bluuebunny/crossref_metadata_2025_split huggingface dataset:
183-LB: A Randomized Placebo-Controlled Trial of the Effectiveness of Early Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE)
Authors: DUNNE FIDELMA P. , ALVAREZ-IGLESIAS ALBERTO , NEWMAN CHRISTINE , SMYTH ANDREW , BROWNE MARIE , DEVANE DECLAN , GILLESPIE PADDY , O'DONNELL MARTIN 
Published: June 2023

The optimal approach to managing GDM is uncertain. We sought to determine whether early introduction of metformin (at diagnosis) plus lifestyle modification was superior to standard care (lifestyle modification alone).
Methods: EMERGE is a phase III, superiority, parallel-group, 1:1 randomized trial comparing effectiveness of early metformin vs placebo initiated before 28 weeks +6 days. GDM was confirmed using WHO 2013 criteria. Metformin (or placebo) was initiated at 500mg/day titrated to 2500mg. The primary outcome was the composite of insulin initiation or fasting glucose ≥ 5.1 mmol/L at weeks 32 or 38.
Results: Between June 2017-September 2022, 535 women were randomized, 268 to metformin, 267 to placebo; mean (SD) age of 34.3 (4.8), 23.7% primigravid, 17.6% non-Caucasian, 31.4% had prior GDM, 39.4% had BMI&lt;30, mean gestation 25.4 weeks. There was no significant difference in the primary outcome between metformin and placebo treatments (56.8% vs 63.7%; RR=0.89 95%CI: 0.78-1.02). Insulin initiation was significantly lower in metformin (38.4%) vs placebo (51.1%) group (RR 0.75; 95%CI 0.62-0.91). Compared to placebo, metformin treated women achieved better glycemic control (HbA1C at 38 weeks; 33.9 vs 35 mmol/mol; P=0.004) and gained less weight between randomization and delivery (0.8kg vs 2.0kg; P=0.03), while infants were less likely to weigh &gt;4000g (7.6% vs 14.8%; P=0.013). There was no significant difference in infants weighing &lt;2500g (6.1% vs 3.4%; P=0.215), in infants needing NICU admission (15.3% vs 12.5%; P=0.439) or in infants born preterm &lt;37weeks (9.2% vs 6.5%; P=0.329) in the metformin versus placebo groups.
Conclusions: In a Phase III trial, early introduction of metformin did not reduce the composite of insulin initiation or elevated fasting glucose at week 32 or 38 in women with GDM, but was associated with important maternal and neonatal benefits with no increase in adverse perinatal events.

Disclosure
F. P. Dunne: None. A. Alvarez-Iglesias: None. C. Newman: None. A. Smyth: None. M. Browne: None. D. Devane: None. P. Gillespie: None. M. O'Donnell: None.

Funding
Health Research Board of Ireland
185-OR: Machine-Learning Approach Reveals Microbiome, Metabolome, Lipidome, and Their Interaction in Type 1 Diabetes Mellitus
Authors: TAN HUILING , SHI YU , YUE TONG , ZHENG DONGXUE , WANG CHAOFAN , LIU ZIYU , YANG DAIZHI , DING YU , XU WEN , YAN JINHUA , LUO SIHUI , WENG JIANPING , ZHENG XUEYING 
Published: June 2023

Background: An increasing amount of research shows that the gut microbiota and metabolites play a role in type 1 diabetes mellitus (T1D). We aimed to use machine learning to explore gut microbiota, serum metabolites, and lipids signatures in T1D individuals.
Methods: We evaluated 137 individuals in a cross-sectional cohort that included 38 T1D patients, 38 healthy controls, and 61 T1D patients for validation. After clinical examination and biospecimen collection, we characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites and lipids with liquid chromatography-mass spectrometry. All molecular data were analyzed using a combination of univariate, multivariate, and machine-learning approaches (Logistic Regression, Support Vector Machine, Gaussian Naive Bayes, and Random Forest).
Results: Machine-learning approaches using microbiota composition did not accurately predict T1D status (model accuracy=0.7555), while the accuracy of model using metabolite composition was 0.9333. Based on bacterial species-level composition, Ruminococcus torques, Anaerostipes, Veillonella, Erysipelotrichaceae UCG-003, Blautia, and Coprococcus were coincident microbes which all increased in T1D. Increased 3-hydroxybutyric acid and 9-oxo-ode (AUC=0.70 and 0.67) were meaningful coincident metabolites in T1D. PC(36:4e)(rep) was the most significant lipid (coefficient index=3.11e-9, increased in T1D). We confirmed the biological relevance of the microbiome, metabolome, and lipidome features in the validation group. Ruminococcus torques was positively associated with 3-hydroxybutyric acid (p&lt;0.01).
Conclusions: By using machine-learning algorithms and multi-omics, we demonstrated that T1D patients are associated with altered microbiota, metabolites, and lipidomic signatures or functions. Machine-learning approaches have potential clinical applications in T1D diagnostics and treatment.

