bluuebunny/crossref_metadata_2025 huggingface dataset:
235-OR: Dorzagliatin as a Glucose Sensitizer Achieved Sustained Glycemic Control with Good Safety Profiles in Drug-Naïve T2D Patients in a 52-Week Phase 3 Monotherapy Trial (SEED)
Authors: CHEN LI , ZHANG YI , ZHU DALONG
Published: June 2021

Improvement of glucose and insulin sensitivity in T2D remains as an unfulfilled task for the treatment of underlying cause of disease. Dorzagliatin is a first-in-class antidiabetic drug that acts as a glucose sensitizer, which repairs the sensor function of glucokinase(GK) and improves glucose sensitivity. The study aimed to confirm the efficacy and safety of dorzagliatin as a monotherapy in T2D patients. In this randomized, double-blind, placebo-controlled trial, 463 eligible drug-naïve Chinese patients were randomized to 75 mg dorzagliatin or placebo (2:1) twice daily (BID) groups for 24 weeks, followed by the dorzagliatin treatment (75 mg BID) for 28 weeks in both groups. The primary endpoint was the change in the HbA1c from baseline to week 24. The mixed models for repeated measures results suggested that the least squares mean change in HbA1c from baseline at week 24 was -1.07% in the dorzagliatin group, significantly lower than the placebo (P<0.0001), with effects sustained till the end of the 52-week treatment. Significantly improved β-cell function was seen at week 24 in the dorzagliatin group measured by the change in homeostasis model assessment 2-β (HOMA2-β) from baseline compared with the placebo group (2.56 vs. -0.72, P<0.05). The homeostatic control rate (HbA1c <7% without hypoglycemia) at week 24, was 42.2% in the dorzagliatin group compared to 17.3% in the placebo group (P<0.0001). No deaths, drug-related serious adverse events, and severe hypoglycemia were reported. Incidence of the clinically significant hypoglycemia (blood glucose <3.0 mmol/L) was low (<1%). Dorzagliatin had a favorable effect on sustained glycemic control and a good safety profile over 52 weeks in Chinese T2D patients. It is the first successful phase 3 trial for a GK activator. As a glucose sensitizer, dorzagliatin targets the restoration of glucose homeostasis, providing new hope for treating T2D patients.

Disclosure

L. Chen: None. Y. Zhang: Employee; Self; Hua Medicine. D. Zhu: None.
242-OR: Single Nuclei Skeletal Muscle Chromatin and Gene Expression Profiling across 287 Individuals Reveals Cell Type-Specific Genetic Regulatory Architectures at T2D GWAS Loci
Authors: PARKER STEPHEN , VARSHNEY ARUSHI , STUDY FUSION TISSUE ,   GROUP AMP-T2D SKELETAL MUSCLE WORKING
Published: June 2021

Skeletal muscle is the largest organ, by weight (>40%), in the human body; insulin resistance in this and other peripheral tissues is a hallmark of type 2 diabetes (T2D). Recent genome wide association study (GWAS) results show enrichment for T2D and fasting insulin SNPs in skeletal muscle regulatory regions. Identifying gene regulatory mechanisms underlying these associations requires pinpointing the set of causal variants, the target genes these variants regulate, and the specific skeletal muscle cell populations in which they function. Here, we generated single nuclei chromatin (snATAC) and transcription (snRNA) profiles across 287 frozen human skeletal muscle biopsies. We integrated 414,982 nuclei across the modalities with LIGER and identified 13 cell types, ranging in abundance from 38.1% (type 1 fiber) to <1% (adipocyte) of all nuclei. We further integrated genotypes and performed expression and chromatin accessibility quantitative trait loci (e/caQTL) scans in the five most abundant cell types (type 1, type 2a, type 2x, mesenchymal stem cell, endothelial). We identified >70k associations (5% FDR) ranging from shared to cell type-specific and performed colocalization with T2D GWAS signals. Of 73 T2D GWAS signals that colocalize with caQTL, 39 (53.4%) are cell type-specific, highlighting the importance of sn-caQTL maps for GWAS functional studies. For example, in mesenchymal stem cells, we identified a cell type-specific caQTL for an ARL15 intronic peak (rs702634, p=6.6x10-10), which colocalizes with the T2D GWAS signal (coloc H4 posterior probability = 0.95). To nominate target genes for this caQTL peak, we scanned peaks in promoters of genes in the 1 Mb neighborhood and computed co-accessibility scores using Cicero in an allele-specific manner, which identified the gene FST, ~493 kb away. FST encodes for follistatin which increases muscle growth and reduces fat mass and insulin resistance.

