: None. J. Krischer: None. S. Virtanen: None.

Funding

NIH NIDDK (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C)
1441-P: Low Morning Cortisol in Early Life Associated with Increased Risk of Islet Autoimmunity
Authors: VEHIK KENDRA , LYNCH KRISTIAN F. , PARIKH HEMANG M. , LERNMARK ÅKE , REWERS MARIAN , MCINDOE RICHARD , TOPPARI JORMA , ZIEGLER ANETTE-GABRIELE , AKOLKAR BEENA , HAGOPIAN WILLIAM , BRUSKO TODD M. , KRISCHER JEFFREY , ROTH ROSWITH L. , JOHNSON SUZANNE B. , STUDY GROUP TEDDY
Published: June 2024

Introduction & Objective: Stress is implicated as a factor in immune reactivity and autoimmune disorders. Adverse experiences and chronic stress may be associated with low morning cortisol levels. Here, we tested if morning saliva cortisol is associated with the development of islet autoimmunity (IA).

Methods: Saliva was collected 30 minutes upon awakening and assayed for cortisol in 1049 children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study at 42 months. Using Cox proportional hazards models, we examined morning log2 cortisol at 42 months in relation to risk of IA between 4 and 15 years of age (any IA: n=89; GADA-first: n=53; IAA-first, n=23) in addition to TEDDY published factors associated with IA.

Results: Morning saliva cortisol (median log2=3.34) at 42 months is inversely associated with the risk of IA from 4 years of age (HR (95%CI) per log2 increase (0.65 (0.51-0.83), p=0.0005) adjusting for HLA-DR-DQ, diabetes family history, sex, weight-z score at age 12 months, and country. Both high (HR=0.19) and low (HR=1.95) morning cortisol levels are significantly associated with risk of IA, independently, as compared to 79% of children with log2 cortisol levels between 2-3.99 (Figure).

Conclusion: These findings suggest that morning saliva cortisol at 42 months of age is inversely associated with risk of IA in genetically at-risk children followed until 15 years of age.

Disclosure

K. Vehik: None. K.F. Lynch: None. H.M. Parikh: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. R. McIndoe: None. J. Toppari: None. A. Ziegler: None. B. Akolkar: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. T.M. Brusko: None. J. Krischer: None. R.L. Roth: None. S.B. Johnson: None.

Funding

NIH NIDDK (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C)
1442-P: Type 1 Diabetes (T1D) Clusters in the SEARCH for Diabetes in Youth Study
Authors: HARRALL KYLIE K. , BIRD SARAH M. , KIM CATHERINE , REDONDO MARIA J. , DABELEA DANA
Published: June 2024

Objective: Youth with T1D are heterogeneous for β-cell insufficiency, insulin sensitivity, autoantibody profile, risk alleles, and inflammatory markers. It is unknown whether subtypes of T1D exist. Such clusters might aid in the identification of youth at increased risk for poor outcomes.

Methods: SEARCH is a population-based observational cohort of youth (< 20 years) with diabetes conducted from 2002 - 2012. Youth with T1D (n=1107) were clustered by inflammatory status and insulin secretion and sensitivity using hierarchical clustering (hclust, R 4.3.1) with C-reactive protein (CRP), C-peptide, and body mass index Z-score (< 1 year since diagnosis). Demographics were compared across clusters.

Results: We found 6 clusters (Table). Youth in clusters 1 and 5 were more likely to be White and younger at diagnosis, with lower C-peptide, BMI Z-score, waist circumference, CRP, and IL-6. Youth in cluster 2 had high prevalence of positive GAD65 antibodies, CRP, and IL-6. Youth in cluster 3 had high prevalence of IA2 antibodies. Youth in cluster 6 were more likely to be Black or Hispanic and older at diagnosis, with higher C-peptide, BMI Z-score, waist circumference, triglycerides, and leptin.

Conclusion: We observed distinct clusters among youth with T1D of short duration. Future studies should examine whether T1D clusters are associated with diabetes outcomes and how T1D clusters compare to conventional risk scores for diabetes complications.

Disclosure

K.K. Harrall: None. S.M. Bird: None. C. Kim: None. M.J. Redondo: None. D. Dabelea: None.

Funding

National Institutes of Health (U18DP006517); National Institutes of Health (R21HD108508)
145-OR: Assessing the Current State of Diabetes Care in Long-Term Facilities Using Continuous Glucose Monitoring
Authors: SLYNE CHRISTINE , ROBERTS KIRSTEN , CONERY COLIN D. , BRABANT HALEY , KRAKOFF NOA , TOSCHI ELENA , MUNSHI MEDHA
Published: June 2024

Introduction: Recommendations for diabetes care in long term care facilities (LTCF) focuses on avoidance of hypoglycemia and symptomatic hyperglycemia. Using continuous glucose monitoring (CGM), we evaluated the current state of glycemia in LTCF residents with multiple comorbidities.

Methods: We conducted a cross-sectional study using CGM in 8 LTC facilities in the United States. A masked Dexcom G6 pro CGM was placed for 10 days on residents with diagnosis of diabetes mellitus (DM) who were on any oral or injectable hypoglycemic medications. Clincial and demographic information were collected from medical records.

Results: We evaluated 65 residents (mean age 65 years, 50% female). Fourteen percent of the cohort was on sulfonylurea medications and 68% were on insulin. CGM data showed 26% of the cohort with >1% time spent in hypoglycemia (time <70 mg/dL). A larger burden of hyperglycemia was seen with 54% of the cohort spending >10% time >250mg/dL, 37% spending >25% time >250 mg/dL, and 14% spending >90% time >250 mg/dL. Only 44% of the cohort had >50% Time-in-Range (70-180 mg/dL). The latest A1C was <7% in 45% of the cohort, 7-8% in 27%, 8.1-9% in 12%, and >9% in 16%. Fingerstick reading frequency was 2 or fewer times/day in 74% of the cohort, 3 times/day in 13%, and 4 or more times/day in 13%. On average, this cohort had 13 comorbidities, with 85% having functional disabilities. There was 14% with dementia and 42% with obesity (BMI>30). All 100% of the participants had polypharmacy(≥5 medications/day).

