bluuebunny/crossref_metadata_2025_split huggingface dataset:
1476-P: Genetic Relationships between Puberty Onset and Type 2 Diabetes
Authors: RAMIREZ-LUZURIAGA MARIA J. , KOBES SAYUKO , WEDEKIND LAUREN E. , HSUEH WEN-CHI , BAIER LESLIE , HANSON ROBERT L. 
Published: June 2023

Early puberty onset is a risk factor for type 2 diabetes (T2D). In this study we aimed to determine whether these phenotypes are associated via genetic variation that contributes to both T2D and puberty onset. We, thus, investigated the associations of a polygenic score (PS) for T2D and a PS for age of menarche (AAM) with parameters of adolescent growth and T2D status in an Indigenous population from the Southwestern US with a high T2D prevalence. Genotypic and clinical data were obtained from a longitudinal study. Two key parameters of the adolescent growth spurt, including age at take-off (ATO) and age at peak velocity (APV), were derived from the Preece-Baines growth model, a parametric growth curve for longitudinal height data. PSs were constructed using imputed genotypes, where variants for the T2D-PS (n=289) and the AAM-PS (n= 275) were selected from genome-wide significant variants in European meta-analyses (DIAGRAM Consortium and Reprogen Consortium, respectively). Associations between PS and T2D status (N=7659) were adjusted for age, sex, birth year and the first 5 genetic PCs. Associations with ATO and APV (N=787) were adjusted for birth year, sex, maternal diabetes and the first 5 genetic principal components (PCs). Associations were calculated using linear mixed models, accounting for genetic relationships. The T2D-PS had a significant, positive association with T2D (OR=1.47 per SD [95% CI 1.38, 1.57]; p=4.05×10−30). We found no association of the T2D-PS with ATO (p=0.11) nor APV (p=0.20). Conversely, genetically-predicted later puberty onset (AAM-PS) had a significant, inverse association with T2D (OR=0.92 per SD [95% CI 0.86, 0.98]; p=0.0194). The AAM-PS also associated with ATO (r=0.11, p=0.0013) and APV (r=0.13, p=1.8×10−04). Our results suggest that many variants that associate with AAM and T2D in large European cohorts also affect these traits in this Indigenous population. They also support the notion that variants that associate with early puberty onset also confer susceptibility to T2D.

Disclosure
M.J.Ramirez-luzuriaga: None. S.Kobes: None. L.E.Wedekind: None. W.Hsueh: None. L.Baier: None. R.L.Hanson: None.
1478-P: Polygenic Risk Score Predicts Incident Cardiovascular Disease in People with Diabetes at Borderline or Intermediate 10-Year ASCVD Risk
Authors: CHOI JAEWON , LEE HYUNSUK , LEE JUNESEONG S. , RHEE TAE-MIN , SOO PARK KYONG , HEON KWAK SOO 
Published: June 2023

People with type 2 diabetes (T2D) and 10-year atherosclerotic cardiovascular disease (ASCVD) of 20% or higher are recommended for intense lipid management. However, the role of genetic predisposition to ASCVD on determining the intensity of statin therapy in patients with T2D at borderline (5-7.5%) or intermediate (7.5-20%) risk for incident ASCVD is unclear. We aimed to investigate the utility of polygenic risk score (PRS) in predicting incident ASCVD in people with T2D at borderline and intermediate risk from UK Biobank. We calculated 10-year ASCVD risk using pooled cohort risk equations and PRS for coronary artery disease by Bayesian regression (PRS-CS) in participants of UK Biobank. We performed time-to-event analysis for incident ASCVD and assessed improvement of C-statistic when PRS was added to 10-year ASCVD risk. In addition, risk of ASCVD was estimated for those who were in the top 20 percentile of PRS compared to the remainders. During a median follow-up of 9 years, the incidence of ASCVD in people with T2D was 5.9% and 8.6% in borderline (N=2511) and intermediate (N=8292) group, respectively. The normalized mean PRS for those who developed ASCVD was higher in each group: 0.20±0.96 vs −0.02±1.01 in borderline and 0.20±1.02 vs −0.02±0.99 in intermediate group (all P&lt;0.01). Adding PRS to 10-year ASCVD risk improved the C statistic from 0.51 (95% CI 0.46-0.55) to 0.57 (0.52-0.62) in borderline and from 0.55 (0.53-0.57) to 0.58 (0.56-0.60) in intermediate group. Standardized PRS was associated with incident ASCVD in each group: HR 1.22 (CI 1.05-1.45, P&lt;0.05) and 1.24 (1.15-1.34, P&lt;0.001). Moreover, those who were in the top 20 percentile had increased risk of ASCVD: HR 1.63 (1.14-2.33, P&lt;0.01) and 1.43 (1.21-1.70, P&lt;0.001), respectively. In conclusion, genetic information in people with T2D at borderline and intermediate ASCVD risk could be used to identify those who are at higher risk for incident ASCVD and require high intensity statin treatment.

