bluuebunny/crossref_metadata_2025_split huggingface dataset:
1552-P: Homeostasis Model Assessment of ß-Cell Function for Diagnosis of Insulinoma
Authors: BÓDIS KÁLMÁN , SCHÖN MARTIN , DAUBEN LAURA , WILKER MIRIAM , STRASSBURGER KLAUS , BURKART VOLKER , RODEN MICHAEL , MÜSSIG KARSTEN 
Published: June 2023

Insulinoma is characterized by uncontrolled hypersecretion of insulin and is currently diagnosed by the 72-h fasting test. Guidelines by Endocrine Society (ES), European (ENETS) and North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria at the end of the fasting test, but parameters assessing ß-cell function noninvasively are not included. This study tested whether homeostasis model assessment of ß-cell function (HOMA-B) as a surrogate for insulin secretion at the end of the fasting test, provide comparable sensitivity and specificity for diagnosis of insulinoma and thus might help to improve current diagnostic guidelines. In 104 persons with suspected insulinoma, 72-h fasting tests were performed with frequent assessment of glucose, insulin, and C-peptide in venous blood. HOMA-B was calculated at time of lowest glucose concentration at the end of fasting test. Follow-up data of patients were collected to exclude false-negative diagnosis of insulinoma. The HOMA-B at the end of the fasting test was &gt;6.5-fold higher in persons with than without insulinoma (insulin and C-peptide, both p&lt;0.001). ENETS/NANETS and ES criteria (insulin and C-peptide) reached a diagnostic sensitivity of ≤0.83 (≤0.61-0.95) and ≤0.96 (≤0.78-1.00) as well as specificity of ≤1.00 (≤0.96-1.00) and ≤0.85 (≤0.76-0.92). The HOMA-B provided high diagnostic sensitivity (cut-off using insulin &gt;253 a.u. and C-peptide &gt;270 a.u.; both 0.96, 0.78-1.00) and specificity (≥0.96, ≥0.89-0.99) at the end of the fasting test for diagnosis of insulinoma (n=23). Using both insulin and C-peptide for HOMA-B, sensitivity even tended to be higher than that of ENETS/NANETS using insulin only (p=0.063) and specificity was higher than that of ES using both insulin and C-peptide (p≤0.002). HOMA-B with defined cut-offs using insulin and C-peptide at the end of the fasting test showed excellent diagnostic sensitivity and specificity and might represent an alternative and precise tool to diagnose insulinoma.

Disclosure
K.Bódis: None. M.Schön: None. L.Dauben: None. M.Wilker: None. K.Strassburger: None. V.Burkart: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. K.Müssig: None.
1576-P: Hepatic Ketogenesis Insufficiency Improves Glycemia in Type 1 Diabetes
Authors: GOPAL REDDY MOOLI RAJA , RAMAKRISHNAN SADEESH KUMAR 
Published: June 2023

Type 1 diabetes (T1D) is a chronic autoimmune disease and is increasing by approximately 2-3% per year. One characteristic feature of T1D is the increased production of ketone bodies. However, the role of ketone bodies and/or ketogenesis in the pathogenesis of T1D remains unknown. We generated mice with conditional ketogenic insufficiency by knocking out the ketogenic enzyme 3-hydroxy methylglutaryl CoA synthase 2 (Hmgcs2) in the liver. Six to eight-week-old Hmgcs2ΔLiv and Hmgcs2F/F(littermates that do not express Alb-Cre) were injected with tamoxifen @200 mg/kg body weight. One week later, Hmgcs2ΔLiv and Hmgcs2F/F mice were injected with strep tozotocin (STZ; 50mg/kg B.W for 5 consecutive days) to induce hyperglycemia. We found that Hmgcs2ΔLiv mice had significantly lower blood glucose than their littermate controls. The improvement in glycemia is not due to a change in food intake or body weight. Moreover, no difference in serum insulin levels and Akt phosphorylation in the liver suggested that ketogenic insufficiency does not improve glycemia in T1D via the insulin signaling pathway. When we assessed glucose production by pyruvate tolerance test, Hmgcs2ΔLiv mice showed lower glucose levels. Further, the mRNA and protein levels of gluconeogenic genes such as G6PCand PCK1 were significantly decreased in the livers of Hmgcs2ΔLivmice. We also observed a significant reduction in PGC-1α, the transcriptional regulator of gluconeogenesis, suggesting that ketogenic insufficiency in T1D reduces hepatic gluconeogenesis. The metabolism of ketone bodies in peripheral tissues impairs their ability to utilize glucose. Our indirect calorimetry analysis showed a trend toward increased respiratory exchange ratio (RER) in STZ-treated Hmgcs2ΔLiv mice, suggesting that ketogenic insufficiency increases carbohydrate metabolism in T1D. Our data show that ketogenesis may contribute to hyperglycemia in T1D by regulating hepatic glucose production and peripheral glucose utilization.