Conclusions: In this multi-morbid cohort of residents with diabetes living in LTCF, we identified a high burden of both hypoglycemia and severe hyperglycemia, despite fair control of A1C. More consistent use of CGM could help identify glycemic excursions to improve therapeutic decision-making.

Disclosure

C. Slyne: None. K. Roberts: None. C.D. Conery: None. H. Brabant: None. N. Krakoff: None. E. Toschi: Consultant; Vertex Pharmaceuticals Incorporated, Sanofi. M. Munshi: Consultant; Sanofi.

Funding

Supported by an investigator initiated grant from Dexcom
1450-P: Associations between Marginalization and Insulin Pump Use among Adults with Type 1 Diabetes in Ontario
Authors: SOLIMAN YOUSTINA , EVERETT KARL , SHULMAN RAYZEL , AUSTIN PETER , LIPSCOMBE LORRAINE , BOOTH GILLIAN L. , WEISMAN ALANNA
Published: June 2024

Introduction & Objective: We evaluated associations between marginalization and pump use in the context of a public funding program, and temporal trends in marginalization among new insulin pump program applicants.

Methods: We conducted population-based studies of adults with type 1 diabetes using administrative data. Unadjusted and adjusted logistic regression was used to assess associations between marginalization [determined by postal code using the Ontario Marginalization Index (ON-MARG)] and insulin pump use on March 31, 2021. Unadjusted ordinal logistic regression was used to evaluate association between insulin pump application year (2007-2022) and odds of being in a higher marginalization quintile.

Results: 16,471 (60%) of 27,453 adults used insulin pumps. Higher ON-MARG quintile was associated with lower odds of insulin pump use [adjusted OR 0.44 (0.39-0.48) for lowest vs. highest quintile]. The most marginalized individuals were the smallest proportion of applicants to the insulin pump program between 2007 and 2022 (Figure 1). While narrowing of marginalization distribution occurred from 2007-2010, widening occurred from 2020-2022.

Conclusion: Disparities in pump use persistent even in the context of public funding, and the COVID-19 pandemic may have disproportionately prevented more marginalized individuals initiating pump therapy. Residual barriers to pump use must be addressed.

Figure: Distribution of material resources quintile for all new applicants to ADP by fiscal year for all ages (n=21,002)

Disclosure

Y. Soliman: None. K. Everett: None. R. Shulman: Advisory Panel; Dexcom Canada. Speaker's Bureau; Dexcom Canada. P. Austin: None. L. Lipscombe: Other Relationship; Novo Nordisk Canada Inc. G.L. Booth: None. A. Weisman: None.

Funding

Banting Research Foundation & Canadian Statistical Sciences Institute (CANSSI) Ontario Discovery Award
1461-P: DNA Methylation (DNAm) and 28-Year Risk of Diabetic Peripheral Neuropathy (DPN) in Type 1 Diabetes (T1D)—The Epidemiology of Diabetes Complications (EDC) Study
Authors: ZHOU JIAYI , MYCHALECKYJ JOSYF , ONENGUT-GUMUSCU SUNA , ORCHARD TREVOR J. , COSTACOU TINA , MILLER RACHEL G.
Published: June 2024

DPN is a common T1D complication that can greatly affect quality of life. DPN likely results from a combination of genetic risk and glycemic exposure. DNAm may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN are lacking. We performed a prospective EWAS of 28-yr DPN risk and assessed associations adjusting for established risk factors in the EDC study of childhood-onset (<17 yrs) T1D (baseline mean age 27, T1D duration 19 yrs). DPN was defined as ≥2 of: DPN symptoms, decreased tendon reflexes, abnormal sensory exam. After quality control, baseline whole blood DNAm (EPIC array) at 683,597 CpGs was analyzed in Cox models for time to DPN in 282 persons free of DPN at baseline. Models were adjusted for T1D duration, sex, smoking pack years, estimated blood cell composition and technical variables. False discovery rate (FDR)<0.05 was considered significant. Genetic variants (meQTLs) associated with significant CpGs were identified. Over 28 yrs, 154 (54.6%) developed DPN. Three CpGs significantly associated with DPN: cg06163904 (CHMP6, log β per 5% DNAm=-0.98±0.19, p=1.05E-07, FDR=0.04), cg10835127 (CACNA1B, log β=-0.79±0.15, p=1.12E-07, FDR=0.04), and cg18945945 (PKNOX1, log β=-0.99±0.19, p=1.93E-07, FDR=0.04). Both cg10835127 and cg18945945 were associated with albumin excretion rate (β=-0.51±0.17, p<0.01; β=0.50±0.23, p=0.03) but their associations with DPN were unaltered after adjustment. There were 75 meQTLs for cg18945945 in the PKNOX1 region, 59 of which were previously reported cg18945945 meQTLs in the Chronic Renal Insufficiency Cohort. This prospective EWAS in T1D identified loci where DNAm associated with DPN after adjusting for known risk factors, highlighting mechanisms for further study including cell repair/death (CHMP6), presynaptic depolarization and calcium channel activity (CACNA1B), and chemokine transcription regulation (PKNOX1).

