bluuebunny/crossref_metadata_2025_split huggingface dataset:
248-OR: Type 1 Diabetes Risk Variants Alter the Transcriptional Profile of Beta Cells
Authors: RATAJCZAK WIKTORIA , ATKINSON SARAH , KELLY CATRIONA 
Published: June 2021

GWAS studies have identified a number of SNPs connected to the development of type 1 diabetes (T1D). It is unclear how these variants confer risk for T1D development and whether this is based on direct effects on the beta cell, or whether the systemic inflammatory environment is detrimental to the beta cell. Using CRISPR mediated homology directed repair (Life Technologies), T1D risk variants rs10517086 and rs1534422 were introduced into the BRIN-BD11 beta cell line and the Jurkat T-cell line. Experiments were conducted in BRIN-BD11 cells expressing each variant and in native BRIN-BD11 cells treated with conditioned media from Jurkat cells expressing each variant. ApoTox GloTM (Promega) was used to assess cell viability, cytotoxicity and apoptosis. In all instances, cell viability and cytotoxicity were unchanged following the introduction of the two variants. However, rs1534422 significantly (P&lt;0.01) increased apoptosis in BRIN-BD11 cells. This was not observed when BRIN-BD11 cells were treated with Jurkat condition media. In all instances, modest reductions (P&lt;0.05) in glucose-stimulated insulin secretion were observed (Insulin ELISA, Mercodia). Expression of beta cell markers (ABCC8, KCNJ11, KCNQ1, SCL2A2, GCK, HNF1A, PDX1, NKX6.1 NGN3) was examined by qPCR (Roche Lightcycler). Irrespective of whether BRIN-BD11 cells were exposed to Jurkat conditioned media or not, induction of rs10517086 or rs1534422 caused significant (P&lt;0.05-0.001) reductions in the expression of all genes examined with two exceptions: both HNF1A and ABCC8 were significantly upregulated (P&lt;0.001). The transcriptional profiles of BRIN-BD11 cells were remarkably similar regardless of whether rs10517086 and rs1534422 were directly induced in BRIN-BD11 cells or whether they were exposed to conditioned media from Jurkat cells expressing the variants. This suggests that soluble secreted factors arising from the expression of these variants may drive the changes observed in the function of BRIN-BD11 cells.

Disclosure
W. Ratajczak: None. S. Atkinson: None. C. Kelly: None.

Funding
European Union Regional Development Fund; European Union Sustainable Competitiveness Programme for Northern Ireland; Northern Ireland Public Health Agency; Ulster University; Northern Ireland Department of Employment and Learning
251-OR: Impact of Vegetarian and the Nordic Diet on Glucose Metabolism: A Human Intervention Study
Authors: HUBER HANNA , STOFFEL-WAGNER BIRGIT , COENEN MARTIN , WEINHOLD LEONIE , SCHMID MATTHIAS , STEHLE PETER , SIMON MARIE-CHRISTINE 
Published: June 2021

Background: Recent epidemiological studies indicate that the so-called ‘Nordic’ diet (rich in berries, fish and nuts) as well as a vegetarian diet improve serum glucose kinetics and, thus, reduce the risk of diabetes development compared to the ‘Western’ diet. Evidence for these effects from controlled human intervention studies is limited.
Methods: One hundred and twenty overweight adults with at least 1 metabolic syndrome trait (60±7 y, BMI 31.1±3.5 kg/m2, WC men 109±9 cm, women 104±9 cm) were randomized into 3 groups, adhering to Nordic diet [ND], lacto-ovo vegetarian diet [VD], or habitual control diet [HD] for 6 weeks, based on a recipe list, which was adapted to individual energy expenditure (RMR measured by QuarkRMR device, multiplied by a factor of 1.5 for physical activity). At baseline and after 6 weeks, OGTT and mixed meal tolerance test [MMTT] (180 min; postprandial measurements at 7 time points [tp]) were performed. Statistical data analysis was conducted using linear mixed-effect models (group-specific comparison: visit*diet*tp interaction).
Results: As expected no changes in body weight (p=0.083) and body composition (p=0.354) were detected. Within groups, fasting glucose (p=0.760) and insulin levels (p=0.066), HbA1c (p=0.979) and HOMA index (p=0.150) did not change after 6 weeks compared to baseline. Insulin sensitivity (Matsuda index p=0.498, OGIS p=0.478, insulinogenic index p=0.203) and ß-cell function (disposition index p=0.997) showed no intergroup variations. In the group comparison, no effect was found after OGTT and MMTT on AUC of glucose (p=0.869/p=0.824) and insulin (p=0.850/p=0.999). However, compared to controls, VD improved kidney values and ND improved blood lipids, liver and kidney values.
Conclusion: Our medium-term isoenergetic intervention study did not confirm earlier results. Improvements in glucose kinetics as observed in epidemiologic studies are possibly due to a loss of body weight (hypoenergetic nutrition) independent of diet composition.

