bluuebunny/crossref_metadata_2025_split huggingface dataset:
302-OR: Hypoimmune Human Primary Pancreatic Islets Survive and Function in Humanized Diabetic Mice
Authors: HU XIAOMENG , GATTIS CORIE , YOUNG CHI , OLROYD ARI G. , CHU ELAINE Y.L. , WHITE KATHY , FRIERA ANNABELLE , SCHREPFER SONJA 
Published: May 2022

Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We set out to engineer human primary pancreatic islets (PI) using our hypoimmune strategy that could engraft and evade host immune detection in the absence of IS. Human cadaveric PIs were engineered to knock-out function of HLA class I and II and overexpress CD47 (HIP PI) . Unedited PIs were cultured identically (Wt PI) as controls. NSG-SGM3 mice were reconstituted with human CD34+ cells and had &gt;45% engraftment of human CD45+ cells. Mice were rendered diabetic (streptozotocin) . A total of 300 HIP PI or Wt PI were transplanted IM. After 6 days, splenocytes and serum were obtained for immune analyses. HIP PI showed no T cell recognition (ELISpot) , no graft-specific antibodies (Abs) , and were protected from NK cell and macrophage killing. Wt PI had a strong adaptive immune response with high ELISpot frequencies and an increase in graft-directed Abs. Serial BLI showed survival of all HIP PI grafts but rapid rejection of Wt PI, confirmed by histopathology at 4 weeks. Glucose levels gradually decreased after HIP PI transplantation and remained stable around 200 mg/dl after 14 days. These data suggest that hypoimmune engineering may generate HIP PI capable of persisting and functioning in diabetic patients without IS.

Disclosure
X.Hu: None. C.Gattis: None. C.Young: Employee; Sana Biotechnology Inc. A.G.Olroyd: None. E.Y.L.Chu: None. K.White: None. A.Friera: None. S.Schrepfer: Other Relationship; Sana Biotechnology Inc.
308-OR: The Circadian Clock Exerts Coordinated Control of Beige Adipocyte Development via Cytoskeleton-MRTF/SRF Signaling Cascade
Authors: XIONG XUEKAI , LI WEINI , LIU RUYA , YECHOOR VIJAY , MA KE 
Published: May 2022

The circadian clock confers temporal regulation in metabolism, and its disruption leads to obesity and insulin resistance. In the current study, we identify that the opposing circadian clock regulators, transcription activator Bmal1 and its repressor Rev-erbα, exert concerted control of the actin cytoskeleton-MRTF/SRF pathway to drive beige adipocyte development, and that this clock regulatory axis is required for beige fat thermogenic capacity. Key components of the MRTF/SRF signaling display circadian oscillations in beige fat, and cistromic analyses revealed Bmal1 and Rev-erbα chromatin occupancy of genes involved in MRTF/SRF regulation. Genetic loss- or gain-of-functions of Bmal1 and Rev-erbα in adipogenic precursors markedly altered actin cytoskeleton organization. Bmal1 silencing inhibits F-actin formation and MRTF/SRF activity whereas its forced expression augments actin cytoskeleton. Notably, Bmal1 and Rev-erbα transcriptional control of the MRTF/SRF signaling modulates beige fat thermogenic capacity in vivo. Prrx1-Cre-mediated subcutaneous beige fat-selective Bmal1 ablation induced browning with augmented mitochondrial metabolism, resulting in resistance to obesity that improved insulin sensitivity. Conversely, overexpression of Bmal1 in beige depot suppressed the thermogenic program with adipose expansion and impaired glucose tolerance. In contrast, Rev-erbα gain-of-function phenocopied that of Bmal1 ablation, leading to browning of beige fat, resistance to obesity and insulin sensitivity. Mechanistically, we show that genetic loss of Bmal1 enhanced beige precursor differentiation and thermogenic induction, whereas Rev-erbα overexpression similarly promoted beige adipogenesis. Collectively, these findings uncover a novel concerted circadian clock control in beige adipocyte development that determines thermogenic capacity via the cytoskeleton-MRTF/SRF signaling cascade.