Disclosure

J. Zhou: None. J. Mychaleckyj: None. S. Onengut-Gumuscu: None. T.J. Orchard: None. T. Costacou: None. R.G. Miller: None.

Funding

American Diabetes Assoication (1-19-JDF-109); NIDDK (R01DK034818); Rossi Memorial Fund (Pittsburgh, PA)
1464-P: Targeted Delivery of shRNA-Lipids to Activated Monocytes and Inhibition of Neovascularization in Proliferative Retinopathy
Authors: IMAM UDDIN MD
Published: June 2024

Introduction & Objective: Proliferative retinopathy is a vision threatening condition in diabetic patients. We observed, using single cell RNA sequencing data analysis, activation of bone marrow-derived cells in peripheral blood from patients with Type-1 diabetes, and also in animal models of proliferative retinopathy. These activated monocytes and progenitor cells migrate into the retina in response to inflammation and neovascularization. However, contribution of these cells to neovascularization is largely unknown. We describe here the synthesis of a new hybrid nanoparticle for targeted delivery and gene silencing in activated monocytes that are associated with pathological neovascularization.

Methods: Single cell RNA sequencing data analysis were performed to characterize mRNA expression in peripheral blood from patients with Type-1 diabetes, and in oxygen-induced retinopathy (OIR) model. Targeted AS-shRNA-lipids were synthesized by conjugating diacyl-lipids to anti-sense short hairpin RNA with an anti-sense sequence complimentary to endoglin mRNA.

Results: Endoglin mRNA expression was associated with CD14high and IL1B positive activated monocytes in peripheral blood from Type-1 diabetic patients, and in OIR model. In addition, endoglin mRNA expression was inhibited by AS-shRNA-lipid. In addition, significant reduction of neovascularization was achieved in OIR after intraperitoneal injection of AS-shRNA-lipids.

Conclusions: Diabetes may contribute to monocyte activation and inhibition of endoglin mRNA could regulate the activation. We have developed a novel method for targeted delivery and inhibition of mRNA targets in activated monocytes in the living tissues using AS-shRNA-lipids. These studies may provide a framework for a novel strategy to inhibit retinal neovascularization.

Disclosure

M. Uddin: None.

Funding

American Diabetes Association (11-22-IBSPM-12); R01EY029693, R01EY023397
1465-P: The C1858T Polymorphism in PTPN22 Modulates the Human Pancreatic Islet Transcriptome
Authors: SULEIMAN MARA , DE LUCA CARMELA , SEMERARO ROBERTO , BOSI EMANUELE , MAGI ALBERTO , TESI MARTA , DEL GUERRA SILVIA , PAGLIAROSI OLIVIA , CUDINI ANNAMARIA , ROSSI LEONARDO , EIZIRIK DECIO L. , CNOP MIRIAM , MARCHETTI PIERO , MARSELLI LORELLA , FIERABRACCI ALESSANDRA
Published: June 2024

Introduction & Objective: PTPN22 encodes for a lymphoid-specific intracellular phosphatase involved in T-cell receptor signaling. The C1858T PTPN22 polymorphism induces gain of function of the encoded Lyp phosphatase and associates with T1D. Since PTPN22 is expressed in human pancreatic islets (HI), we assessed whether the C1858T variant affects HI function and molecular features.

Methods: Genomic DNA of 105 nondiabetic (ND) donors was analyzed and HI were isolated from the same subjects. Islet insulin release was assessed in response to 16.7 mM glucose (G), glyburide (Glyb) and arginine (Arg). RNA-sequencing was performed in hand-picked HI. Islet functional and transcriptomic data of 8 carriers of the polymorphism and 11 wild type (WT) matched donors were compared.

Results: Insulin stimulation indexes in response to G, Glyb and Arg did not differ significantly between C1858T and WT islets (respectively 3.17±1.18 vs 2.80±0.94, 3.85±1.41 vs 3.75±1.30, and 3.20±1.14 vs 2.16±1.13). Comparison between the mutated vs WT islet transcriptomes evidenced 21 differentially expressed genes (FDR<0.05, absolute fold-change>1.5): 3 were up-regulated (DCD, MIR205HG, SNORA72) and 18 down-regulated (the top 5 being H2BC17, RRM2, IQGAP3, CYBB and FN1). GSEA retrieved 34 gene sets significant at FDR < 25% threshold. At nominal p value of < 1%, 6 of them were positively enriched in C1858T islets (Myc target_V1 and Myc target_V2, Unfolded protein response, Pancreas beta cells, DNA repair, E2F targets) and 18 were negatively enriched (including IFN-gamma response, IFN-alpha response, TNFA signaling via NFKB, Complement, Inflammatory response).

Conclusion: These results suggest that the C1858T PTPN22 polymorphism affects the islet transcriptome, including cellular stress, inflammation, and innate immunity pathways, without a major impact on insulin secretion. The ultimate mechanism(s) behind the role for the C1858T PTPN22 polymorphism in T1D-mediated beta cell damage remains to be clarified.

Disclosure

M. Suleiman: None. C. De Luca: None. R. Semeraro: None. E. Bosi: None. A. Magi: None. M. Tesi: None. S. Del Guerra: None. O. Pagliarosi: None. A. Cudini: None. L. Rossi: None. D.L. Eizirik: None. M. Cnop: None. P. Marchetti: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. L. Marselli: None. A. Fierabracci: None.