Disclosure
R.Mooli: None. S.Ramakrishnan: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK110537)
162-OR: Diabetes Stigma and Use of Diabetes Technologies among U.S. Adults Living with Type 1 Diabetes
Authors: GARZA MATTHEW , SHOGER ERIK , HOLMES-TRUSCOTT ELIZABETH , JOINER KEVIN , ADDALA ANANTA , NARANJO DIANA , BEVERLY ELIZABETH A. , SPEIGHT JANE 
Published: June 2023

Nearly 80% of adults living with diabetes report experiences of diabetes stigma. We aimed to examine associations between diabetes stigma and the use of diabetes technologies among adults with type 1 diabetes (T1D). In August 2022, 594 adults with T1D (mean age: 55±15 years; duration T1D: 29±17 years; 71% women) from the dQ&A US Patient Panel completed an online survey. Questions included the Type 1 Diabetes Stigma Assessment Scale (DSAS-1) and diabetes and demographic characteristics. DSAS-1 Total and subscale (Treated Differently, Blame and Judgment, Identity Concerns) scores were compared by device use (independent samples t-test). Individuals who did not use diabetes technologies reported greater stigma (Total; Treated Differently; Identity Concerns) but did not differ from those using technologies on Blame and Judgment (Table). The relationship between diabetes stigma and technology use is a novel finding, warranting further investigation with larger, more heterogeneous samples to determine whether diabetes stigma may be a barrier to device use or whether it is mitigated by device use.

Disclosure
M.Garza: Other Relationship; Sanofi. E.Shoger: Other Relationship; Dexcom, Inc., Abbott Diabetes, Tandem Diabetes Care, Inc., Beta Bionics, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. E.Holmes-truscott: Research Support; Sanofi, AstraZeneca. K.Joiner: None. A.Addala: None. D.Naranjo: None. E.A.Beverly: None. J.Speight: Research Support; Sanofi, Medtronic, Abbott Diabetes, Lilly, Novo Nordisk A/S, Speaker's Bureau; Sanofi.
1681-P: RNA Binding Protein HuR Is Essential for Adaptive Thermogenesis
Authors: PARK KUN-YOUNG , CHOI SUNGWOO , MYOUNG SUH JAE 
Published: June 2023

Brown adipose tissue (BAT) plays a key role in the regulated production of heat in response to cold temperatures, known as adaptive thermogenesis. While the transcriptional mechanisms underlying the thermogenic function of BAT has been widely studied, the role of posttranscriptional processes in BAT thermogenesis remain largely unexplored. RNA binding proteins are central to the control multiple aspects of posttranscriptional RNA biology. Here, we identify brown fat HuR as a critical regulator of adaptive thermogenesis. Mice with adipocyte-specific HuR deletion (AKO) were unable to increase energy expenditure in response to a cold challenge, resulting in marked hypothermia. HuR AKO mice housed at thermoneutrality also failed to increase energy expenditure upon beta-3 adrenoreceptor agonist treatment, indicating a defect in thermogenic BAT. HuR-deleted brown adipocytes displayed impaired mitochondrial respiration under β-adrenergic stimulation. RNA sequencing data revealed that loss of HuR led to downregulation of genes associated with TCA cycle, β-oxidation, and mTORC1 signaling in BAT. Our findings reveal an essential role for RNA binding protein HuR in thermogenic programs of the brown adipocyte and highlight the importance of posttranscriptional processes in BAT thermogenesis.