Disclosure
X.Xiong: None. W.Li: None. R.Liu: None. V.Yechoor: n/a. K.Ma: None.

Funding
NIH 1R01DK112794 to KM and DK097160 to VY
31-OR: Almond Milk Has No Additional Benefits over 2% Milk on Postprandial Glycemia, Lipidemia, and Gastrointestinal Hormones in Patients with Type 2 Diabetes
Authors: MITRI JOANNA , TOMAH SHAHEEN , DREYFUSS JONATHAN , AL-BADRI MARWA , DHAVER SHILTON E. , GARDNER HANNAH , TASABEHJI MHD WAEL , HAMDY OSAMA 
Published: May 2022

Almond milk is often used in lieu of dairy milk with the perception of being a healthier substitute, however, its effect on postprandial glycemia compared to 2% milk is not understood. In this study, we compared the 4-hour postprandial effects of almond milk versus carbohydrate- or caloric-matched 2% milk, each served with a similar amount of oatmeal in patients with T2D. In this cross-over, three-way, open-label study, 22 overweight or obese patients with T2D consumed ½ cup (40 g) of oatmeal served with 360 mL almond milk (ALM) or carbohydrate-matched (246 ml) 2% milk (CarbM) or calorie-matched (182 ml) 2% milk, on separate days, in random order. The primary outcome was glucose incremental area under the curve (iAUC 0-240) while changes in other analytes were secondary outcomes. Blood samples for glucose, free fatty acids (FFA) , gastrointestinal (GI) satiety and hunger hormones were drawn at baseline, 15, 30, 60, 90, 120, 180 and 240 minutes. Incremental AUCs were compared between groups using Wilcoxon signed rank test. P-values for analytes other than glucose were adjusted with the false discovery rate (FDR) . P&lt;5% for glucose or FDR&lt;5% were considered significant. There were no differences in iAUC 0-240 for glucose, triglycerides, PYY, active GLP-1 or amylin, leptin, GIP, cholecystokinin, ghrelin or FFA in any pair-wise comparison. However, iAUC 0-240 for insulin and glucagon were significantly higher in CarbM vs. ALM (FDR 0.002 and 0.02 respectively) .
In conclusion, compared to almond milk used with oatmeal, carbohydrate- or caloric-matched 2% milk has similar effects on postprandial glucose, FFA, triglycerides and GI hormones for up to 4 hrs, indicating no additional benefits of almond milk over 2% milk. On the contrary, carbohydrate-matched 2% milk increased insulin and glucagon secretion compared to almond milk. The long-term significance of this increase in insulin release needs to be further elaborated in a long-term study.

Disclosure
J.Mitri: Consultant; dairy management, Lnutra. S.Tomah: None. J.Dreyfuss: None. M.Al-badri: None. S.E.Dhaver: None. H.Gardner: None. M.Tasabehji: None. O.Hamdy: Advisory Panel; L-Nutra Inc., Nestlé, Consultant; Abbott, Sanofi, Research Support; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Healthimation.
316-OR: Genetic Deletion of Beta-Cell Pkm1, Pkm2, and Pck2 Identifies PEP as an Essential Signal for Compartmentalized KATP Closure and Cycling of the Insulin Secretory Pathway
Authors: FOSTER HANNAH R. , HO THUONG , POTAPENKO EVGENIY , CARDONE REBECCA L. , KIBBEY RICHARD , MERRINS MATTHEW J. 
Published: May 2022

