bluuebunny/crossref_metadata_2025_split huggingface dataset:
1665-P: Uncovering the Cell-Type Specificity in Human T1D Immune Activation Using iPSC-ß-Cells
Authors: LEITE NAYARA 
Published: June 2020

It is known that T1D involves a complex interaction between pancreatic β-cells and cells of both the innate and adaptive immune systems. Innate immune signaling is involved in the initiation of the autoimmune process, which results in the destruction of β cells by cytotoxic T cells during T1D pathogenesis. Here, we show that exposing human induced pluripotent stem cells derived β cells (hiPSC-β cells) to autologous peripheral immune cells in vitro reveals an activation signature of T1D β cell rejection across multiple immune cell types. We profiled innate and adaptive immune activated populations and identified relevant populations to T1D autoimmunity. After co-culture of donor-matched target and effector cells, we performed mass cytometry (CyTOF). We used an immunophenotyping CyTOF panel containing 32 markers to identify activation in different immune populations. As a negative control, we used unstimulated effector peripheral immune cells. As a positive control, we used unmatched β cells from other donors. Finally, all experiments were performed with hiPSC-α cells and donor-matched peripheral immune cells, and we did not observe the activation of immune cells in the hiPSC-α cells donor-matched coculture. Exposing T1D hiPSC-β cells to donor-matched peripheral immune cells in vitro revealed the activation of distinct immune cell populations that participate in T1D β cell rejection. We observed differences within T1D patient samples, we anticipate that we can use this model to study T1D patient heterogeneity.

Disclosure
N. Leite: None.

Funding
American Diabetes Association (1-19-PMF-024)
1669-P: Immune Checkpoint Inhibitor Induced Diabetes and Diabetic Ketoacidosis
Authors: HAFEEZ SHAHZEENA , VELLANKI PRIYATHAMA , XING MINZHI , UMPIERREZ GUILLERMO E. 
Published: June 2020

Immune checkpoint inhibitors (CPI) are increasingly used to improve survival rates in cancer patients. CPI therapy has been associated with new onset diabetes due to immune-mediated damage of beta-cells, with many patients presenting with diabetic ketoacidosis (DKA). We used Emory University’s Clinical Data Warehouse to examine clinical characteristics and outcomes of adult patients with new onset diabetes and DKA after CPI therapy from 01/01/2014 to 08/01/19. Comparisons of covariates were made with analysis of variance, χ2 and Fisher’s exact tests; log-rank test was used to analyze survival.
A total of 2279 patients received CPIs during the study period. Of these, 1622 had no DM, 540 had a previous history of DM, and 117 patients (5.1%) developed new onset DM after CPI treatment. Pembrolizumab, Nivolumab and Ipilimumab were the most common CPIs associated with DM. A total of 13 patients developed DKA, on average at 140 days from CPI initiation. Compared to no-DM group, patients with new-onset DM and DKA had higher DM-related hospitalization (p&lt;0.01), mortality (p=0.02), and reduced survival from CPI initiation, p=0.03.
In summary, incidence of new-onset DM is 5.1% and is associated with higher DM-related hospitalizations. DKA patients have reduced survival compared to no-DM after CPI treatment. Healthcare professionals caring for patients undergoing CPI therapy need to be aware of this potential complication.

Disclosure
S. Hafeez: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M. Xing: None. G.E. Umpierrez: None.
167-OR: Exercise Training Alters Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha (PGC-1 Alpha) DNA Methylation in Human Skeletal Muscle
Authors: LEE SUNG , GARCIA LUIS , LEON ALMA D. , BUSTOS ROCIO ZAPATA , CAMPOS BALTAZAR , KRENTZEL JUDY A. , MANDARINO LAWRENCE , COLETTA DAWN K. 
Published: June 2020

Exercise training improves insulin sensitivity in skeletal muscle and increases mitochondrial function. These improvements are due, in part, to an increase in expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). The effect of exercise training on epigenetic factors, such as DNA methylation remains elusive. The aim of this study was to determine whether an 8-week exercise training alters DNA methylation of PGC-1 alpha. Fourteen participants (5M/9F; age 34.2±3.0 years) were studied before and after 8-weeks of supervised exercise training (60% of VO2peak for 20 minutes, 3 times per week; gradually increased to 70% of VO2peak for 45 minutes, 4 times per week). Euglycemic hyperinsulinemic clamps in combination with vastus lateralis muscle biopsies were obtained before and after the exercise training. Training increased peak aerobic capacity (VO2peak) from 31.9±1.0 to 36.5±1.4 ml∙min-1∙kg FFM-1 (P = 0.013) and improved insulin sensitivity from 7.0±2.1 to 9.2±2.3 ml·kg FFM−1·min−1. Genomic DNA was extracted and pyrosequencing methylation analysis was performed on CpG -816 and -783 bp upstream transcription start site (TSS). Methylation analysis revealed a significantly decreased methylation at CpG -816 bp following exercise (pre = 16.8±0.9 % versus post = 14.2±0.5 %, P = 0.035). For CpG -783 bp, methylation did not change following exercise (pre = 11±0.6 % versus post = 11.5±0.7 %, P = NS). Our results showed that exercise training improved insulin sensitivity and peak aerobic capacity. In addition, we provide evidence that exercise training alters PGC-1 alpha methylation at CpG -816 bp. We propose that the increased response of insulin action in muscle following exercise training is due, in part, to epigenetic modifications.