Funding

RF-2019-12369889 AND Innovative Medicines Initiative 2 (115797, 945268)
1470-P: Modeling Familial Partial Lipodystropy Type 2 (LMNAp.R482W) Utilizing iPSC-Derived Adipocytes
Authors: BORREGO ALVAREZ ALUET , LIU KATIE , GOBBLE MCKINLEE R.S. , GRUPE MICHAEL , MOHAMMED ALI LINA , BUCHSER WILLIAM J. , BALDRIDGE DUSTIN , STONE STEPHEN I.
Published: June 2024

Familial partial lipodystrophy type 2 (FPLD2) is a genetic syndrome characterized by loss of adipose tissue in the trunk and limbs and accumulation of supraclavicular fat. The most common genetic cause of FPLD2 is a pathogenic variant in the lamin A gene (LMNA; c.1444C>T; p.R482W). Our goal was to model FPLD2 in an induced pluripotent stem cell (iPSC) line. CRISPR/Cas9 gene editing was used to knock-in the heterozygous LMNA p.R482W variant into AN1.1 control iPSCs. Wild type and mutant iPSCs underwent a 2-stage differentiation process, first to mesenchymal cells then to adipocytes. Functional studies included 2-deoxyglucose (2-DG) uptake and mitochondrial stress testing. Adipocytes also underwent flow cytometry, RNA sequencing, and microscopy. We observed that both wild-type and mutant clones successfully differentiated to adipocytes after 26 days in adipogenic differentiation media. Adipogenic differentiation was diminished in mutant cells. Basal and insulin-stimulated uptake of 2-DG was impaired in mutant cells. Mitochondrial stress testing in mutant cells demonstrated decreased oxygen consumption rate (OCR), which was driven by a significant decrease in maximal respiration and coupling efficiency. RNA sequencing showed that the mutant cells had significant reduction in the expression of key adipogenic genes including ADIPOQ, CD36, ITIH5, CHCR7, LIPE, ITGA7, and OMD. Preliminary results from flow cytometry and high content microscopy both demonstrated decreased lipid droplet accumulation in the mutant cell lines. Our results show that an iPSC-based model system can recapitulate the adipose tissue dysfunction seen in FPLD2. We propose that this system is a useful model for studying pharmaceuticals aimed at restoring the metabolic function of adipose tissue in FPLD2. Additionally, our work suggests that iPSC-derived adipocytes may be used to study novel candidate disease genes in individuals with atypical lipodystrophy.

Disclosure

A. Borrego Alvarez: None. K. Liu: None. M.R.S. Gobble: None. M. Grupe: None. L. Mohammed Ali: None. W.J. Buchser: None. D. Baldridge: None. S.I. Stone: None.

Funding

UL1TR002345 Clinical and Translational Research Funding Program. This project is funded through the Pilot Translational and Clinical Studies function of the WU ICTS.
1475-P: Genetic Evaluation of Human Lipidome Identifies Multiple Loci Associated with Metabolite Phenotypes Involved in Energy Metabolism and Inflammation in Type 2 Diabetes—Results from the Asian Indian Diabetic Heart Study (AIDHS)
Authors: ROUT MADHUSMITA , SANGHERA DHARAMBIR K. , BEHALF OF THE INVESTIGATORS OF THE AIDHS CONSORTIUM ON
Published: June 2024

Background: Despite the success of genome-wide association studies (GWAS), the genetic mechanisms that predispose people to type 2 diabetes (T2D) remain poorly understood. Metabolomics has rapidly progressed from a single-gene/single-metabolite association to a genome-wide/metabolome-wide approach. However, limited data are available on non-white populations. Here, we have performed global lipidomic profiling and a targeted genetic association study to understand the genetic influences of T2D-associated variants on circulating lipid metabolites using a T2D cohort of Punjabi Sikhs from India.

Methods: Untargeted lipidomic analysis was performed on blood samples of 3000 individuals (1723 T2D cases and 1277 controls) using liquid chromatography and high-resolution mass spectrophotometry (LC-MS). The association of T2D with 7463 (1743 known and 5720 unknown) metabolites was identified using multivariate mixed regression modeling. We further analyzed the association of 366 and 391 T2D-associated metabolites in serum and plasma, respectively, by conducting a GWAS using up to 14,959,825 million imputed SNPs as part of discovery and replication cohorts.

Results: Our study identified 11 significant associations (p ranging from 6.8×10−10 to 4.8x10-20), including nine robust signals in the genes (TRPV4, RIPOR2, LDHC, MYRF, FADS1, and DNAH11) involved in transient receptor potential (TRP) channel, and calcium signaling pathways with the metabolites connected with energy metabolism, fatty acid transport, inflammation, and glucose metabolism.

Conclusions: In our first metabolome-GWAS in Asian Indians, we have identified novel molecular signatures and pathways associated with T2D. If validated, these results can potentially contribute to developing new therapeutic strategies to improve the prediction and treatment of T2D.

Disclosure

M. Rout: None. D.K. Sanghera: None.

Funding

National Institutes of Health (R01DK082766, R01DK118427); National Institute of Diabetes and Digestive and Kidney Diseases grants from the Presbyterian Health Foundation of Oklahoma
148-OR: Increased Insulin Secretion and Decreased Insulin Sensitivity in South Asian Youth without Diabetes
Authors: STEFANOVSKI DARKO , KELLY ANDREA , HITT TALIA A. , ZEMEL BABETTE S. , MAGGE SHEELA N.
Published: June 2024

Introduction & Objective: The mechanisms underlying increased T2DM risk at lower BMI in South Asians (SA) compared to other ancestries are not known, but greater visceral fat (VFAT) for given BMI has been implicated. We examined the relationships of VFAT with insulin sensitivity (Si) and insulin secretory rate (ISR) in SA vs White (W) and African American (AA) adolescents and young adults (AYA).

Methods: SA, W, and AA aged 12-21y, BMI ≥ 80%ile for age and sex or BMI ≥ 23 kg/m2, without diabetes, underwent DXA for VFAT area and a 3-hr, 10-sample OGTT with Si by Minimal Model, and ISR by parametric deconvolution of C-peptide kinetics (2-compartment model). ISR incremental AUC was calculated. Ancestry groups were compared using Kruskal Wallis or chi2; Spearman correlations tested associations between VFAT and metabolic indices. Linear regression with adjustment for age, sex and inclusion of a VFAT-by-ancestry interaction term examined ancestry differences in Si and ISR.