Disclosure
J.Choi: None. H.Lee: None. J.S.Lee: None. T.Rhee: None. K.Park: None. S.Kwak: None.

Funding
National Human Genome Research Institute (FAIN U01HG011723)
1481-P: Islet Cell Autoantibody Formation and Its Effect on Insulin Requirement after Total Pancreatectomy with Islet Autotransplantation (TPIAT)
Authors: LAVIK ANDREW R. , LOWE COLLEEN M.O. , TELLEZ SIOBHAN E. , HORNUNG LINDSEY , HEINZMAN CHRISTIE , NATHAN JAIMIE D. , ABU-EL-HAIJA MAISAM , ELDER DEBORAH A. 
Published: June 2023

Introduction: Long term insulin requirements following TPIAT range from insulin independence to full (high) dose daily insulin (&gt;0.5 units/kg/day). Markers of islet cell autoimmunity are used in children to predict type 1 diabetes risk. However, no studies have explored whether an association exists between islet cell autoimmunity and insulin requirement following TPIAT in children. We hypothesized that children with islet cell autoantibody formation were more likely to have a persistent insulin requirement following TPIAT.
Methods: All children who underwent TPIAT between 2015 and 2021 at our institution were eligible for inclusion. Islet cell autoimmunity was defined as positive islet cell autoantibody screen for one or more of the following types of autoantibodies: Glutamic Acid Decarboxylase (GAD), Islet Antigen-2 (IA-2), Insulin (IAA), or Zinc Transporter 8 (ZnT8). Patients were screened prior to TPIAT and every six months following TPIAT for up to three years. In all, 73 patients were included in the analysis. Total daily insulin dose was determined for each patient at each time interval. Chi-square or Fisher’s exact tests were used to compare proportions.
Results: Of patients with 12-month data (n=38), 47% of islet cell autoantibody negative patients were off insulin vs 26% of antibody positive patients (p=0.19). This trend was significant at 18, 24, and 36 months after TPIAT. At 18 months, 90% (9/10) of antibody negative patients were off insulin vs 29% (4/14) of antibody positive patients (p=0.005). At 24 months, 73% (8/11) of antibody negative patients were off insulin vs 23% (3/13) of antibody positive patients (p=0.04). At 36 months, 100% (8/8) of antibody negative patients were off insulin compared to 0% (0/9) of antibody positive patients (p&lt;0.0001).
Conclusions: The presence of pancreatic islet cell antibodies was associated with persistent insulin requirement after TPIAT.

Disclosure
A.R.Lavik: None. C.M.O.Lowe: None. S.E.Tellez: None. L.Hornung: None. C.Heinzman: None. J.D.Nathan: None. M.Abu-el-haija: None. D.A.Elder: None.
1486-P: Effects of the COVID-19 Booster Vaccine on Glycemia and Insulin Resistance in People with Type 1 Diabetes—A Prospective Pilot Study
Authors: ZILBERMINT MIHAIL , MOTEVALLI MAHSA , BATTY KRISTINE , VENNER-WALCOTT JEMILA , EDWARDS ALEXIS , BURLEY TANYA , JACKSON KEITH , AKHTAR MAHRUKH , DEMIDOWICH ANDREW 
Published: June 2023

Background: Inflammation is well-known to worsen glycemia in people with type 1 diabetes (T1D). COVID-19 vaccines are vital for protection against SARS-CoV-2 infection, but by necessity trigger an acute immune response. Case reports have described hyperglycemic crises shortly after a booster dose. However, effects of COVID-19 vaccines on glycemic control in T1D is poorly understood.
Methods: This was a prospective cohort study of adults with T1D receiving a COVID-19 booster dose. At the baseline visit a blinded Dexcom G6 Pro CGM was placed, subjects received COVID-19 booster vaccine 3-4 days later, and returned 6 days post-vaccination to have the CGM removed. Primary outcome was change in mean daily glucose level from baseline. Secondary outcomes included total daily insulin dose (TDI), total daily insulin resistance (TDIR = mean glucose * TDI), and time in range (TIR = %glucose readings between 70-180mg/dL). Data were transformed as necessary to maintain normality.
Results: We enrolled 20 adults with T1D; one subject was excluded for nonadherence with study procedures. Baseline characteristics included (mean±SD) age: 48.9±19.4y, sex: 68.4%F, BMI: 29.6±6.2kg/m2, A1c: 7.0±1.0%. 42% received a Moderna and 58% Pfizer-BioNTech booster. Mean glucose on Day#2 post-vaccination was significantly greater than baseline (165.1±27.4 vs 154.5±30.2 mg/dL, p=0.04), as was TDIR (7970±4113 vs 7036±3999; p=0.02). No other days had significant differences in glycemic metrics as compared to baseline. There were no differences in any outcome metrics between booster vaccine manufacturers.
Conclusions: These results suggest that adults with T1D may experience transient glycemic elevations after receiving a COVID-19 booster. Clinicians may need to warn people with T1D to be more vigilant with glucose testing and insulin dosing temporarily after vaccination. Larger studies are warranted to corroborate these findings.