Disclosure
S. Lee: None. L. Garcia: None. A.D. Leon: None. R. Zapata Bustos: None. B. Campos: None. J.A. Krentzel: None. L. Mandarino: None. D.K. Coletta: None.

Funding
National Institutes of Health (R01DK094013)
1679-P: Islet Autoimmunity in Adults with Impaired Glucose Tolerance (IGT) and Newly Diagnosed, Treatment-Naïve Type 2 Diabetes (NDX T2D) in the Restoring Insulin Secretion (RISE) Study
Authors: BROOKS-WORRELL BARBARA , TJADEN ASHLEY H. , EDELSTEIN SHARON , PALOMINO BRENDA M. , UTZSCHNEIDER KRISTINA , ARSLANIAN SILVA A. , MATHER KIEREN J. , BUCHANAN THOMAS A. , NADEAU KRISTEN J. , ATKINSON KAREN M. , BARENGOLTS ELENA , KAHN STEVEN E. , PALMER JERRY P. ,   RISE CONSORTIUM
Published: June 2020

In obesity, immune cells establish a systemic inflammatory state associated with development of insulin resistance and T2D. Previous studies have shown that peripheral blood mononuclear cell (PBMC) responses to islet proteins (IPs) in adults with established T2D on glucose-lowering therapies identify those patients with more severe β-cell dysfunction. Moreover, attenuation of PBMC responses to IPs in adults with established T2D improves β-cell function. However, the presence of IP reactive PBMCs, glutamic acid decarboxylase autoantibodies (GADA), and their relationship to insulin sensitivity and β-cell function has never been evaluated in IGT or Ndx T2D. We measured at baseline and after 12 months of RISE medication interventions (12 months with either metformin or liraglutide plus metformin or for 3 months with insulin glargine followed by 9 months of metformin), PBMC responses to IPs, GADA, insulin sensitivity, and β-cell function in 258 RISE participants (mean ± SD) 53.3 ± 9.2 years of age, BMI 35.1 ± 5.4 kg/m2, with IGT (n=180) or Ndx T2D (&lt;12 months duration, n=78). At baseline, IP reactive PBMCs were present in 46% of participants with IGT and 40% of participants with Ndx T2D. However, 97% of IGT and 98% of Ndx T2D were GADA negative. There were no significant relationships between the presence of PBMC reactivity to IPs, GADA positivity and insulin sensitivity or β-cell function. RISE treatments did not alter PBMC responses to IPs, GADA, or the relationship between IP reactive PBMCs or GADA with glycemic responses.
In summary, IP reactive PBMCs are present in a large percentage of adults with very early dysglycemia, However, the presence of IP reactive PBMCs did not correlate with insulin sensitivity or early β-cell dysfunction. Further studies are needed to unravel the pathogenesis of IP reactive PBMCs and GADA and their effects on β-cell function during progression of T2D.

Disclosure
B. Brooks-Worrell: None. A.H. Tjaden: None. S. Edelstein: None. B.M. Palomino: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. T.A. Buchanan: None. K.J. Nadeau: None. K.M. Atkinson: None. E. Barengolts: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. J.P. Palmer: None.

Funding
National Institutes of Health (R01DK107560)
1689-P: Perioperative Hyperglycemia around Renal Transplantation Surgery and the Development of New-Onset Diabetes Mellitus after Transplantation
Authors: FERREIRA MARÍA LETICIA MÉNDEZ , BUENO ELVIO D. , BENITEZ ALDO , PALACIOS CONCEPCION M. , JIMENEZ JORGE T. , AMARILLA ALEJANDRA , PONTE FERNANDO DA , STANLEY IDALINA 
Published: June 2020