Results: AYA (n= 51 SA, 39 W, 25 AA) were of similar age (median (IQR); SA 20.3y (18.9, 21.5); W 19.3y (18.3, 21.1); AA 19.0y (18.0, 20.4)), BMIZ (mean ± SD; SA 1.21 ± 0.53; W 1.14 ± 0.57; AA 1.38 ± 0.60), and BMI (SA 27.9 kg/m2 (25.1, 29.4); W 25.9 (24.6, 29.7); AA 27.3 (25.3, 35.5)), but differed by female sex: SA 52.9%; W 56.4%; AA 88.0% (p=0.009). SA had higher VFAT (97.5 cm2 (82.0,121.0)) than W (87.2 (64.1,108.0) and AA (75.0 (51.2,102), p= 0.029. One cm2 increase in VFAT associated with 41% lower Si (p=0.03) and 82% greater increase in ISR (p<0.001) in SA compared to W. Compared to AA, for 1cm2 VFAT increase, SA had similar Si decrease, but 82% greater ISR increase (p=0.004).

Conclusion: Among AYA of similar BMI, SA had higher VFAT than W and AA. However, for similar increase in VFAT, SA had a greater reduction in Si and higher ISR increase compared to W. SA had a similar reduction in Si compared to AA, but again a greater increase in ISR. Thus, the higher T2DM risk in SA may be due to greater hyperinsulinemic compensation, resulting in beta cell exhaustion.

Disclosure

D. Stefanovski: None. A. Kelly: None. T.A. Hitt: None. B.S. Zemel: None. S.N. Magge: None.

Funding

National Institutes of Health (R01DK115648); National Institutes of Health (UL1TR001878); National Institutes of Health (UL1TR001079)
1485-P: Clinical Utility of Type 1 Diabetes and Type 2 Diabetes PGS for Informing Type 2 Diabetes Treatment and Disease Severity
Authors: BILLINGS LIANA K. , SHI ZHUQING , MULFORD ASHLEY , ASHWORTH ANNABELLE , XU JIANFENG , SANDERS ALAN R.
Published: June 2024

Introduction: Type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk scores (PGST1D and PGST2D) can differentiate T1D and T2D, but it remains unclear whether PGST1D and PGST2D can inform T2D treatment and disease severity.

Methods: Among T2D patients in the Genomic Health Initiative (GHI) (N=2,716) and UK Biobank (UKB) (N=39,957), PGST1D and PGST2D were examined for association with anti-diabetes medications (ADM), number of ADM classes ever used, metabolic (BMI>30, triglycerides>150mg/dL, hypertension diagnosis) and autoimmune (hypothyroidism, celiac disease) phenotypes, and diabetic ketoacidosis with adjustment for HbA1c, age of recruitment and top 4 principal components.

Results: We confirmed previous UKB findings in the GHI that PGST1D and PGST2D differentiate T1D and T2D diagnoses. Among T2D patients in the GHI and UKB, a high vs. low PGST2D associated with more prevalent usage of insulin and non-insulin ADM, a greater number of ADM classes ever used, earlier age of T2D onset, and higher mean HbA1c. In the UKB, high PGST1D wasassociated with insulin treatment and number of ADM classes ever used (Table 1). Lastly, PGST1D associated with autoimmune phenotype and diabetic ketoacidosis, while the PGST2D associated with metabolic phenotype.

Conclusion: These findings emphasize the potential of polygenic risk scores to inform diabetes treatment and provide insights into disease onset and severity in T2D.

Disclosure

L.K. Billings: Advisory Panel; Novo Nordisk, Pfizer Inc. Z. Shi: None. A. Mulford: None. A. Ashworth: None. J. Xu: None. A.R. Sanders: None.

Funding

NorthShore Auxiliary Scholars Award (internal)
1488-P: A Novel Combination Therapy to Treat Autoimmune Type 1 Diabetes
Authors: HUSSEINY MOHAMED I. , COBB JACOB , RAWSON JEFFREY , GONZALEZ NELSON , KANDEEL FOUAD R.
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) is a complex disease characterized by loss of immune tolerance to self-autoantigens and destruction of insulin-producing beta-cells. No single therapy confronts the several contributors to the disease. We developed an oral Salmonella-based vaccine that provides autoantigen in combination with TGFβ, IL10, and anti-CD3. The vaccine partially prevented and reversed autoimmune diabetes in mice. We also found that the hormone gastrin was beneficial to human islets in vitro and prevented, to a degree, autoimmune diabetes in mice. We hypothesized that the vaccine in combination with a gastrin analogue (GAST-17) would be more salutary in rodents with T1D than either agent alone.

Methods: The vaccine and GAST-17 combination were administered to autoimmune diabetic mice and outcomes compared with animals that received the vaccine or gastrin alone. Effects on glucose metabolism, islet cellular infiltration, and specific immune cells were characterized. The tolerogenic mechanisms of the combination therapy were examined.

Results: Administration of the vaccine with GAST-17 in combination reversed disease in 80% of diabetic mice compared to 63% of vaccine alone and 5% of GAST-17 alone treated animals. This was associated with increased antigen-specific regulatory T-cells, decreased islet-infiltrating lymphocytes, and increased beta-cell mass. As well, combination treated mice showed increased serum levels of the tolerogenic cytokine IL10 and decreased inflammatory cytokines (IFNγ, GM-CSF, IL1-alpha, IL12).

Conclusion: A novel combination treatment of an oral diabetes vaccine and GAST-17 was superior in the reversal of established T1D in mice. This combination strategy could be worthwhile examining in individuals with autoimmune diabetes.

Disclosure

M.I. Husseiny: None. J. Cobb: None. J. Rawson: None. N. Gonzalez: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.