Disclosure
H.Tan: None. J.Yan: None. S.Luo: None. J.Weng: None. X.Zheng: None. Y.Shi: None. T.Yue: None. D.Zheng: None. C.Wang: None. Z.Liu: None. D.Yang: None. Y.Ding: None. W.Xu: None.

Funding
National Natural Science Foundation of China (82100822); Anhui Provincial Natural Science Foundation (2008085MH248, 2008085MH278); Guangdong Basic and Applied Basic Research Foundation (2019A1515010979); National Key R&D Program (2017YFC1309600)
189-OR: FGF21-Mediated Signaling Defects and Their Effects on Insulin Resistance in Insulin-Mediated Pseudoacromegaly
Authors: PHAN NHUNG , ORNITZ DAVID M. , STONE STEPHEN I. 
Published: June 2023

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome linked to digenic mutations in FGFR1 and KLB. These proteins form the receptor complex for FGF21, a hepatokine that plays a critical role in adipose tissue insulin sensitivity. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels, tall stature, and obesity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Western immunoblotting demonstrated that the uncorrected (mutant) cells demonstrated decreased levels of FGFR1 and pERK1/2 in response to insulin and/or FGF21 compared to corrected (wild-type) cells. Additionally, mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY. To complement the iPSC work, a humanized transgenic knock-in mouse line was created using CRISPR gene editing. When exposed to a high fat diet (HFD), female mice harboring variants in FGFR1 and KLB (DM - Double Mutant) developed significant weight gain compared to wild-type (WT) littermates. The difference in body weight was attributed to a difference in body fat. Similar to the human phenotype, the DM mice experience intermittent hyperglycemia and significant hyperinsulinemia. Explants of gonadal white adipose tissue demonstrated decreased lipolysis and pAKT and pERK. Mac-2 staining of white adipose tissue demonstrated abundant adipose tissue macrophages forming crown-like structures, suggesting adipose tissue inflammation. Additionally, we measured gene expression in brown adipose tissue, and noting that Ucp1 expression in DM mice was 37% when compared to WT. These results suggest pathogenic mechanisms in which FGFR1 and KLB mutations lead to IMPA via decreased FGF21-mediated signaling in the adipose tissue.

Disclosure
N.Phan: None. D.M.Ornitz: None. S.I.Stone: None.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098872); National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK124574, P30DK020579, P30DK056341); National Center for Advancing Translational Sciences
191-LB: The Impact of Urbanization on the People of the Upper Amazon
Authors: GERHOLD CHAD , ROBBINS DAVID C. , GARCIA-TOUZA MARIANA , DEAN BARTHOLOMEW C. 
Published: June 2023