β-cells use pyruvate kinase to sense nutrients and respond with appropriate insulin secretion. Here, we used β-cell deletion to identify the functions of constitutively active PKm1 and allosterically recruitable PKm2, and assess their regulation by mitochondrial PEP from PCK2. We demonstrate that both PKm isoforms are present in the KATP channel microcompartment. Compartmentation nullifies the disparities in PK isoform expression and activity, allowing the minor but recruitable PKm2 isoform to fully participate in KATP regulation. However, this shared control does not extend to β-cell response to amino acids, which requires PKm1 for the initiation of Ca2+ influx and insulin secretion and PKm2 for their termination. Mitochondrial PEP is required for this cycling between “on” and “off” states, as demonstrated by β-cell-specific deletion of PCK2. PCK2 was revealed to be an essential mechanism of β-cell cataplerosis, possessing metabolic control over cytosolic ATP/ADP generation in response to anaplerotic fuels. Further, PCK2 is required for amino acid-stimulated Ca2+ influx (via PKm1) and efflux (via PKm2) . These data provide strong genetic evidence for a revised oscillatory model of β-cell metabolism in which PKM1- and PKM2-driven PEP cycles play unique roles in the initiation and termination of nutrient-stimulated insulin secretion.

Disclosure
H.R.Foster: None. T.Ho: None. E.Potapenko: None. R.L.Cardone: n/a. R.Kibbey: Consultant; Agios, Inc. M.J.Merrins: None.

Funding
NIH/NIDDK (R01DK113103) HRSA (T32HP10010) NIH/NIA (T32AG000213)
323-OR: Associations of Leukocyte Telomere Length and Related Allelic Variations with the Risk of Coronary Events in People with Long-Standing Type 1 Diabetes
Authors: SANCHEZ MANUEL , POTIER LOUIS , VENTECLEF NICOLAS , FUMERON FRÉDÉRIC , SCHEEN ANDRÉ , GAUTIER JEAN-FRANÇOIS , MARRE MICHEL , ROUSSEL RONAN , MOHAMMEDI KAMEL , VELHO GILBERTO 
Published: May 2022

Backgrounds and Aims: Leukocyte telomere length (LTL) is associated with cardiovascular risk. We evaluated associations between LTL, allelic variations (SNPs) in LTL-related genes (associated with LTL in the literature) and the incidence of coronary artery disease (CAD) in adults with long-standing type 1 diabetes.
Participants and Methods: LTL was measured by real-time PCR in 260 participants of the GENEDIAB cohort (males 60%, age 45±12 years, duration of diabetes 29±years at baseline, mean±SD) . Thirty-three SNPs in LTL-associated genes were genotyped in 826 participants from GENEDIAB and GENESIS cohorts (males 55%, age 43±12 years, duration of diabetes 27±9 years at baseline) . The risk for CAD (myocardial infarction or coronary artery revascularization) during follow-up was analyzed using Cox models according to LTL (expressed in tertiles of distribution) and SNPs.
Results: The cumulative incidence of CAD in GENEDIAB (11±7-year follow-up) was 21.2%. The incidence of CAD by LTL tertiles was 27.6% (shorter LTL) , 23.3% (intermediate LTL) and 12.6% (longer LTL) . Hazard ratio (HR) for shorter vs. longer LTL was 1.63 (95%CI 1.15-2.37) , p=0.005, unadjusted model, and 1.58 (95%CI 1.08-2.39) , p=0.02, after adjustment on sex, age, duration of diabetes, blood pressure, kidney function and history of CAD at baseline. The cumulative incidence of CAD in GENEDIAB and GENESIS pooled data (followed by 11±6 years) was 15.1%. Six SNPs located in three genes (TERC, NAF1 and TNKS) were significantly associated with the incidence of CAD.
Discussion: Shorter LTL at baseline was associated with an increased risk of CAD during the follow-up in adults with long-standing type 1 diabetes. Allelic variations in LTL-related genes were also associated with coronary risk in these subjects.