Background: New onset of diabetes after transplantation (NODAT) is an important problem as it increases infectious and cardiovascular complications reducing patient and graft survival.
Aim: To establish the impact of perioperative hyperglycemia on the development of NODAT and the other known risk factors for its development in patients who go to renal transplant surgery, in a renal transplant unit dependent on an academic center.
Methods: Study of cases and controls of patients with renal transplantation who developed or not NODAT within the year of follow-up, with more than 18 years of age, with the same immunosuppressive scheme (prednisone, tacrolimus, mycophenolate mofetil).
Results: Of 71 transplanted patients, 14 (19.7%) developed NODAT per year, with an average age of 37.57 ± 15.02 years vs. 36.08 ± 12.43 years for those who did not develop it (p: 0, 73) respectively; those who developed NODAT were male in 57.14% vs. 70.18% of those who did not develop it respectively. Patients whose preoperative laboratory evaluation showed blood glucose equal to or greater than 100 mg/dl and less than 126 mg/dl had a NODAT frequency of 21.3% vs. 5.26% (OR 4.9 p: 0.005) in those who they had values ​​lower than 100 mg/dl at the same time of the evaluation. In addition, if the blood glucose prior to hospital discharge was ≥140 mg/dl, the frequency of NODAT was 35.71% vs. 1.75% (OR 31.11 p: 0.0003) if the blood glucose was lower than 140 mg/dl at the same time of the evaluation. None of the other risk factors considered: age &gt;40 years, female sex, overweight, obesity, hypertriglyceridemia, family history of diabetes had significant statistical differences between the two groups.
Conclusion: In our experience, poor glycemic controls, especially before surgery and prior to hospital discharge, marked a higher frequency trend of NODAT one year after follow-up. The patients presenting with this phenomenon should be observed with special attention in the follow up.

Disclosure
M. Méndez Ferreira: None. E.D. Bueno: None. A. Benitez: None. C.M. Palacios: None. J.T. Jimenez: None. A. Amarilla: None. F. Da Ponte: None. I. Stanley: None.
171-LB: Evaluation of Universal Diabetes Diagnostic Testing at First Prenatal Visit
Authors: LARCO PHILIPPE , BAPTISTE EDDY JEAN , MOISE KEDDY , LARCO MARIE-NANCY CHARLES , JEROME BELLO S. , VON OETTINGEN JULIA E. , CHARLES RENE 
Published: June 2020

Diabetes mellitus (DM) in pregnancy is not routinely screened for in Haiti. If done, screening relies on OGTT at 24-28 weeks (w) of gestation. It is unclear whether this is an optimal approach in Haiti. We aimed to evaluate the implications of a universal DM diagnostic testing before 24 w.
All consecutive pregnant women aged ≥18 y without known DM attending their first pregnancy visit in 4 prenatal clinics of Port-au-Prince and surroundings were invited to participate. Using a Contour NextR glucometer, eligible subjects underwent: Fasting blood glucose (FBG) test at 1-23 w and ≥36 w, 75g 2-h OGTT at 24-28 w for FBG &lt;126 mg/dL before 24 w or at 24-35 w-first visit. We used WHO/IADPSG diagnostic criteria for DM in pregnancy (DIP) (FBG ≥126 mg/dL and/or 2h ≥200 mg/dL) and for gestational DM (GDM) (1 or more: FBG 92-125 mg/dL, 1-h BG ≥180 mg/dL, 2-h BG 153-199 mg/dL).
A total of 945 women (mean age 29.78 ± 5.77 y, parity 2.04 ± 1.29, pre-eclampsia: 3.80%, caesarian section: 18.75%, preterm birth: 7.13%, single or living alone: 10.13%, family history of DM: 10.11%) were studied. Women with first visit at &lt; and ≥24 w were 332 and 613, respectively. Prevalence of DIP and GDM by first screening period was: 7.20% and 13.02% overall, 12.35% and 13.86% at &lt;24 w, and 4.40% and 12.56% at ≥24 w. Median FBG progressively decreased from 83 mg/dL at ≤5 w to 73 mg/dL at ≥36 w, p=0.0000. Of the 40 women with GDM at &lt;24 w, 20 had GDM confirmed and 20 were normal on OGTT. A cut-off value of FBG &gt;100 mg/dL at &lt;24 w for DM (DIP and GDM) diagnosis on OGTT had: specificity (SP) 98.8%, sensitivity (SE) 19.3%, and positive predictive value (PPV) 78.6%. A cut-off value of FBG &lt;72 mg/dL at &lt;24 w to rule out DM on OGTT had: SP 12.2%, SE 98.3%, and NPV 96.8%. Women with these cut-offs represented 14.9% of those undergoing OGTT after the &lt;24 w screening.
Our findings suggest that universal screening for DM before 24 w of gestation leads to diagnosis of DM in about 20% of pregnant women. A rule in/rule out approach using FBG &lt;72 mg/dL and &gt;100 mg/dL values at &lt;24 w can help reduce the number of OGTT at ≥24 w.