Although it has gotten little attention, T2D has become a public health issue in the Peruvian Amazon, particularly among urban dwellers. The growing rate of T2D in the global south has been attributed to greater access to industrial foods and sedentary lifestyles ensuant of rapid urbanization. In Amazonia, people migrate from rural communities to urban hubs searching for socioeconomic opportunities. As a result, prevalence of T2D and obesity has rapidly increased in these cities. Our study compared the diabetes status of people living in Yurimaguas (YU) with those living in traditional rural villages in the Balsapuerto District (BD), Peru, to understand health differences between rural and urban Amazonians.
Methods Participants were recruited in YU (M/F = 114/52) and 11 rural villages in BD (F/M = 92/77). We collected blood pressure, glucose, insulin, glycosylated hemoglobin (A1c), lipids panels, and body measurements. T2D status was determined using ADA guidelines for A1c and glucose.
Results Mean age of participants was younger in BD (44.4 yrs) compared to YU (50.3 yrs; t335 = 3.52, p &lt; 0.01). After adjusting for age, we found participants in YU had greater A1c (F2, 328 = 49.14, p &lt; 0.01), BMI (F2, 328 = 28.79, p &lt; 0.01), glucose (F2, 328 = 8.85, p &lt; 0.01), insulin (F2, 328 = 7.11, p &lt; 0.01), triglycerides (F2, 328 = 3.84, p &lt; 0.01), and systolic pressure (F2, 328 = 37.45, p &lt; 0.01) compared to participants living in BD. The proportion of individuals with diabetes and prediabetes was greater in YU (37%, 34% respectively) compared to BD (4%, 12% respectively; χ2 = 119.9, df =2, p &lt; 0.01). The percentage of individuals with BMIs &gt; 25 in YU was 68% (n = 112) and 29% (n = 49) in BD respectively (χ2 = 51.8, df =1, p &lt; 0.01).
Discussion Results suggest Peruvians living in YU generally had poor health profiles, higher incidence of diabetes, and higher BMIs compared to their rural counterparts 40km away. Given the stark differences between these communities, efforts should be made to understand the nutritional and lifestyle factors leading to this health decline.

Disclosure
C. Gerhold: None. D. C. Robbins: None. M. Garcia-touza: None. B. C. Dean: None.

Funding
Kansas University Diabetes Institute
191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice
Authors: EL-AGROUDY NERMEEN N. , SCHUMANN TINA , KURZBACH ANICA , SANCAR GENCER , SANDFORTH LEONTINE , HERRMANN CHRISTINE , SHULMAN GERALD I. , BIRKENFELD ANDREAS L. 
Published: June 2023

Background and Aims: Recent GWAS in large human populations identified the monocarboxylate transporter SLC16A11 as a candidate gene for T2D. While previous studies postulated that SLC16A11 plays a role in hepatic lipid and glucose metabolism, the existing data are controversial and exact mechanisms of how SLC16A11 affects T2D are missing. Here, we aimed at elucidating the role of SLC16A11 in the development of metabolic disease.
Methods: HEK293 cell lines expressing murine and human SLC16A11 were established. Moreover, using CRISPR/Cas9, a SLC16A11 knockout mouse model was generated. Finally, SLC16A11 mRNA expression was measured in various insulin responsive tissues of ob/ob and db/db mice.
Results: In HEK293 cells, substrates of the transporter were identified. mRNA expression of SLC16A11 was reduced in skeletal muscle of ob/ob and db/db mice (-69.8% and -22.8%; p&lt;0.05) compared to littermate controls. SLC16A11 KO and WT littermate mice fed NCD or HFD did not differ in body weight and composition, energy expenditure or food intake. While basal glucose and insulin in SLC16A11 KO and WT littermates on a HFD were not different, glucose infusion rate during hyperinsulinemic euglycemic clamp was lower in SLC16A11 KO mice (SLC16A11 WT= 36.4±3 mg/kg/min; SLC16A11 KO= 24.7±2 mg/kg/min; P&lt;0.01), indicating reduced whole-body insulin sensitivity. No changes were observed in hepatic glucose production, liver fat content or hepatic mitochondrial function using PINTA method. Instead, clamped 2-deoxy-glucose uptake was significantly reduced in skeletal muscle (-41%; p&lt;0.05) of SLC16A11 KO, together with increased DAGs levels and PKCθ activation, indicating skeletal muscle insulin resistance.
Conclusions: Our data show for the first time that in contrast to previous assumptions, SLC16A11 impairs skeletal muscle insulin sensitivity without affecting hepatic metabolism. Taking also human GWAS into account, we propose that SLC16A11 may be an interesting target for the treatment of T2D.