Funding

The Juvenile Diabetes Research Foundation (JDRF-2-SRA-2022-1214-S-B)
149-OR: Liver Health in Adolescents with Youth-Onset Type 2 Diabetes
Authors: SHAH AMY S. , XANTHAKOS STAVRA , TROUT ANDREW T. , KELSEY MEGAN M. , JENKINS TODD M. , HELMRATH MICHAEL , INGE THOMAS , BROWNE LORNA , SCHAAF LISA R. , BAUMGARTNER AMY , RIEGLER ALLEN , BAILEY ALEXANDER , DOBBS TYLER , WITT KAITLYN , HINES ASHTON , RUSK SHENA , NADEAU KRISTEN J.
Published: June 2024

Introduction: Youth-onset type 2 diabetes (Y-T2D) and metabolic liver disease (MASLD) commonly coexist. MASLD can advance to fibrosis/cirrhosis with no treatments beyond lifestyle intervention. Limited liver data in Y-T2D led us to investigate MASLD in the ST2OMP study, which will compare metabolic bariatric surgery (MBS) to medical treatment for Y-T2D.

Methods: Liver fat (MRI proton density fat fraction (PDFF), liver stiffness (MR elastography), and ALT (inflammation) were measured in Y-T2D at ST2OMP enrollment. Linear regression examined differences in liver outcomes adjusted for sex, race/ethnicity, BMI, HbA1c and glucagon-like peptide 1 receptor agonists (GLP-1RA) use.

Results: At baseline, participants (n=56) had mean age 16.6yrs and BMI 43.8 kg/m2; median HbA1c 6.3% and diabetes duration 1.7 yrs. Elevated ALT occurred in 76.4%, PDFF in 89.0% and stiffness in 14.8%. Analyses adjusted for age, BMI and HbA1c (Table), found higher PDFF and ALT in males (vs. females) and in youth not taking GLP-1RA (each p<0.05). Non-Hispanic White youth had the highest stiffness (p<0.05).

Conclusions: MASLD is prevalent in Y-T2D with evidence of inflammation and stiffness. Males had higher measures of fat and inflammation, and non-Hispanic white youth had the highest stiffness. GLP-1RA use may be associated with less fat and inflammation, independent of BMI, but not stiffness. Future ST2OMP results will compare MASLD outcomes pre- and post-MBS.

Disclosure

A.S. Shah: None. S. Xanthakos: None. A.T. Trout: Research Support; Siemens Healthcare Diagnostics, GE Healthcare, Perspectum Ltd. Consultant; GE Healthcare. M.M. Kelsey: Other Relationship; Rhythm Pharmaceuticals, Inc., Lilly Diabetes. T.M. Jenkins: None. M. Helmrath: None. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. L. Browne: None. L.R. Schaaf: None. A. Baumgartner: None. A. Riegler: None. A. Bailey: None. T. Dobbs: None. K. Witt: None. A. Hines: None. S. Rusk: None. K.J. Nadeau: None.

Funding

National Institutes of Health (R01DK119450)
1493-P: Transglutaminase-Expressing Adipose Tissue Macrophages Positively Regulate Adipose Tissue Profibrotic Profile in Diet-Induced Obese Mice
Authors: HOLLIS MELANIE , ELIZONDO DIANA , P PATEL TUSHAR , ROBERSON ROBIN , CHEN JOCELYN , YANOVSKI JACK A.
Published: June 2024

Introduction: Adipose tissue fibrosis (ATF) in obesity-driven diabetes is characterized by increased extracellular matrix (ECM) deposition. Cell populations that induce ATF in diabetes have yet to be fully elucidated. Transglutaminase 2 (TGM2) is known to contribute to ECM stabilization. The objective of this study was to investigate adipose tissue macrophage (ATM)-derived TGM2 as a potential modulator of ATF in diabetes.

Methods: C57BL/6 mice were placed on chow diet (CD) or high-fat diet (HFD) for 10 weeks and evaluated for ATF and TGM2 expression in epididymal white adipose tissue (eWAT). Next, TGM2 was silenced in HFD mice via in vivo RNAi silencing to evaluate effects on ATF. Lastly, TGM2 CRISPR-silenced macrophages were co-cultured with differentiating adipocytes and evaluated for adipo/lipogenesis. Readout indices included, picrosirius red, qPCR, western blot, RNAscope, and flow cytometry.

Results: TGM2 and Col6A1 eWAT expression were increased in HFD mice compared to CD. TGM2 was increased within the ATMs from HFD mice, suggesting ATMs as the main TGM2 contributor in eWAT during obesity. Successful silencing of TGM2 within HFD ATMs decreased eWAT fibrosis, plausibly caused by observed changes in abundance of AT pro-inflammatory immune cells in TGM2 silenced mice. Finally, differentiating adipocytes co-cultured with TGM2-silenced macrophages showed reduced adipocyte expansion, supporting the notion that macrophage-derived TGM2 contributes to AT ECM alterations also involved in adipocyte growth.

Conclusion: Results suggest that ATMs secreting TGM2 in HFD mice contribute to ATF in obesity. We identify TGM2 in ATMs as a potential cell-specific candidate marker for therapeutics directed at obesity-associated ATF.