Disclosure
P. Larco: None. E. Jean Baptiste: None. K. Moise: None. M. Charles Larco: None. B.S. Jerome: None. J.E. von Oettingen: None. R. Charles: None.
1735-P: Effect of TLR4 Inhibition in Fat-Induced Insulin Resistance in Human Subjects
Authors: LIANG HANYU , SATHAVARODOM NATTAPOL , COLMENARES CLAUDIA V. , GANAPATHY VINUTHA , MUSI NICOLAS 
Published: June 2020

Obese subjects have increased levels of free fatty acids (FFA) in plasma that may mediate the inflammation and insulin resistance seen in these individuals. Data generated mostly in cells and rodents suggest that toll like receptor 4 (TLR4) mediates the inflammatory and insulin resistant states induced by FFA. In the present study, we tested the hypothesis that pharmacologic blockade of TLR4 with eritoran would prevent lipid-induced insulin resistance. We recruited 10 lean, healthy subjects (Age: 51 ± 1 y, Sex: 6M/4F, BMI: 23.8 ± 0.7 kg/m2, Fasting plasma glucose (FPG): 5.5 ± 0.1 mmol/l). They were randomized to receive the following 72 h long i.v. treatments on separate occasions: saline (30 ml/h)+vehicle (12 mg every 12 h); Intralipid (30 ml/h)+vehicle; Intralipid (30 ml/h)+eritoran (12 mg every 12 h). After these infusions, insulin sensitivity was measured with an hyperinsulinemic clamp. Infusion of Intralipid significantly decreased insulin sensitivity (M value) by 14%. FPG and fasting plasma insulin concentrations increased with Intralipid infusion by 7% and 22%, respectively. Intralipid also caused a low-grade inflammatory state, evidenced by increases in plasma levels of TNFa (32%), lipopolysaccharide (14%), LPS binding protein (21%), and blood monocytes counts (15%). However, metabolic and inflammatory outcomes were not different between the Intralipid+vehicle and the Intralipid+eritoran groups. We conclude that short-term TLR4 inhibition with eritoran fails to prevent lipid-induced inflammation and insulin resistance. Studies with longer acting TLR4 inhibitors may be needed to clarify the role of TLR4 on the pro-inflammatory and insulin resistant states seen obesity and type 2 diabetes.

Disclosure
H. Liang: None. N. Sathavarodom: None. C.V. Colmenares: None. V. Ganapathy: None. N. Musi: None.

Funding
American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (R01DK080157)
1745-P: High Prevalence of Thyroid Abnormalities in Patients with Congenital Generalized Lipodystrophy
Authors: FERNANDES VIRGINIA O. , LIMA GRAYCE ELLEN D. , MONTENEGRO ANA PAULA D. , CARVALHO ANNELISE B. , RODRIGUES GRETNA M. , MELO IVANA P. , MARTINS LIVIA V. , BATISTA LIVIA A. , AGUIAR LINDENBERG , MONTENEGRO RENAN M. ,   UIRED LIPODYSTROPHIES (BRAZLIPO) BRAZILIAN GROUP FOR THE STUDY OF INHERITED AND ACQ
Published: June 2020

Background: It is related that thyroid appears can be affected by insulin resistance (IR). Early and severe IR is a characteristic of Congenital Generalized Lipodystrophy (CGL), characterized by near to total absence of subcutaneous adipose tissue. There are few studies about thyroid abnormalities in CGL.
Aim: To describe thyroid structure and function in patients with CGL and correlate with HOMA-IR. Methods: The patients were submitted to a medical interview, physical examination, thyroid ultrasonography and biochemical, lipid profile and thyroid hormones evaluation.
Results: Twenty-three patients with a CGL were included, median age was 13.3 years (3.6 to 38.7), 15 (65%) were younger than 19 years, 14/23 (60.8%) were women and 14 (60.8%) patients had diabetes. All patients had low leptin levels, low HDL cholesterol and 18/23 (78,2%) had hypertriglyceridemia (316.55-1052mg/dL). The prevalence of thyroid hormonal dysfunction was 17.4% (4/23): subclinical (1/23) and clinical hypothyroidism (1/23), subclinical (1/23) and clinical hyperthyroidism (1/23). TSH level was 1.27 uUI/mL (0.48 - 6.71), fT4, 1.06 ng/dL (0.82 - 1.92) and T3, 1.27 ng/dL (0, 69 - 1.76). Antithyroperoxidase (ATPO) and anti-titreoglobulin (ATG) antibodies were positive in 4% (1/23) and in 17.3% (4/23). There was a negative correlation between HOMA-IR and fT4 (r= 0.036). The thyroid volume was 4.3 cm³ (1.04 - 60.4), it was altered in 19% of the patients: 33% had nodules and another 33%, parenchyma heterogenicity. There was a positive correlation between HOMA-IR and volume (r= 0.035). A case of thyroid carcinoma was diagnosed in an 8 years-old girl.
Conclusion: The prevalence of thyroid abnormalities was higher than in population data, especially in a young population. IR correlated positively with thyroid volume and negatively with T4l levels. This study did not show correlation between IR and autoimmunity. These data support that thyroid may be directly influenced by the high levels of insulin present in CGL.