Disclosure
N.N.El-agroudy: None. T.Schumann: None. A.Kurzbach: None. G.Sancar: None. L.Sandforth: None. C.Herrmann: None. 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. A.L.Birkenfeld: None.
193-LB: Refining Diabetes Risk for Individuals with Prediabetes
Authors: KIM SUN H. , HSIA DANIEL S. , LEBLANC ERIN S. , STATEN MYRLENE , CHATTERJEE MONTGOMERY RANEE , RASOULI NEDA , ARODA VANITA R. , PITTAS ANASTASSIOS G. 
Published: June 2023

Rate of progression from prediabetes to diabetes varies greatly, and better risk stratification would help guide prevention efforts. We evaluated predictors of incident diabetes in the placebo arm (n=1212) of the vitamin D and type 2 diabetes (D2d) study. At baseline, participants met 2 or 3 ADA glycemic criteria for prediabetes (fasting glucose, FPG, 100-125mg/dL; 2-hour glucose during a 75-g OGTT, 2hPG, 140-199 mg/dL; HbA1c, 5.7-6.4%). Diabetes was diagnosed based on semiannual testing. After a median follow up of 2.5 years, 27% met criteria for diabetes. Among those who did and did not develop diabetes, mean BMI (±SD) was similar (32.1 kg/m2 ± 4.4), as well as other demographic factors including age, race, and ethnicity. More men than women developed diabetes (29% vs 23%, p=0.02). Incident diabetes rates differed by prediabetes subgroups (Figure); and those meeting all three prediabetes criteria at baseline (35.4%) were most likely to develop diabetes (log-rank p &lt;0.001). There were no differences in the incident diabetes rate among those people meeting only 2 of the prediabetes criteria (Figure). Also, area under the receiver operator characteristic curves for incident diabetes at 36 months increased when all 3 criteria were used in the diagnosis (0.736) vs only FPG and HbA1c (0.686). We conclude that ‘prediabetes’ is heterogeneous, and the 2hPG may refine diabetes risk and guide intervention strategies in adults with high-risk prediabetes.

Disclosure
S. H. Kim: Advisory Panel; GI Dynamics, Consultant; Aligos, Research Support; Fractyl Health, Inc. D. S. Hsia: None. E. S. Leblanc: Other Relationship; Dexcom, Inc. M. Staten: None. R. Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. N. Rasouli: Research Support; Novo Nordisk, Eli Lilly and Company, Somalogic. V. R. Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. A. G. Pittas: None.

Funding
National Institutes of Health (U01DK098245)
20-OR: Loss of Characteristic ß-Cell Function in Autoantibody-Positive (Ab+) Individuals during the Progression to Type 1 Diabetes (T1D)
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , SKYLER JAY S. , EVANS-MOLINA CARMELLA , SOSENKO JAY 
Published: June 2023

We used correlations of C-peptide secretion between follow-up time points (autocorrelation) of Ab+ relatives in the TrialNet Pathway to Prevention study to assess the loss of characteristic β-cell function during progression to T1D. Measures of β-cell function: AUC C-peptide; C-peptide Index (30-0 min C-peptide)/(30-0 min glucose); and Index60 (composite of glucose and C-peptide during first 60 minutes of OGTT)] were assessed (table 1). Spearman correlations of AUC C-peptide from baseline to pre-diagnosis (6 months before) OGTTs of progressors (Pro; Age=8.7±3.6 yrs; n=182) were lower than correlations of AUC C-peptide from baseline to last OGTTs of non-progressors (NPro; Age=9.6±3.8 yrs; n=3,137; p&lt;0.001 for all). Among Pro, correlations of AUC C-peptide from baseline to diagnosis OGTTs were considerably lower than correlations of AUC C-peptide from baseline to pre-diagnosis OGTTs (p=&lt;0.001 for all). In conclusion, the lower C-peptide autocorrelation from baseline to last OGTTs of Pro compared to NPro indicates that β-cell function is already appreciably altered 6 months before diagnosis. Among Pro, the substantial decline of C-peptide autocorrelation from 6 months before diagnosis to diagnosis suggests a marked loss of β-cell function in that interval. Autocorrelation offers another approach for providing insight into β-cell compromise.