Disclosure
M.Zilbermint: Consultant; EMD Serono, Other Relationship; American Association of Clinical Endocrinologists. M.Motevalli: None. K.Batty: None. J.Venner-walcott: None. A.Edwards: None. T.Burley: None. K.Jackson: None. M.Akhtar: None. A.Demidowich: Research Support; Dexcom, Inc.

Funding
Dexcom, Inc. (IIS-2021-136)
1493-P: Immune-Mediated Diabetes Mellitus—A Rare Complication of Nivolumab Therapy
Authors: IQBAL SHUMAILA M. , HOUSTON CAROLINE 
Published: June 2023

Background: Immune mediated diabetes mellitus (DM) is a rare complication of immune checkpoint inhibitor (ICI) therapy, with an incidence of less than 1%. We present a case of immune-mediated DM with nivolumab therapy presenting as diabetic ketoacidosis (DKA).
Case: A 74-year-old Caucasian male with no history of DM or autoimmune disease was diagnosed with stage III metastatic melanoma and started on treatment with nivolumab, an ICI. He tolerated treatment well and had no evidence of endocrine dysfunction on routine laboratory monitoring. Shortly after completing his 14th cycle of nivolumab therapy, he presented to the emergency department with a one-week history of fatigue, poor appetite, polydipsia, and polyuria. He was found to have DKA with serum blood glucose 446 mg/dL, anion gap 20 mEq/L, serum bicarbonate 14 mEq/L, arterial pH 7.23, and 4+ urine ketones. His hemoglobin A1c was 7.3%, increased from 5.4% one year earlier. He was treated with intravenous insulin then transitioned to basal-bolus subcutaneous insulin therapy, which was continued at discharge. Evaluation in the outpatient setting revealed no measurable GAD65 antibodies or anti-insulin antibodies, but his serum c-peptide was found to be &lt;0.10 ng/mL with corresponding serum blood glucose level 214 mg/dl. This supported a diagnosis of endocrine pancreatic insufficiency, in his case likely immune mediated due to nivolumab therapy. He completed an additional 6 cycles of nivolumab with no further complications. Meanwhile his DM became well-controlled with subcutaneous insulin injections, and he was eventually transitioned to insulin pump therapy.
Discussion: ICIs such as nivolumab are known to cause multiple autoimmune complications that can appear at any point during treatment. The underlying mechanisms of beta cell immunotoxicity are incompletely understood, but progression to insulin-dependency appears to be rapid. It is important to recognize new or worsening DM early to avoid life-threatening complications such as DKA.

Disclosure
S.M.Iqbal: None. C.Houston: None.
1495-P: Bionic Pancreas-3D Bioprinting of Pancreatic Tissue Petals—Results of Transplantation in Large Animals
Authors: KLAK MARTA , BERMAN ANDRZEJ , JANOWSKA OLIWIA , DOMANSKI SYLWESTER , SZKOPEK DOMINIKA , ROSZKOWICZ-OSTROWSKA KATARZYNA I. , KONDEJ AGATA , WOLINSKI JAROSLAW , WSZOLA MICHAL 
Published: June 2023