Disclosure
K.Park: None. S.Choi: None. J.Suh: None.
17-LB: Diabetic Nephropathy Prediction with Machine-Learning Models for Patients with Type 1 Diabetes
Authors: SRIPADA SRISHTI , SRIPADA SHREYA , BELAPURKAR SONALI 
Published: June 2023

Cardiovascular disease (CVD) is the leading cause of global mortality in type 1 Diabetes (T1D). This risk remains largely under-managed, leading to a future significant CVD burden. Diabetic nephropathy (DN) is considered a risk factor for CVD and overall mortality in patients with T1D. Identifying risk factors that contribute to the development and progression of DN is therefore important in T1D. Early identification of DN may support earlier intervention for patients with T1D and in turn, reduce future risk for CVD. Using the T1D Exchange Registry database of individuals with T1D in the USA, we sought to develop a machine-learning algorithm to predict patients with DN. With performance metrics of F1-score = 0.67, AUC = 0.78, in our Random Forest model, and F1-score= 0.66, AUC = 0.77 in our Logistics Regression model demonstrates the potential to assist in mitigating DN development and progression.

Disclosure
S. Sripada: None. S. Sripada: None. S. Belapurkar: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. Other Relationship; T1D Exchange. Research Support; Medtronic.
1713-P: Dietary Manganese (Mn) Intake Is Independently Associated with a Lower BMI in Younger Japanese with Type 2 Diabetes Mellitus (T2DM)
Authors: MON KHIN LAY , FUJIHARA KAZUYA , HATTA MARIKO , TAKEDA YASUNAGA , MORIKAWA SAKIKO Y. , HORIKAWA CHIKA , KATO NORIKO , KATO MITSUTOSHI , MAEGAWA HIROSHI , SONE HIROHITO ,   JDDM STUDY GROUP
Published: June 2023

We analyzed the association between dietary Mn intake and obesity measured by BMI after adjustment for intake of nutrients and food groups in people with T2DM in Japan. Participants were 1567 people, 63% male, aged 30 to 89 y who were in the Japan Diabetes Clinical Data Management Study Group (JDDM), one of the largest cohorts of Japanese with diabetes. Intake of food groups was determined by a validated self-administered food frequency questionnaire based on food groups. Obesity was defined as BMI ≥25 kg/m2. Multivariate logistic regression analysis assessed the relationship between quartiles of dietary Mn intake and obesity stratified by age. Participants aged 30 to 89 y were grouped according to the following quartiles for age: 30-54 y, 55-63 y, 64-71 y, and 72-89 y. Compared to the lowest quartile (Q1) for Mn, a significant negative association between Mn and BMI was found in males for all quartiles of Mn (OR [95%CI] of Q2= 0.643 [0.424 - 0.973], Q3= 0.607 [0.374 - 0.986], Q4= 0.398 [0.218 - 0.728], p trend = 0.028) with adjustment for characteristics such as age, sex, current smoking, drinking, insulin, oral hypoglycemic agents treatment, activity, energy intake and macronutrients intake. However, statistical significance disappeared after adding total fiber as a covariate. Compared to the lowest quartile for Mn, the highest quartile of Mn was inversely associated with BMI in the younger age group (30-54 y [OR= 0.296 [0.088 - 0.996]]) even after total fiber adjustment. Multivariate analysis of food groups (rice, vegetables, soy products) that were highly correlated with Mn as covariates showed that the relationships between Mn intake and obesity were maintained (p trend for rice, vegetables, soy = &lt;0.001, 0.187, 0.010) in all participants. In summary, higher dietary Mn intake was independently associated with a lower BMI, especially in the younger group and males. Future prospective or intervention studies are expected to confirm this result.

Disclosure
L.Khin: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Jddm study group: n/a. K.Fujihara: None. M.Hatta: None. Y.Takeda: None. S.Y.Morikawa: None. C.Horikawa: None. N.Kato: None. M.Kato: None. H.Maegawa: None.
173-OR: CGM-Measured Differences in Pregnancies With vs. Without Gestational Diabetes (GDM) and Adverse Perinatal Outcomes (APO)
Authors: DURNWALD CELESTE , BECK ROY , LI ZOEY , NORTON ELIZABETH , BERGENSTAL RICHARD M. , BANFIELD MATTHEW , JOHNSON MARY L. , DUNNIGAN SEAN , SIBAYAN JUDY , CALHOUN PETER , CARLSON ANDERS L. 
Published: June 2023