Disclosure
H.M.Ismail: Consultant; Rise Therapeutics. D.D.Cuthbertson: None. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. J.Sosenko: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK129799-01A1)
200-OR: Role of Insulin-Degrading Enzyme (IDE) in the Tubulin–Primary Cilium Axis to Regulate Glucagon Secretion
Authors: CASANUEVA-ALVAREZ ELENA , SANZ-GONZÁLEZ ALBA , MERINO BEATRIZ , PERDOMO GERMAN , COZAR-CASTELLANO IRENE 
Published: June 2023

Hyperglucagonemia is a hallmark of T2D, although molecular mechanisms underlying glucagon secretion dysregulation are poorly understood. We have recently reported that genetic ablation of IDE in α-cells (A-IDE-KO mouse) leads to constitutive glucagon secretion, hypertrophy, hyperplasia and increased proliferation. αTC1.9-KD-IDE cells (~30% IDE-knock-down) displayed reduced tubulin and acetylated-α-tubulin protein levels, impaired primary cilium and increased proliferation. Thus, we aimed to elucidate the role of IDE in α-cells tubulin network and ciliogenesis, and how this axis may be part of the glucagon secretion machinery. We have studied by western-blot IDE, tubulin, acetylated-α-tubulin and Arl13b (primary cilium marker) levels in αTC1.9 cells under low- and high-glucose conditions. We have found that high-glucose lowers IDE protein levels by 50% compared to low-glucose conditions, leading to a similar decrease in tubulin, acetylated-α-tubulin and Arl13b protein levels. These findings agree with our previous results using αTC1.9-KD-IDE cells, suggesting a relevant role of IDE in microtubule dynamics to control glucagon granules exocytosis. On the other hand, αTC1.9-KD-Arl13b cells (~70% Arl13b-knock-down) were used as a model of impaired ciliogenesis, showing 50% decrease in tubulin, and dysregulated glucagon secretion, mimicking αTC1.9-KD-IDE cells phenotype. In parallel, insulin-mediated inhibition of glucagon secretion is lost and insulin receptor protein levels were decreased by 40% in both, αTC1.9-KD-IDE and αTC1.9-KD-Arl13b cells, showing the relevance of IDE and primary cilium in the paracrine regulation of α-cells. Furthermore, these results have been reproduced in A-IDE-KO mice isolated islets. In conclusion, our results show that IDE-tubulin-primary cilium axis is regulated during glucose-stimulated glucagon secretion, this axis is also required for the paracrine action of insulin on α-cells to inhibit glucagon secretion.

Disclosure
E.Casanueva-alvarez: None. A.Sanz-gonzález: None. B.Merino: None. G.Perdomo: None. I.Cozar-castellano: None.

Funding
Ministerio de Ciencia e Innovación-Spain (PID2019-110496RB-C21)
206-LB: Overview of the All of Us Research Program 2023 Data Release for Type 2 Diabetes
Authors: DEDE YILDIRIM ELIF , SULIEMAN LINA , GIANNINI JOHN , OSTCHEGA YECHIAM , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA 
Published: June 2023

The National Institutes of Health's All of Us Research Program is collecting data from one million or more participants throughout the U.S. to advance precision medicine. The program enrolls individuals from diverse backgrounds with a focus on groups that are traditionally under-represented in biomedical research. The spring 2023 curated dataset release makes All of Us the world's largest and most diverse dataset of its kind available for broad research use, with nearly 45% of the data from people who identify with a racial or ethnic minority group.
The expanded phenotypic data includes survey data from 413,396 participants and electronic health record data from 287,012 participants that can be used to study diabetes and other metabolic disorders. The platform supports Jupyter notebooks to build queries using R or Python3, as well as custom interface tools that allow identification of data and health conditions within the large relational database using the OMOP common data model. Currently, the dataset includes 33,849 participants with at least one T2D condition code, one T2D drug exposure, or one T2D lab result, excluding T1D condition codes.
We will discuss the utility of this expansive dataset for T2D researchers and participants, and its potential to answer critical questions about metabolic health outcomes.

Disclosure
E. Dede yildirim: None. L. Sulieman: None. J. Giannini: None. Y. Ostchega: None. E. Ochsenfaber: None. L. Berman: None. A. Ramirez: n/a.