Disclosure

M. Hollis: None. D. Elizondo: None. T. Patel: None. R. Roberson: None. J. Chen: None. J.A. Yanovski: Research Support; Rhythm Pharmaceuticals, Inc., Soleno Pharmaceuticals, Inc, Versanis Bil, Hikma Pharmaceuticals, Inc., National Institutes of Health.
1496-P: The Highly Immunodeficient SRG Rat for Modeling Diabetes
Authors: WALTON GRACE
Published: June 2024

Immunocompromised rodents are essential for pre-clinical testing of cell-based therapies. The SRG rat (Sprague Dawley Rag2-/-, Il2rg-/-) lacks mature B, T, and NK cells, and is normoglycemic under standard conditions. Compared to mice, the SRG rat offers more human-like metabolism, easier surgical manipulations, and greater volume and frequency of blood collection. Compared to nude rats, the SRG is more permissive to a wider range of human xenografts. Given the advantages of the SRG rat, we determined whether it could serve as a model of streptozotocin-induced (STZ) Type 1 Diabetes or diet-induced obesity (DIO) as a model of Type 2 Diabetes. We compared the effects of STZ on blood glucose levels in SRG versus wild-type Sprague Dawley (SD) male rats. Rats were given vehicle, STZ 40 mg/kg, or STZ 65 mg/kg. After low dose STZ, day 6 non-fasting glucose was 262 ± 41 (SEM) mg/dL in SD rats and 565 ± 64 (SEM) mg/dL in SRG rats. After high dose STZ, day 6 non-fasting glucose was 679 ± 23 (SEM) mg/dL in SD rats and 505 ± 72 mg/dL in SRG rats. Weight loss associated with hyperglycemia was more pronounced in SRG rats compared to SD rats. To induce T2D, obesity, and insulin resistance, SRG rats were fed control or high fat diet (60% kcal from fat). Food intake and body weight were measured weekly. SRG rats underwent IPGTT (after 10 and 24 weeks of high fat diet) and ITT (after 11 weeks of high fat diet). Compared to low fat diet, DIO rats had increased caloric intake and body weight throughout the study. After 10 weeks, DIO rats had impaired glucose tolerance without elevated fasting insulin. Insulin tolerance did not differ at 11 weeks. At 24 weeks, glucose tolerance did not differ between diet groups, but DIO SRG rats displayed elevated fasting insulin (P < 0.01).

In conclusion, SRG rats display increased sensitivity to 40 mg/kg STZ when compared to SD rats, with rapid induction of weight loss and hyperglycemia. The SRG glycemic response to chronic DIO is complex and changes over time, likely due to compensatory hyperinsulinemia.

Disclosure

G. Walton: None.
1498-P: Intermittent Hypoxia Increased the Expression ofIL-1ß, IL-6, and IL-8 in Human Monocytes through the Downregulation of MicroRNA-146a
Authors: TAKASAWA SHIN , MAKINO MAI , SHOBATAKE RYOGO , YAMAUCHI AKIYO , SAKURAMOTO-TSUCHIDA SUMIYO , UCHIYAMA TOMOKO , TAKEDA MAIKO , TAKEDA YOSHINORI , MIZUTA KEITA , ASAI KEITO , OTA HIROYO
Published: June 2024

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for systemic inflammation. Serum inflammation markers such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) in SAS patients have been reported to be elevated. However, the details of why IH leads to induce the elevations remain unclear. We investigated inflammation-related transcripts in human monocytes (HL-60 and THP-1 cells) exposed to IH by real-time RT-PCR and found that IL-1 β, IL-6, and IL-8 mRNAs were significantly increased. ELISA confirmed that IL-1β, IL-6, and IL-8 in the HL-60 and THP-1 culture media were significantly increased by IH (P=0.011 and 0.0339 in IL-1β, P=0.0419 and 0.369 in IL-6, P<0.0001 and <0.0001 in IL-8, respectively). We next investigated promoter activities of the genes and revealed that they were not increased by IH. On the other hand, target mRNA search of microRNA (miR)s revealed that the mRNAs have a potential target sequence for miR-146a. The miR-146a level of IH-treated cells was significantly decreased than that of normoxia-treated cells. Thus, we introduced miR-146a mimic and non-specific control RNA (miR-146a mimic NC) into HL-60 and THP-1 cells and measured the mRNA and protein levels of IL-1β, IL-6, and IL-8. The IH-induced expression of IL-1β, IL-6, and IL-8 was abolished by introduction of miR-146a mimic but not by miR-146a mimic NC. Our results demonstrate that IH stress up-regulates the levels of IL-1β, IL-6, and IL-8 in human monocytes to accelerate systemic inflammation including diabetes through the miR-146a mediated mechanism, resulting in onset or aggravation of systemic inflammation.

Disclosure

S. Takasawa: None. M. Makino: None. R. Shobatake: None. A. Yamauchi: None. S. Sakuramoto-Tsuchida: None. T. Uchiyama: None. M. Takeda: None. Y. Takeda: None. K. Mizuta: None. K. Asai: None. H. Ota: None.
1500-P: Oral Exposure to Cigarette Smoke Condensate Leads to Glucose Intolerance and Immune-Cell Alterations in the Gut
Authors: BOSCH ANGELA J.T. , KELLER LENA , LOW ANDY J.Y. , KELLENBERGER WANJA T. , CAVELTI-WEDER CLAUDIA
Published: June 2024

Introduction & Objective: Smoking is associated with an increased risk for diabetes, yet the underlying mechanism remains elusive. Since smoking correlates with many gastrointestinal tract diseases, we aimed to investigate whether cigarette smoke influences metabolic health through gut exposure.

Methods: Male C57Bl/6N and Rag2-/- mice were exposed to cigarette smoke condensate (CSC) by oral gavage (5 days/week; 0.5mg/day). Metabolic health was evaluated by glucose and insulin tolerance tests. At the end of the experiment, immune cells of different organs were characterized by flow cytometry.

Results: Mice treated with CSC exhibited impaired glucose tolerance combined with increased insulin secretion and reduced insulin sensitivity, indicative for insulin resistance. Additionally, oral exposure to CSC led to changes in colonic immune cells as characterized by increased eosinophils and inflammatory macrophages. In the liver, macrophages and monocytes were elevated, while in the adipose tissue, there was an increase in Th2 and regulatory T-cells. Rag2-/- mice, lacking mature T- and B-lymphocytes, were not protected from metabolic impairment, but rather developed glucose intolerance after a shorter period of CSC exposure.