Disclosure
H. Huber: None. B. Stoffel-wagner: None. M. Coenen: None. L. Weinhold: None. M. Schmid: None. P. Stehle: None. M. Simon: None.

Funding
German Federal Ministry of Education and Research (01EA1809A)
252-OR: Virtual Multidisciplinary Lifestyle Intervention Is as Effective as the Physical Program for Patients with Diabetes and Obesity during COVID-19 Pandemic
Authors: AL-BADRI MARWA , KILROY CARA L. , SHAHAR JACQUELINE I. , TOMAH SHAHEEN , GARDNER HANNAH , SIN MALLORY , VOTTA JENNIE L. , PHILLIPS-STOLL ALIZA , PRICE AARON M. , BEATON JOAN M. , DAVIS CHANDRA L. , RIZZOTTO JO-ANNE M. , HAMDY OSAMA 
Published: June 2021

Intensive lifestyle intervention (ILI) is essential for diabetes management. The Weight Achievement and Intensive Treatment (Why WAIT) program is a 12-week multidisciplinary weight management program that has been implemented in real-world clinical practice and has shown long-term maintenance of weight reduction for 5 years. During COVID-19 pandemic, the program went virtual using telemedicine and mobile-applications (Healthimation and Good Measures™). We evaluated the outcomes of virtual program (VP) in comparison to in-person physical program (PP). Sixteen subjects were enrolled in VP and were compared to 22 subjects who completed the last 2 PPs. Body weight decreased by -16.49±8 lbs. (-7 % ± 0.3%) from baseline in VP (p&lt;0.001) compared to -15.2± 7.8 lbs. (-6 % ± 0.3%) in PP (p&lt;0.001) (p= 0.6 between groups). A1C decreased by -1.03% ± 1.2% from baseline in VP (p=0.002), and by -1.0% ± 1.2% in PP (p=0.001) (p=0.9 between groups). At the end of the intervention, CGM analysis showed TIR (70-180 mg/dL) was 87%±14% in VP and 72%±23% in PP (p=0.6 between them). BP and lipid profile improved in both groups with no significant difference between them. The number of anti-hyperglycemic medications reduced by -0.9± 0.6 in VP and by -0.8± 0.8 in PP (p=0.5 between them). Among insulin-treated patients with type 2 diabetes, 5 patients (50%) in VP and 5 patients (33.3%) in PP stopped insulin at 12 wks (p=0.4 between them). Patients in VP reported reduced barriers to exercise from a score of 17.2±12.2 to 4.6±3.9 (p&lt;0.001).
In conclusion, virtual multidisciplinary ILI is as effective as the in-person physical program in improving body weight, A1C, BP, lipid profile and in reducing the number of anti-hyperglycemic medications. These results suggest that scaling the Why WAIT program in a virtual format to a larger population of patients with diabetes and obesity is potentially as successful as the costly in-person program.