An objective of the study was to characterize if continuous glucose monitor (CGM) glycemic patterns throughout pregnancy are indicative of gestational diabetes (GDM) and adverse pregnancy outcomes (APOs). A prospective observational cohort of 760 pregnant patients enrolled &lt;17 weeks with A1c &lt;6.5% wore a blinded CGM sequentially during pregnancy. Patients with ≥14 days of CGM data overall with ≥10 days in the 2nd trimester, oral glucose tolerance test (OGTT), and an APO assessment were included. The primary outcome was GDM diagnosis by abnormal OGTT. Large gestational age (LGA) birthweight &gt;90% and hypertensive disorder of pregnancy (HDP) were analyzed. Glycemic metrics using CGM between those with and without GDM and each APO were compared. Participants had a mean±SD of 112±42 days of CGM data. Prevalence of GDM, LGA, and HDP were 7%, 16%, and 27%. Mean glucose, glucose standard deviation, time &gt; 120 mg/dL and &gt; 140 mg/dL were significantly higher during the entire gestational period prior to OGTT (mean 27 ± 2 weeks) in those who developed GDM. TIR 63-120 mg/dL and 63-140 mg/dL were significantly lower in those who developed GDM (Table 1). Similar findings were noted for the diagnosis of LGA and HDP. CGM use during pregnancy revealed glycemic differences between those with vs without GDM, LGA, and HDP throughout gestation. Higher glucose levels during pregnancy are associated with these APOs.

Disclosure
C.Durnwald: None. P.Calhoun: None. A.L.Carlson: Advisory Panel; MannKind Corporation, Novo Nordisk, Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Insulet Corporation, UnitedHealth Group, Sanofi. R.Beck: Consultant; Eli Lilly and Company, Novo Nordisk, Diasome, Insulet Corporation, Research Support; Tandem Diabetes Care, Inc., Beta Bionics, Inc., Dexcom, Inc., Bigfoot Biomedical, Inc., Medtronic, Ascensia Diabetes Care, Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk. Z.Li: None. E.Norton: None. R.M.Bergenstal: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Hygieia, Onduo LLC, Sanofi, Vertex Pharmaceuticals Incorporated, Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, UnitedHealth Group. M.Banfield: None. M.L.Johnson: Research Support; Abbott, Lilly, Insulet Corporation, NIH - National Institutes of Health, Patient-Centered Outcomes Research Institute, Novo Nordisk, Tandem Diabetes Care, Inc., Medtronic, Hemsley Charitable Trust, Jaeb Center for Health Research. S.Dunnigan: None. J.Sibayan: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust; United Health Group
1732-P: Correlation of Cyclin D2 with Cell Proliferation in Human Pancreatic Beta Cells and Possible Regulation by CCND2-AS1
Authors: OSONOI SHO , SASAKI TAKANORI , TAKEUCHI YUKI , MIZUKAMI HIROKI 
Published: June 2023

Though Cyclin D2 (CCND2) has been considered to be essential for rodent beta cell proliferation, its expression in human beta cells is controversial. We reported CCND2 protein was abundantly expressed also in human perinatal beta cells at ADA 2019. This exclusive expression of CCND2 in the perinatal period would implicate a relationship with beta cell proliferation which is by far rare in human adults, while its regulation mechanism is unclear. GWAS studies identified rs76895963 in CCND2 locus as a genotype that reduced the susceptibility for type 2 diabetes by 50%. The SNP is also located in the sequence of CCND2-AS1, an anti-sense RNA. In this study, we explored the relationship between CCND2 and beta cell proliferation in humans, figuring out any possible regulations associated with CCND2-AS1. We obtained 49 pancreas samples from autopsies. Subjects were divided into 6 groups by age; fetus (F: gestational age 24 to 40 weeks), newborn (N: 0 days to1 month), infant (I: 2 to 12 months), toddler (T: 3 months to 4 years), child (C: 5 to 12 years), and adolescent (A: 13 to 19 years). Formalin-fixed paraffin-embedded sections were used for immunostaining and in situ hybridization analysis. Beta cell proliferation labeled with Ki67 was most abundant in N and rapidly decreased after T. Nuclear CCND2 expression was the highest in F followed by I and was almost not detected in C and A, showing a positive correlation with Ki67 though their peaks were different (p&lt;0.01). CCND2 mRNA was abundant in F and N but was also detectable in C and A. The correlation between CCND2 mRNA and protein was linear (p=0.0513). On the other hand, the expression of CCND2-AS1 was significantly correlated with CCND2 protein and Ki67 (p&lt;0.01 and &lt;0.05). Antisense RNAs are reported to show a variety of post-transcriptional regulations on their corresponding mRNA and protein. Our results suggest that CCND2-AS1 may positively regulate CCND2 expression and be a provisional therapeutic target for beta cell proliferation.