Conclusion: Gut exposure to CSC results in glucose intolerance and insulin resistance. Additionally, oral CSC exposure leads to gut and liver inflammation. Innate immunity seems to play a central role in driving this inflammation, as mice lacking B- and T-cells demonstrate early onset of glucose intolerance. These findings point towards an immune-mediated mechanism of CSC-induced diabetes through gut exposure.

Disclosure

A.J.T. Bosch: None. L. Keller: None. A.J.Y. Low: None. W.T. Kellenberger: None. C. Cavelti-Weder: None.

Funding

Swiss National Science Foundation (SNSF) (32003B_204937 / 2)
1506-P: Genomic Monitoring of Islet Graft Injury in Type 1 Diabetic Patients after Islet Transplantation
Authors: HUSSEINY MOHAMED I. , COBB JACOB , ORR CHRIS , HACKER-STRATTON JEANNETTE , FOROUHAR ELENA , EL-SHAHAWY MOHAMED A. , KANDEEL FOUAD R.
Published: June 2024

Introduction & Objective: Early detection of islet graft injury after islet transplantation (IT) may allow timely intervention to preserve islet graft health and function. We hypothesized that in response to IT injury, islet beta-cells will release cell-free DNA (cfDNA) into the circulation allowing for early detection of graft injury.

Methods: Real-time bidirectional pyrophosphorolysis-activated PCR (Bi-PAP) and methylation-specific PCR (MSP) assays were developed to detect donor cfDNA and beta-cell specific unmethylated insulin DNA in plasma of individuals with type 1 diabetes who received IT. Under approved protocols at the City of Hope National Medical Center, blood samples from type 1 diabetic IT individuals (n=22) were collected before and after the procedure and analyzed using the Bi-PAP and MSP assays. The longitudinal relationships between the metabolic and immunologic parameters and the appearance of donor-specific cfDNA in circulation of individuals after IT were analyzed.

Results: All individuals that underwent IT showed donor-specific cfDNA in plasma (by both methods) on day one after the procedure. Donor-specific cfDNA decreased gradually and was no longer detected in the plasma by day 18 post-IT. Insulin independence and less variation in blood glucose levels after IT was associated with minimal to no plasma donor cfDNA during the study period. In contrast, individuals that did not achieve insulin independence, had wide swings in blood glucose, or that had immune activation after IT were found to have increases in donor cfDNA.

Conclusion: Donor islet cfDNA persisted in individuals with poorer outcomes after IT. These findings suggest that donor cfDNA may be markers of islet injury after allo-transplantation. It remains to be seen if donor cfDNA levels provide more insights sooner than other techniques currently employed to monitor islet health after transplantation.

Disclosure

M.I. Husseiny: None. J. Cobb: None. C. Orr: None. J. Hacker-Stratton: None. E. Forouhar: None. M.A. El-Shahawy: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.
1507-P: Mixed-Meal Tolerance Test (MMTT) C-Peptide and BETA-2 Score Predict Underlying ß-Cell Secretory Capacity following Islet Transplantation for Type 1 Diabetes (T1D)
Authors: FLATT ANNELIESE , MATUS AUSTIN M. , GALLOP ROBERT J. , MARKMANN EILEEN M. , DALTON-BAKES CORNELIA V. , PELECKIS AMY , LIU CHENGYANG , NAJI ALI , RICKELS MICHAEL R.
Published: June 2024

Introduction and Objective: Assessment of β-cell secretory capacity by glucose-potentiation of arginine-induced insulin secretion (AIRpot) provides a gold-standard measure of functional β-cell mass post-islet transplantation. However, glucose-potentiated arginine (GPA) testing procedures are intensive and not feasible for routine islet graft monitoring. We examined the association between simple measures of islet graft β-cell function (MMTT C-peptide and BETA-2 score) and β-cell secretory capacity (AIRpot) in a longitudinal cohort.

Methods: Individuals with T1D complicated by problematic hypoglycemia underwent intrahepatic allogeneic islet transplantation under the Clinical Islet Transplantation 07 (CIT07) protocol between 2008 - 2012. MMTT and GPA procedures were completed on adjacent days at 2.5 months and yearly up to 7 years post-transplant. Relationships between measures were assessed by repeated-measures correlation analysis.

Results: 11 individuals (mean±SE age: 45±3 years; T1D duration: 28±4 years; and BMI: 25±1 kg/m2) received 694,895±48,498 islet equivalents over one (n=7) or two (n=4) transplants. 63 paired procedures in individuals with sustained islet graft function were assessed, representing an average of 5.73 repeated measures per participant. MMTT C-peptide correlated moderately with AIRpot at 60-min (r2=.16; P<0.01), 90-min (r2=.24; P<0.001) and at peak (r2=.22; P<0.001). Assessment of C-peptide/glucose ratio improved the relationship at 60-min (r2=.20; P<0.001). BETA-2 score was a better predictor of AIRpot (r2=.23; P<0.001) than fasting C-peptide/glucose (r2=.14; P<0.01).

Conclusion: MMTT C-peptide and BETA-2 score predict underlying β-cell secretory capacity however with only moderate effect sizes. The BETA-2 score holds additional value as a fasting measure that can inform changes in β-cell secretory capacity.

Disclosure

A. Flatt: None. A.M. Matus: None. R.J. Gallop: None. E.M. Markmann: None. C.V. Dalton-Bakes: None. A. Peleckis: None. C. Liu: None. A. Naji: None. M.R. Rickels: Consultant; Vertex Pharmaceuticals Incorporated, Sernova, Corp. Research Support; Dompé.

Funding

National Institutes of Health Public Health Services Research Grants (R01 DK091331; U01 DK070430; UL1 TR000003; UL1 TR001878; and P30 DK19525)