Disclosure
M. Al-badri: None. J. M. Beaton: None. C. L. Davis: None. J. M. Rizzotto: None. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC. C. L. Kilroy: None. J. I. Shahar: None. S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. H. Gardner: None. M. Sin: None. J. L. Votta: None. A. Phillips-stoll: None. A. M. Price: None.
253-OR: Plasma Ghrelin Changes and Successful Weight Loss in Patients with Obesity: The POUNDS Lost Trial
Authors: HEIANZA YORIKO , XUE QIAOCHU , BRAY GEORGE , SACKS FRANK , QI LU , TONG JENNY 
Published: June 2021

The orexigenic gut hormone, ghrelin, has been implicated in the regulation of appetite, energy homeostasis, and adiposity. We investigated associations of plasma ghrelin changes after consuming weight loss diets with improvements in general adiposity, body fat accumulation, and energy metabolism among overweight and obese adults. We also tested whether short-term ghrelin changes in response to weight-loss diets were predictive of long-term successful weight loss. This study included 217 overweight and obese adults who participated in a weight-loss diet intervention study, the POUNDS Lost trial. Plasma ghrelin levels were measured at baseline and 6 months after the intervention. We examined associations of the 6-month changes in plasma ghrelin levels from the baseline with changes in weight, waist circumference (WC), body fat composition assessed by dual-energy X-ray absorptiometry (DEXA), fat distribution assessed by CT scans, and resting energy expenditure (REE). At baseline, higher ghrelin levels were significantly associated with lower adiposity (weight, WC, and body fat composition) and REE (p &lt;0.05 for all). We found that plasma ghrelin levels tended to be increased at 6 months after the intervention among the total participants (with a median 6-month change of 77 pg/ml). Greater increases in plasma ghrelin were associated with larger decreases in weight (p &lt;0.001), WC (p =0.002), trunk fat % (p &lt;0.001), whole-body fat % (p &lt;0.001), total adipose tissue (p=0.007), as well as REE (p=0.01). Further, greater 6-month increases in ghrelin levels were significantly associated with the achievement of successful weight loss (-5% or more weight reduction) at 1 year (P for linear trend=0.0059). Our study suggests that weight-loss diet-induced increases in ghrelin are associated with improvements in adiposity and body fat composition. Plasma ghrelin changes in response to weight-loss diets may be predictive of long-term weight loss success among patients with overweight and obesity.

Disclosure
Y. Heianza: None. Q. Xue: None. G. Bray: None. F. Sacks: None. L. Qi: None. J. Tong: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK115679)
255-OR: Blinded, Randomized Trial of Banded Roux-en-y Gastric Bypass vs. Sleeve Gastrectomy for Type 2 Diabetes after Five Years
Authors: MURPHY RINKI , CUTFIELD RICHARD G. , BOOTH MICHAEL W.C. 
Published: June 2021

Background: Bariatric surgical procedures such as laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are increasingly being utilized to manage type 2 diabetes in those with morbid obesity. It is unclear which procedure is more effective for diabetes remission.
Methods: In a prospective, parallel, two-arm, study conducted in a single centre, eligible patients aged 20-55 years, with BMI 35-65kg/m2 and type 2 diabetes of at least 6 months duration were randomized 1:1 to silastic ring (SR)-LRYGB or LSG using random number codes. Patients and assessors remained blinded to treatment allocation until after primary outcome of type 2 diabetes remission was assessed at 5 years, defined by HbA1c &lt;6% (42mmol/mol) without the use of glucose lowering medications.
Results: Of the 114 patients randomized, 5 died during the 5 year follow up. Diabetes remission assessed in 108/109 (99%) patients, was achieved by 26/53 (49%) after SR-LRYGB vs. 18/55 (33%) after LSG (adjusted odds ratio 6.8; 95% confidence interval, 2.1 to 22.1, p=0.002). Percentage body weight loss assessed in 99/109 (91%) patients, was also greater after SR-LRYGB than after LSG, (26.9± 8.5% vs. 16.3±8.2%, p&lt;0.0001). Acute, 30-day complication rates were similar in both groups. Late re-intervention rates were higher after SR-LRYGB (20 vs. 12). General health and physical functioning domains improved after both types of surgery, with greater improvements in physical functioning after SR-LRYGB (p&lt;0.01).
Conclusions: Among patients with obesity and type 2 diabetes, SR-LRYGB provides greater diabetes remission and weight loss compared to LSG at 5 years.