Disclosure
M.Sanchez: None. G.Velho: None. L.Potier: Board Member; Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Consultant; AstraZeneca, Sanofi. N.Venteclef: None. F.Fumeron: None. A.Scheen: Advisory Panel; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Gautier: Other Relationship; Novo Nordisk, Sanofi, Speaker's Bureau; Eli Lilly and Company. M.Marre: Board Member; AstraZeneca, Consultant; Novo Nordisk. R.Roussel: None. K.Mohammedi: Board Member; Lilly, Novo Nordisk, Sanofi, Research Support; Cyclerion Therapeutics, Inc., Speaker's Bureau; Abbott, AstraZeneca.
324-OR: Pathway-Specific Role of Insulin in an In Vivo Model of Restenosis
Authors: LIU ZHIWEI , GONZALEZ MAREL , OU SONGXIAN , QIU LANHUI , GIACCA ADRIA 
Published: May 2022

Percutaneous transluminal coronary angioplasty is an effective treatment for stenotic lesions, but restenosis remains as a common adverse effect and contributes to post-angioplasty failure. Patients with type 2 diabetes have higher risk of post-angioplasty restenosis due to insulin resistance. In vitro studies showed that insulin has a vasculoprotective effect on endothelial cells (ECs) which is likely mediated by phosphoinositide 3-kinase (PI3K) /Akt pathway, while its mitogenic effects are mainly manifested on vascular smooth muscle cells (VSMCs) and likely mediated via mitogen-activated protein kinase (MAPK) pathway. Currently, there is not much information about pathway-specificity of insulin’s vascular effects in in vivo models. This study aims to determine the Akt2- and MEK1 (MAPK kinase activator) -mediated effects on neointimal growth in a murine model of restenosis. Akt2/MEK1 floxed mice were crossed with tamoxifen-inducible Cre recombinase under the control of vascular endothelial cadherin (Cdh5) or smooth muscle myosin heavy chain (SMMHC) promoters. Mice were implanted subcutaneously with either insulin pellets (0.U/day) or blank pellets three days prior to femoral artery wire injury surgery. Femoral arteries were collected 28 days after surgery for histology analysis. We found that both neointimal area (NA) and intima-to-media ratio (I/M) were lowered in Akt2 floxed Cre- and and wild type Cre+ control mice following insulin treatment, however, insulin failed to have the same effect in both EC and SMC Akt2 deficient mice. Preliminary data suggest that the effect of insulin on decreasing NA and I/M may be greater in EC MEK1 deficient mice but not in SMC MEK1 deficient mice than controls. These data suggest that both EC and VSMC Akt2 contribute to the beneficial effects of insulin, while EC-specific MEK1 knockdown may accentuate the beneficial effects of insulin.

Disclosure
Z.Liu: None. M.Gonzalez: None. S.Ou: None. L.Qiu: None. A.Giacca: None.
331-OR: Gestational Diabetes Knowledge Improves with Interactive Online Training Modules
Authors: KRUTILOVA PETRA , WILLIAMS ROXANN C. , MOREY REBECCA , FIELD CAROLE , BYRTH RONNI , TEPE MELISSA D. , HERRICK CYNTHIA J. 
Published: May 2022

Background: GDM (gestational diabetes mellitus) increases the lifetime risk of maternal T2DM by 7-fold and increases the risk for maternal and fetal complications. Prenatal education on nutrition, exercise, and T2DM risk among women with GDM increases the likelihood of postpartum diabetes screening. However, access to diabetes education is limited. To address this gap, we created four GDM training modules for nurses and community health workers (CHW) and studied changes in knowledge, attitudes, and intentions before and after training completion.
Methods: Online modules (45-60 minutes each with interactive cases and integrated knowledge check questions) were distributed through multiple professional organizations to clinical staff providing care for women with GDM with optional pre- and post-evaluation surveys.Data were not normally distributed. We described baseline population characteristics, GDM knowledge, attitudes, and intentions using median score and interquartile range. We evaluated changes in scores on knowledge, attitude, and intention scales before and after training using non-parametric Wilcoxon matched pair signed rank tests.
Results: Seventy-eight individuals completed baseline evaluation (99% female, median age 40, 65% white non-Hispanic; 54% LPN/RN, 22% CHW, 24% other degree) . Nineteen individuals completed all 4 modules and post-training assessments. GDM knowledge improved significantly after training (median pretest - posttest score: 56% to 78%, p&lt;0.001) . The biggest improvement in knowledge was noted in monitoring, medications, and hypoglycemia prevention (51% to 77%, p&lt;0.001) . Intention to recommend diabetes prevention methods also increased after training (median pretest - posttest score: 35.5 to 39.4, max. score 40, p=0.009) .
Conclusion: Interactive online modules improved knowledge and intention to recommend diabetes prevention methods. Access to such curricula is critical for improving access to diabetes education among patients.