Disclosure
S.Osonoi: None. T.Sasaki: None. Y.Takeuchi: None. H.Mizukami: None.
1739-P: Ontogeny of Bihormonal Islet Cells within the Human Pancreas
Authors: HAHM JIWON , FERNANDEZ ANDRADE JUAN A. , ARANY EDITH , HILL DAVID J. 
Published: June 2023

Bi-hormonal islet endocrine cells have been proposed to represent an intermediate state during cellular trans-differentiation, enabling plasticity of islet beta-cells in response to metabolic stress. Beta-cell plasticity and regenerative capacity are thought to decrease with age. We investigated bi-hormonal islet endocrine cell populations present throughout the human lifespan between 11 days to 79 years of age. Immunohistochemical staining was performed on paraffin-embedded sections of pancreata from 24 individuals without diabetes for insulin, glucagon, and somatostatin. The sections were imaged with epifluorescence microscopy, and hormone-positive cells were manually counted using ImageJ software considering cells where more than 50% of the area was immunopositive. The mean proportional presence of glucagon-, insulin-, and somatostatin-immunopositive cells within islets was 28.8%, 65.1%, and 13.8% respectively, similar to previous reports for human islets. The relative presence of alpha- and beta-cells increased, and for delta-cells decreased, with advancing age. With respect to bi-hormonal cells the overall presence of glucagon+/insulin+ cells was 3.3%, for somatostatin+/insulin+ cells was 2.4%, and for glucagon+/somatostatin+ cells was 1.7% relative to total islet cell number. The proportion of glucagon+/somatostatin+ cells in the islets of female individuals, in particular, diminished with age (r2=0.43), whereas the other cell types remained largely constant with age in both sexes. The prevalence of tri-hormonal islet cells was low (0.45%). The findings suggest that bi-hormonal islet cells are present within human pancreatic islets throughout life, perhaps reflecting an ongoing potential for endocrine cell plasticity.

Disclosure
J.Hahm: None. J.A.Fernandez andrade: None. E.Arany: None. D.J.Hill: None.

Funding
Lawson Foundation
1767-P: “Leader” ß-Cells within the Pancreatic Islet Are a Functionally Stable Subpopulation In Vitro and In Vivo
Authors: DELGADILLO SILVA LUIS F. , RUTTER GUY A. , CHABOSSEAU PAULINE L. , PROVENCHER-GIRARD AUDREY , PRAT ALEXANDRE , LOPEZ NORIEGA LIVIA 
Published: June 2023

β-cell coordination within the islet is critical for normal glucose-stimulated insulin secretion. Recently, we and others have identified a subpopulation of β-cells termed “leaders” which are the first cells to show an increase intracellular Ca2+ during glucose-induced Ca2+ waves. In the Zebrafish, photo ablation of leader cells disrupts pan-islet coordination identifying these as likely pacemakers alongside connected “hub” cells. Our earlier studies were conducted over relatively short time windows (~1hr), leaving open the possibility that leader cells may simply reflect the emergence of a transient functional state rather than a stable subpopulation. To address this question, we used islets from Ins1Cre:GCaMP6ffl/fl transgenic mice which express the Ca2+ sensor GCaMP6f selectively in β-cells. Fast (3-6 Hz) confocal imaging and cell-tracking were used to record calcium dynamics with cellular resolution during stimulation in vitro at 11 mM glucose. Adenoviral delivery of photo-activable PA-mCherry, and excitation with UV light, allowed the identification and labelling of leader cells. Re-imaged 24 h later, 80% (8/10; 4 mice in 2 separate experiments) of islets had the same leader cell as in the earlier session. Correspondingly, after islet engraftment into the anterior chamber (ACE) of the mouse eye, and revascularization, multi-photon imaging revealed calcium waves that were initiated from the same region of the islet in vivo in imaging sessions 24 h apart. These findings establish leader β-cells as a stable subpopulation in vitro and in vivo whose dysfunction may contribute to defective insulin secretion in some forms of diabetes.

Disclosure
L.F.Delgadillo silva: None. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. P.L.Chabosseau: None. A.Provencher-girard: None. A.Prat: None. L.Lopez noriega: None.