The first milestone of a new therapy for the treatment of T1D is the development of 3D bioprinted petals consisting of: pancreatic islets and biomaterials. The aim of the study was to demonstrate the functionality of pancreatic islets in in vivo studies on large animals.
Material and Methods: Domestic pigs were the research model. The animals were divided into 4 groups:(1)healthy pigs (Control; n=3);(2) animals with T1D after pancreatectomy, treated with insulin (T1D;n=3);(3) animals after pancreatectomy and autotransplantation of pancreatic islets to the liver (LIVER; n=3);(4) animals with T1D after pancreatectomy, which were autotransplanted with bionic petals (3D-PETALS; n=3). The effectiveness of the transplantation (TX) was assessed by the concentration of glucose, insulin intake and C-peptide. The observation lasted 1 month.
Results: The results showed that in the LIVER group, insulin intake within 3 weeks decreased by 71% compared to the demand before TX. Whereas 1 month after TX, the demand was lower by 62%. The 3D-PETALS group showed that the insulin intake in 3 weeks after TX decreased by 65%, and within a month decreased by 84%. In the 4th week after TX, the insulin intake average in the T1D group was 8.17U, while in the LIVER group=2.44U and in the 3D-PETALS group=1.06U. Islet TX significantly reduced insulin intake (T1D vs LIVER; p=0.0001 and T1D vs 3D-PETALS; p&lt;0.0001). Glucose measurement showed significant changes. After 1 month of follow-up, glucose levels were significantly lower in the LIVER vs T1D (265.8mg% vs 310.2mg%; p&lt;0.0001) and 3D-PETALS & T1D (198.3mg% vs 310.2mg%; p=0.0354). Most importantly, glycemic levels were also significantly lower between the LIVER & 3D PETALS groups (265.8mg% vs 198.3mg%; p=0.0021). The concentration of C-peptide during the study was 0.14ng/ml.
Conclusion: Bioprinted petals with dECM-based bioink significantly reduces diabetic parameters. Thus, it seems to be an effective therapy for people with T1D.

Disclosure
M.Klak: Employee; Polbionica Sp. z o.o., Stock/Shareholder; Polbionica Sp. z o.o. A.Berman: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd. O.Janowska: Employee; POLBIONICA Sp. z o.o. S.Domanski: Employee; Polbionica. D.Szkopek: None. K.I.Roszkowicz-ostrowska: None. A.Kondej: None. J.Wolinski: None. M.Wszola: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd.
1501-P: Deletion of miR-494 Induces Adipocyte Browning and Slows Aging in Mice
Authors: SUGAWARA LUCIA , MORINO KATSUTARO , IWASAKI HIROTAKA , IDA SHOGO , YANAGIMACHI TSUYOSHI , LEMECHA MENGISTU , MAEGAWA HIROSHI , FUJITA YUKIHIRO , KUME SHINJI 
Published: June 2023

Adipocyte browning is a potent therapeutic strategy for obesity and metabolic disorders. We previously reported that miR-494 served as a negative regulator of mitochondrial biogenesis during browning in cultured adipocytes. However, the in vivo evidence has not been provided. In this study, we examined the role of miR-494 in adipocyte browning and aging using miR-494 knockout (KO) mice.
KO mice were generated using CRISPR/Cas9 system. KO mice had equivalent energy expenditure, physical activity, food intake and body weight compared to wild-type (WT) mice; had lower resting respiratory quotient (0.95±0.006 vs 0.91±0.004), less visceral fat (16.3±1.08 vs 13.4±0.96 g/kg body weight) and 3.7-fold increased expression of Ucp1 in subcutaneous fat. In addition, KO mice showed cold tolerance during 3 hours exposure to 4ºC and increased oxygen consumption than WT mice after administration of a β3 agonist in thermoneutral condition, indicating an increase in non-shivering thermogenesis. In adipose tissues of KO mice, increased expression of Pgc-1α, a target gene of miR-494, and tendency to increase in mitochondrial DNA were observed. Primary adipocytes derived from KO mice showed enhanced mitochondrial respiration driven by fatty acids as determined by extracellular flux analysis. Finally, KO mice showed an extended median lifespan 29% relative to WT mice (from 113.7 to 146.7 weeks). Aged KO mice (≥ 2 years old) showed reduced age-related changes, such as hair graying and low physical activity.
In conclusion, deletion of miR-494 demonstrated increased adipocyte browning and survival advantage in mice. Although there are numerous studies that focused on promoting adipocyte browning, its long-term effect has not been well evaluated. Thus, our data showing the association among miR-494, adipocyte browning and longevity provide a novel insight into adipocyte biology and aging study. The gene sequence of miR-494 and its binding site to Pgc-1α are conserved from mice to humans; it is expected to be applied to human research.

Disclosure
L.Sugawara: None. K.Morino: Research Support; AstraZeneca, Astellas Pharma Inc., Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co., Ltd. H.Iwasaki: None. S.Ida: None. T.Yanagimachi: None. M.Lemecha: None. H.Maegawa: None. Y.Fujita: Research Support; Terumo Corporation, Boehringer Ingelheim Japan, Inc., Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd. S.Kume: Research Support; Boehringer Ingelheim International GmbH, Japan Society for the Promotion of Science.