Disclosure
P.Krutilova: None. R.C.Williams: None. R.Morey: None. C.Field: None. R.Byrth: None. M.D.Tepe: Other Relationship; Merck & Co., Inc. C.J.Herrick: Consultant; Teladoc Health, Other Relationship; Eli Lilly and Company, Merck & Co., Inc.

Funding
NICHD K23HD096204NIDDK T32DK007120
332-OR: Success of Virtual Patient Simulation at Improving Comprehensive Management of Type 2 Diabetes
Authors: LARKIN AMY , LACOUTURE MICHAEL 
Published: May 2022

We sought to determine if online, virtual patient simulation (VPS) -based continuing medical education (CME) can improve performance of diabetologists/endocrinologists (D/Es) and PCPs in comprehensive management of T2D.
Methods: The CME comprised a patient presenting at two different time points in a VPS platform that allows learners to order lab tests, make diagnoses, and prescribe treatments similar to actual practice. Tailored clinical guidance (CG) , based on current evidence, was provided, followed by opportunity to modify choices. Decisions were collected post-CG and compared with baseline (pre-CG) decisions using a McNemar’s test to determine P values. The activity posted July 8, 2021; initial data collected through December 7, 2021.
Results: 48 D/Es and 494 PCPs completed all decisions within at least 1 case and were included. Case 1: Primary Prevention: 48% relative increase of D/Es (56% pre-CG vs. 83% post-CG; P&lt;.001) and 21% relative increase of PCPs (70% pre-CG vs. 85% post-CG; P&lt;.001) who assessed glycemic control and CV risk. 425% relative increase of D/Es (8% pre-CG vs. 42% post-CG; P&lt;.001) and 1150% relative increase of PCPs (4% pre-CG vs. 50% post-CG; P&lt;.001) who accurately ordered treatments for primary prevention. Case 2: Secondary Prevention: 23% relative increase of D/Es (66% pre-CG vs. 81% post-CG; P&lt;.05) and 11% relative increase of PCPs (76% pre-CG vs. 84% post-CG; P&lt;.001) who assessed glycemic control and CV risk. 163% relative increase of D/Es (19% pre-CG vs. 50% post-CG; P&lt;.01) and 103% relative increase of PCPs (29% pre-CG vs. 59% post-CG; P&lt;.001) who accurately ordered treatments for secondary prevention. Continued Gaps: 58% of the D/Es and 50% of PCPs failed to provide effective primary prevention risk reduction in case one, and 50% of the D/Es and 41% of PCPs failed to provide effective secondary prevention risk reduction in case two.
Conclusion: This CME strategy improved evidence-based clinical decisions related to comprehensive management of T2D.

Disclosure
A.Larkin: None. M.Lacouture: None.