Disclosure
R. Murphy: None. R. G. Cutfield: None. M. W. C. Booth: None.
267-OR: Assessing Patient Knowledge about Diabetic Foot Ulcer Offloading
Authors: BURMEISTER REBECCA A. , HOLMES CRYSTAL , JAROCKI CHRISTINE , STROM TYSON , TORRENCE GARNEISHA M. , SCHMIDT BRIAN M. 
Published: June 2021

Introduction: Standard of care for diabetic foot ulcers (DFU) includes wound debridement, dressing changes, diabetes control, and offloading. Despite this, half of all patients fail to heal when standard of care is met. Offloading DFU is critical to promote wound healing, yet patient adherence is undesirably low and contributes to failed wound healing. We evaluated patient knowledge of DFU offloading through a voluntary telephone survey.
Methods: Participants were recruited from a tertiary care center podiatry department and completed a 21-item telephone survey. All subjects had a history of diabetes and were included regardless of DFU history. Descriptive statistics and chi square were calculated to evaluate survey responses.
Results: Currently 92 of 167 subjects (55.1%) completed the telephone survey. All subjects regardless of DFU history correctly identified DFU increases risk of amputation (DFU95.7%; n=88/92). All subjects regardless of DFU history identified “offloading” and “pressure relief” as important factors to improve DFU healing (97.8%; n=90/92; 98.9%; n=91/92, respectively). Only a minority (43.5%; n=40/92) of participants were able to correctly identify the best offloading strategy, regardless of DFU history (DFU history 48.5%; n=16/33 vs. No DFU history 40.7%; n=24/59; p=0.5155).
Discussion: We hypothesized people with a history of a DFU would understand the concept of offloading better, but yet patients who had a history of a DFU were as likely to misunderstand the term “offloading” compared to patients who have no history of a previous DFU. Our findings importantly identify a gap in patient education surrounding an essential component of DFU standard of care.

Disclosure
R. A. Burmeister: None. C. Holmes: None. C. Jarocki: None. T. Strom: None. G. M. Torrence: Research Support; Self; Kent Imaging. B. M. Schmidt: None.
268-OR: Cost-Effectiveness and Cost Utility of At-Home Foot Skin Temperature Monitoring for Ulcer Prevention in People with Diabetes: A Multicenter Randomized Controlled Trial (diatemp)
Authors: VAN NETTEN JAAP , AAN DE STEGGE WOUTER B. , DIJKGRAAF MARCEL , BUS SICCO A. 
Published: June 2021

Introduction: The skin of people with diabetic foot disease is thought to heat up from ambulatory activity before it breaks down into ulceration. We assessed cost-effectiveness and cost-utility of at-home foot skin temperature monitoring for ulcer prevention in people with diabetes.
Methods: In this outcome-assessor-blinded multicenter RCT, we randomly assigned people with diabetes, neuropathy, foot ulcer history or Charcot’s neuro-arthropathy to usual care (i.e., podiatric treatment, education, and therapeutic footwear) or usual care plus measuring skin temperatures at 6-8 plantar sites per foot each day (enhanced therapy). Foot care costs from a societal perspective were obtained via institute for Medical Technology Assessment questionnaires and from health records. Utilities were calculated based on health-related quality of life as assessed with the EQ-5D-3L. Primary clinical outcome for effectiveness was foot ulcer recurrence. Group differences were assessed by calculating 95% confidence intervals after correction for bias and using accelerated non-parametric bootstrapping.
Results: Total foot care costs per participant during 18-months follow-up were significantly lower in the intervention group (n=151; €4007 (SD: €6349)) compared to usual care (n=153; €6872 (SD: 15251); p=0.033). The intervention had 99.3% probability of being cost-effective at a willingness-to-pay of €50,000. Quality-adjusted life years were lower in the intervention group (1.09 (SD: 0.35)) than in usual care (1.12 (SD: 0.34); p=0.397). The intervention had 69.0% probability of achieving cost-utility at a willingness-to-pay of €50,000.
Conclusion: In this first-ever societal-perspective cost-effectiveness RCT in the field of diabetic foot disease, we found at-home foot skin temperature monitoring a cost-effective intervention in foot ulcer prevention, at the expense of lower quality of life.

Disclosure
J. Van netten: None. W. B. Aan de stegge: None. M. Dijkgraaf: None. S. A. Bus: None.