Disclosure
V.O. Fernandes: None. G.D. Lima: None. A.D. Montenegro: None. A.B. Carvalho: None. G.M. Rodrigues: None. I.P. Melo: None. L.V. Martins: None. L.A. Batista: None. L. Aguiar: None. R.M. Montenegro: None.
1812-P: Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia
Authors: LUBACZEUSKI CAMILA , BOZADJIEVA NADEJDA , BLANDINO-ROSANO MANUEL , BERNAL-MIZRACHI ERNESTO 
Published: June 2020

Elevation of glucagon levels and increase in α-cell mass are associated to states of hyperglycemia in diabetes. However, little is known about the mechanisms that control glucagon secretion and α-cell mass expansion in normal or diabetogenic conditions. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2KO), we showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of α-cell proliferation, cell size and mass expansion. Hyperglucagonemia in αTSC2KO was associated to increase in glucagon content, enhanced glucagon secretion and defective adaptation to fasting. This model allowed us to identify the beneficial effects of chronic hyperglucagonemia in glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in αTSC2KO mice was characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Surprisingly, hyperglucagonemia in αTSC2KO mice was associated to improved glucose levels in models of Streptozotocin (STZ)-induced β-cell destruction and high fat diet-induced glucose intolerance. Contrary to our current understanding of glucagon action, these studies demonstrate that endogenous chronic hyperglucagonemia improve glucose homeostasis by augmenting insulin secretion and by inducing glucagon resistance in the liver. These novel in vivo findings support the concept that enhancing glucagon action could be used as an alternative strategy to treat hyperglycemia in diabetes.

Disclosure
C. Lubaczeuski: None. N. Bozadjieva: None. M. Blandino-Rosano: None. E. Bernal-Mizrachi: None.

Funding
U.S. Department of Veterans Affairs (IBX002728A); Diabetes Research Connection
1830-P: Therapeutic Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in CDHFD-Induced NASH and Fibrosis Mice
Authors: CHOI JAEHYUK , KIM JUNG KUK , LEE SEON MYEONG , KWON HYUNJOO , LEE JONGSOO , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG 
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease characterized by steatosis and inflammation, which results in fibrosis. In particular, advanced fibrosis due to NASH is associated with a high risk of liver-related mortality, becoming one main cause for liver transplant. To date, there are, however, no pharmacological therapy approved. One major hurdle for the drug development is limited pathologic features of current animal models, in terms of clinical relevance. The choline-deficient and high fat diet (CDHFD) mice have known to develop multiple aspects of NASH and fibrosis similarly with those in human, being increasingly recognized as a feasible disease model. HM15211 is a novel long-acting GLP-1/GIP/Glucagon triple agonist. Previously, HM15211 treatment improved liver fat and fibrosis in various animal models of NASH and fibrosis. Here, we further explored its efficacy in CDHFD mice. In CDHFD mice (8 wks induction), HM15211 significantly reduced hepatic TG and TBARS (oxidative stress marker). Histological analysis indicated a significant reduction both in hepatic inflammatory marker expression and NAFLD activity score. Of note, when compared to FXR agonist or ACC (acetyl CoA carboxylase) inhibitor, HM15211 treatment was associated with greater efficacy improvement. To further confirm, CDHFD mice with an extended induction period (up to 16 wks) was used. Despite the severe disease progression featured by advanced liver fibrosis, HM15211 reduced hepatic hydroxyproline (-42% vs. vehicle) and sirius red positive area (11.9% vs. 4.1% for vehicle and HM15211) markedly in addition to significant liver TG reduction (66.2% vs. vehicle). Therefore, consistent efficacy in various animal models including CDHFD mice suggests the beneficial effect of HM15211 on NASH and fibrosis. Efficacy studies in biopsy proven NASH patients are ongoing to assess the clinical relevance of these findings.

Disclosure
J. Choi: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.