Funding
Eli Lilly and Company
341-OR: Enhanced Responsiveness of ß- and α-Cells to Glucagon-Like Peptide-1 (GLP-1) in Youth vs. Adults with Impaired Glucose Tolerance (IGT) or Drug-Naïve Type 2 Diabetes (T2D)
Authors: NADEAU KRISTEN J. , TJADEN ASHLEY H. , EHRMANN DAVID A. , ARSLANIAN SILVA A. , CAPRIO SONIA , EDELSTEIN SHARON , HANNON TAMARA S. , TEMPLE KARLA A. , XIANG ANNY , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: May 2022

In the Restoring Insulin Secretion (RISE) Study, youth (Y) compared to adults (A) had enhanced β-cell (greater incremental C-peptide [CP] responses) and α-cell responsiveness (greater glucagon [GG] suppression) . As GLP-1 increases CP and decreases GG, we measured GLP-1 (Mercodia) during a 3-h oral glucose tolerance test (OGTT) in 65 Y (age: 14.2 y) and 65 A (51.0 y) to determine if greater GLP-1 release explained age-related differences in CP and GG responses. Groups were matched for sex (71% female) , race/ethnicity (29% white, 22% black, 37% Hispanic) and IGT/drug naïve T2D (80/20%) status and did not differ by BMI (36.7±6.0 vs. 35.3±4.1 kg/m2) . We calculated fasting, early (0-to-30 mins; ∆) and incremental area under the curve (iAUC) responses for G, CP and GLP-1, and decrements in GG (d∆; dAUC) . Y and A did not differ in fasting or OGTT glycemic responses, but Y had greater fasting CP, ∆CP and iAUC CP, more d∆GG suppression, and a trend for more diGG suppression, than A (Table) . Fasting GLP-1 was not different in Y vs. A, but stimulated GLP-1 was lower in Y throughout the OGTT.
In conclusion, in Y higher CP and lower GG during an OGTT, paired with lower GLP-1 concentrations, suggest that the enhanced β- and α-cell responsiveness to GLP-1 could be due to increased sensitivity of the islet cells to the incretin, rather than a primary increase in GLP-1 release.

Disclosure
K.J.Nadeau: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. A.H.Tjaden: None. D.A.Ehrmann: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Caprio: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. K.A.Temple: None. A.Xiang: None.

Funding
American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California
346-OR: Race/Ethnicity-Specific Relationships of Physical Markers of Adiposity to Clamp-Measured Insulin Sensitivity (IS) and ß-Cell Function (ßCF) in Obese Youth
Authors: ROSENBERG JARED , CHO WONHEE , ARSLANIAN SILVA A. , KIM JOON YOUNG 
Published: May 2022

Physical markers of adiposity including BMI, WC and WHtR have been utilized as physical surrogates of IS and βCF to examine type 2 diabetes risk but without attention to race/ethnicity specific differences. Herein, we examined race-specific differences in the relationships between those physical surrogates and clamp-measured IS and βCF in obese African American (AA) vs. American White (AW) youth. A total of 183 obese youth (age 14.6 ± 0.1 yrs [SE]) completed a hyperinsulinemic-euglycemic clamp to evaluate peripheral IS and a hyperglycemic clamp to measure 1st-phase insulin (1st-PhI) . In AW, BMI, WC and WHtR correlated significantly with peripheral IS and 1st-PhI while in AA with only peripheral IS (Table) . The relationships of BMI to peripheral IS and 1st-PhI were stronger in AW vs. AA youth, with no differences in the correlation coefficients by race for WC and WHtR (Table) . There was a larger decrease in peripheral IS from the lowest to the highest tertiles of BMIs in AW vs. AA youth (63 vs. 39%, interaction p&lt;0.01) , with no interaction on 1st-PhI.The strong relationship of BMI with IS and 1st-PhI in AW but not AA youth may suggest that other factors besides BMI may play a role in the insulin resistance/hyperinsulinemia reported in AA youth. In AW youth, increases in BMI may be more detrimental for reductions in insulin sensitivity than is the case for AA youth.

Disclosure
J.Rosenberg: None. W.Cho: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. J.Kim: n/a.

Funding
National Institute of Child Health and Human Development grant (K24-HD01357 and R01-HD27503) National Center for Advancing Translational Sciences Clinical and Translational Science Award (UL1TR000005) National Center for Research Resources grant (UL1RR024153)