Funding
Netherlands Organization for Health Research and Development (837002508); Dutch Society for Podiatrists; Dutch Branch Organization for Pedicures
270-OR: Relationship between Chronic Renal Disease and Risk Stratification for Chronic Ulcer on the Diabetic Foot: Results of a Prospective Cohort
Authors: BONNET JEAN-BAPTISTE , SZWARC ILAN , AVIGNON ANTOINE , JUGANT SEBASTIEN , SULTAN ARIANE 
Published: June 2021

Introduction: Diabetes is the leading cause of non-traumatic lower limb amputation and end-stage renal disease (ESRD). Monitoring of the risk of diabetic foot wounds is guided by the recommendations of the International Working Group for Diabetic Foot (IWGDF), in particular through the gradation of the podiatric risk. Although chronic kidney disease (CKD) is a known risk factor for diabetic foot wounds, the relationship between CKD stage and IWGDF foot risk grade has never been explored. The purpose of the study was to analyze the relationship between CKD stage and foot grade according to IWGDF 2019.
Materials and Methods: We conducted a bi-centric cross-sectional study. All patients were recruited from Diabetes or Nephrology outpatient’s clinic. Foot risk gradation was established during the consultation. Renal function was estimated based on a recent biologic workup.
Results: We included 250 patients between November 2019 and August 2020. Podiatric risk grade was associated with stage of renal failure (p&lt;0.001) and dialysis (&lt;0.001). The best sensitivity/specificity ratio to predict a podiatric risk grade 2 or 3 was 33ml/min/1.73m2 (AUC curve ROC 0.740). Nevertheless, if there was a difference in foot risk grade between patients with ESRD and each of the other CKD stages. There was no difference in foot risk grade between the other CKD stages. Age, smoking, diabetic retinopathy and albuminemia were associated with foot grade in multivariate analysis.
Conclusion: There is an association between podiatric risk grade and stage of CKD. This link is dominated by the impact of dialysis. There is interest in strengthening collaborations between dialysis centers, Nephrologists and diabetic foot expert centers with enhanced therapeutic and prevention education programs. A clearance of 30ml/min/1.73m2 appears as a relevant alert threshold to predict a podiatric risk grade 2 or 3.

Disclosure
J. Bonnet: None. I. Szwarc: None. A. Avignon: None. S. Jugant: None. A. Sultan: None.
280-OR: CTCFL Is a Fasting-Induced Epigenetic Regulator That Modulates Lipid and Cholesterol Metabolism in the Liver
Authors: EFTHYMIOU VISSARION , CHIMENE-WEISS JEREMY I. , ZHOU LIYUAN , OSATAPHAN SORAVIS , SU LEI , PATTI MARY-ELIZABETH 
Published: June 2021

Physiologic adaptations to fasting ensure health when food intake is limited; engaging these regulatory mechanisms is a potential tool for T2D and obesity. One approach utilizes SGLT2 inhibitors (SGLT2i), which reduce glucose, weight and cardiovascular/renal complications. In preclinical studies, we demonstrated SGLT2i induce a fasting-like transcriptional program in liver, and identified Ctcfl (CCTC-binding factor (CTCF)-like, also known as Boris, or Brother Of Regulator of Imprinting sites), as a top-ranking upregulated transcript in SGLT2i-treated C57BL/6J mice (↑1.5-fold, p=0.017). Ctcfl was also upregulated 2.5-fold with fasting as compared to ad lib-fed littermates. Thus, we hypothesize Ctcfl mediates fasting-related transcription via dynamic epigenetic regulation of chromatin accessibility.To identify drivers of increased Ctcfl expression in the fasting state, we performed in vitro studies in cultured AML12 hepatocytes revealing a key role for AMPK activation and mTOR inhibition as upstream regulators of Ctcfl. Transcriptomic analysis in siRNA-mediated Ctcfl knockdown (KD) vs. wild type (WT) cells indicates Ctcfl regulates critical pathways of lipid/carbohydrate metabolism, mitochondrial biogenesis, and transcriptional mediators of fasting (e.g., Hnf4, Srebf, Chrebp, Pgc1α). Single-cell RNAseq revealed distinct populations in Ctcfl-KD vs. WT cells, with the two largest sub-clusters of Ctcfl-KD cells enriched in genes associated with mTOR and insulin signaling and Tfeb target genes. Conversely, gain-of-function studies via overexpression of human CTCFL resulted in significant repression of key transcription factors and enzymes regulating lipid/cholesterol metabolism and gluconeogenesis (Pgc1α).
In conclusion, we demonstrate that AMPK and mTor-mediated pathways regulate Ctcfl, a mediator of fasting-associated lipid and glucose transcriptional programs in the liver, potentially via alterations in chromatin accessibility.