Funding
Grants-in-Aid for Scientific Research (22K08650)
1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo
Authors: HUBBARD BRANDON T. , GASPAR RAFAEL C. , ZHANG DONGYAN , KAHN MARIO , NASIRI ALI , SHULMAN GERALD I. 
Published: June 2023

Recently, our group demonstrated that 3-week high fat diet feeding (HFD) impairs insulin signaling in the renal cortex at the level of the insulin receptor kinase (IRK). Specifically, IRKY1162 and AKTS473 phosphorylation were reduced by ~50% during hyperinsulinemic-euglycemic clamp (HEC); however, it is unknown how renal cortical insulin resistance (IR) may affect gluconeogenic (GNG) and oxidative metabolism. To address this, here we measure renal cortical GNG fluxes in vivo using Q-Flux. In regular chow (RC) fed mice, hyperinsulinemia significantly suppressed mitochondrial pyruvate carboxylase (PC), as PC flux relative to α-ketoglutarate dehydrogenase flux (VPC/VOGDH) was 1.25 under basal conditions, but decreased by ~50%, to 0.57 during HEC. Similarly, PEPCK flux relative OGDH flux (VPEPCK/VOGDH) was reduced by ~60% during HEC. In contrast, insulin failed to suppress both PC and PEPCK fluxes with HFD. Using a [13C6]glucose tracer, we also find insulin-stimulated mitochondrial pyruvate oxidation to be impaired by ~30% with HFD. Mechanistically, we previously found HFD led to a 2-fold increase in plasma membrane (PM) sn-1,2-diacylglycerol (DAG) and a 4-fold increase in Protein Kinase Cε (PKCε) translocation, suggesting renal cortical IR may be mediated by an sn-1,2-DAG-PKCε-IRK axis. We further interrogated this possibility here by assessing inhibitory phosphorylation at IRKT1150, the key target of PKCε, finding a 42% increase with HFD. In addition, IRKT1150A knockin mice, whose IRK cannot be phosphorylated by PKCε, were protected from HFD-induced signaling and pyruvate oxidation defects.
Conclusion: HFD inhibits renal cortical insulin signaling at the level of the IRK, which is associated with perturbed mitochondrial GNG and oxidative metabolism. IRKT1150A mice are protected from HFD-induced defects, indicating a PM sn-1,2-DAG-PKCε-pIRKT1150 mechanism for lipid-induced renal cortical IR.

Disclosure
B.T.Hubbard: None. R.C.Gaspar: None. D.Zhang: None. M.Kahn: None. A.Nasiri: Other Relationship; Medtronic. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc.
1517-P: Interactive Calculator to Estimate Insulin Sensitivity (IS) in Type 1 Diabetes
Authors: JANUSZEWSKI ANDRZEJ S. , NIEDZWIECKI PAWEL , SACHITHANANDAN NIRUPA , WARD GLENN M. , O'NEAL DAVID N. , ZOZULINSKA-ZIOLKIEWICZ DOROTA , URUSKA ALEKSANDRA , JENKINS ALICIA 
Published: June 2023

Introduction: Euglycemic hyperinsulinemic clamps, although costly, time- and labor-intensive, are “gold standard” in measuring insulin sensitivity (IS). Several formulae to estimate IS in people with Type 1 diabetes (T1D) exist (DOI: 10.1007/978-3-030-81303-1_18-1), using various routine and research assays, and with wide ranging IS results.
Aim: To develop a free online tool to estimate IS using different metrics and existent formulae and compare estimated IS with measured glucose disposal rate (GDR) from 104 clamp studies.
Methods: We prepared an online tool for calculating IS using 17 formulae. Suitable formula(e) are suggested based on available (clinical and research) data. We also compare calculated IS with measured IS (GDR) from clamp studies in 104 adults with T1D (mean±SD) age 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%, 33 with microvascular complications). Logistic regression was used to infer probability of calculated IS being below GDR=4.45 mg/kg/min or above GDR=6.5 mg/kg/min, which represent respectively the median and 75th percentile of measured GDR values.
Results: A calculator is available at www.bit.ly/estimated-GDR and an example result in the Figure 1. Estimated IS varied widely, but results interpretation is generally consistent.
Conclusion: We developed an interactive tool to estimate IS in T1D for clinical and research use.

Disclosure
A.S.Januszewski: None. P.Niedzwiecki: None. N.Sachithanandan: None. G.M.Ward: None. D.N.O'neal: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Abbott, Lilly, Lilly, Novo Nordisk, Medtronic, Speaker's Bureau; Abbott, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Boehringer-Ingelheim, AstraZeneca. A.Uruska: Other Relationship; Lilly, Boehringer-Ingelheim, AstraZeneca, Ascensia Diabetes Care, Sanofi. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health.