Disclosure
V. Efthymiou: None. J. I. Chimene-weiss: None. L. Zhou: None. S. Osataphan: None. L. Su: None. M. Patti: Consultant; Self; Cello Health, Fractyl Laboratories, Inc., MBX, Poxel SA, WGBH, Other Relationship; Self; Xeris Pharmaceuticals, Inc., Research Support; Self; Dexcom, Inc.
284-OR: Hepatocyte-Specific CCN2 Gene Deletion Prevents NASH Fibrosis in a Mouse Model of High-Fat Feeding and Diabetes
Authors: PARRY SARAH N. , WANG XIAOYU , MIN DANQING , LOURDESAMY JACINTHA S. , WILLIAMS PAUL F. , LEASK ANDREW , TWIGG STEPHEN M. 
Published: June 2021

Introduction: CCN2, formerly known as CTGF, is a pro-fibrotic protein that is implicated in several diabetes-related complications. The role of CCN2 in mediating NASH fibrosis in diabetes has not been fully elucidated. We hypothesize that targeting liver CCN2 can prevent NASH fibrosis in diabetes.
Aim: To examine whether hepatocyte specific homozygous gene deletion of CCN2 leads to less severe liver fibrosis compared with control mice exposed to high fat feeding and diabetes.
Methods: Male control mice (B6.Cg-Tg(AlbCre)21Mgn/J (AlbCre) and homozygous CCN2fl/fl (CCN2fl/fl)), and hepatocyte specific CCN2 knockout mice (CCN2flxB6.Cg-Tg(AlbCre)21Mgn/J (CCN2KO)) were fed either standard chow or high fat diet (HFD; 45% kCal fat). HFD mice were rendered diabetic (HFD+DM) after 15 wks with low dose streptozotocin (2-3 x 0.65 mg/kg ip) then maintained for a further 10 wks. Liver fibrosis was assessed histologically with Picro Sirius Red (PSR) staining. Gene expression of fibrosis markers were measured by RT-qPCR. Biochemical assays were undertaken.
Results: There was less fibrosis by PSR staining in the HFD+DM CCN2KO mice at the central vein (24% reduction, 2.20±0.84 controls vs. 1.66±0.82 CCN2-KO, p=0.03, one tailed Mann-Whitney test) and portal tract (18% reduction, 2.51±0.85 controls vs. 2.06±0.84 CCN2KO, p=0.04) compared with HFD+DM control mice. In HFD+DM CCN2KO mice, there were significant reductions in gene expression of collagen-I (44%, p=0.04), -III (44%, p=0.04) and -IVα1 (40%, p=0.01) but not in collagen-VI or fibronectin. Compared with chow fed mice, HFD+DM mice had higher body weight, BGLs, insulin levels, fat mass and AST and ALT activity but there was no difference in metabolic outcomes between control strains and CCN2KO mice.
Conclusion: Our study has shown partial prevention of NASH fibrosis in diabetes in a novel model with hepatocyte specific CCN2 knockout mice. CCN2 is increasingly a potential target for limiting progression of NASH fibrosis in diabetes.

Disclosure
S. N. Parry: None. X. Wang: None. D. Min: None. J. S. Lourdesamy: None. P. F. Williams: None. A. Leask: Stock/Shareholder; Self; FibroGen. S. M. Twigg: Advisory Panel; Self; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis, Consultant; Self; Aktivo Labs, Sanofi-Aventis, Research Support; Self; Abbott Diabetes, Speaker’s Bureau; Self; Abbott Diabetes, AstraZeneca.