Disclosure

S. Parker: None. A. Varshney: None. Fusion tissue study: n/a. Amp-t2d skeletal muscle working group: n/a.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-07 to S.P.); National Institutes of Health (R01DK117960, U01DK06237017, UM1DK126185)
246-OR: Probing the Role of Alternative Splicing of IKZF1 in Risk for Type 1 Diabetes
Authors: PALOMO LUCIA PASTOR , NEWMAN JEREMY R.B. , ATKINSON MARK A. , CONCANNON PATRICK J.
Published: June 2021

Genome wide association studies have identified a region at chromosome 7p12.2, containing the IKZF1 gene, that is associated with type 1 diabetes (T1D). IKZF1 encodes Ikaros, a transcription factor and critical regulator of lymphocyte development and homeostasis. The IKZF1 gene includes 9 exons that produce at least 10 distinct transcripts. Exons 3-5 encode 4 zinc finger motifs that mediate DNA binding, while the last exon encodes 2 zinc fingers that allow homo- or heterodimerization. We examined the expression of IKZF1 using RNA-seq data from different lymphocyte populations. Individual coding exons of IKZF1, notably exons 3 and 5, displayed significant differences in usage between CD4+ T cells, CD8+ T cells and CD19+ B cells among T1D cases as well as between cases and controls in memory CD4+ T cells. This suggested that specific transcript isoforms of IKZF1 are differentially expressed in lymphocyte subtypes as well as in T1D. To explore the role of alternative splicing of IKZF1 in T1D, CRISPR/cas9 was used to generate Jurkat T cell lines with truncating mutations in either IKZF1 exon 3, exon 5 or both. Clones were isolated by serial dilution and characterized by PCR amplification and DNA sequencing. Twenty clones with different IKZF1 mutations were identified. Immunoblots revealed shifts in Ikaros protein isoform abundance consistent with the exon targeting in individual clones. Mutation of exons 3 or 5 resulted in the upregulation of 218 genes and the downregulation of 309 genes, as assayed by RNA-seq. Interrogation of ENCODE project data showed that most of these differentially expressed genes have an IKZF1 ChIP-seq peak within 1kb of the gene, consistent with their being targets of Ikaros regulation. These results suggest that the number of zinc finger domains in Ikaros, rather than their sequence or structure, modulates their impact. More broadly, the differential expression of IKZF1 transcripts distinguishes the transcriptomes of specific lymphocyte populations in both T1D cases and controls.

Disclosure

L. Pastor palomo: Employee; Spouse/Partner; Cox Business. J. R. B. Newman: None. M. A. Atkinson: None. P. J. Concannon: Stock/Shareholder; Self; Amgen Inc.

Funding

National Institutes of Health (R01DK116954, P01AI042288)
247-OR: Variant-to-Gene-Mapping Analyses Reveal a Role for Pancreatic Islet Cells in Conferring Genetic Susceptibility to Sleep-Related Traits
Authors: LASCONI CHIARA , PAHL MATTHEW C. , PIPPIN JAMES A. , SU CHUN , JOHNSON MATTHEW , CHESI ALESSANDRA , WELLS ANDREW D. , KAESTNER KLAUS H. , GRANT STRUAN F.A.
Published: June 2021

Altered glucose metabolism observed in sleep dysregulation has been reported to contribute to obesity and type 2 diabetes (T2D) risk. We elected to investigate if known sleep loci exert any of their effect in the pancreatic alpha and beta-cell setting. To establish genetic commonalities between sleep and metabolic disorders, we conducted linkage disequilibrium (LD) genetic correlation analyses with publicly available GWAS summary statistics for 4 sleep-associated traits (insomnia, chronotype, short and long sleep), T2D and obesity. Insomnia was significantly correlated with both T2D (genetic correlation (rg)=0.2; P=2.4x10-11) and obesity (rg=0.13; P=0.0021), as was short sleep (T2D, rg=0.2; P=1.8x10-10; obesity, rg=0.22; and P=5.1x10-7) and long sleep (T2D, rg=0.23; P=3.1x10-10; obesity rg=0.09; P=0.019). Chronotype was significantly correlated with T2D only (rg=0.05; P=0.038). Using partitioned LD score regression we then intersected summary statistics with our ATAC-seq and high-resolution promoter-focused Capture C data to assess enrichment of sleep trait SNPs within promoter-interacting open chromatin regions in both the human beta-cell line, EndoC-BH1, and sorted human alpha-cells. EndoC-BH1 was highly significantly enriched for chronotype loci (P=2.2x10-7). Furthermore there was significant enrichment for insomnia (P=0.01) and short sleep (P=0.017). The alpha-cells were also significantly enriched for chronotype (P=0.0016), insomnia (P=0.0076), short sleep (P=0.022), along with long sleep (P=0.034). Motivated by these observations, subsequent variant-to-gene mapping implicated 32, 37 and 6 putative effector genes for insomnia, chronotype and short sleep, respectively, in EndoC-BH1. For alpha-cells, 55, 54, 10 and 5 genes were implicated for insomnia, chronotype, short and long sleep, respectively. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets.

Disclosure

C. Lasconi: None. M. C. Pahl: None. J. A. Pippin: None. C. Su: None. M. Johnson: None. A. Chesi: None. A. D. Wells: None. K. H. Kaestner: None. S. F. A. Grant: None.

Funding

National Institutes of Health (UM1DK126194)
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<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<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<0.05-0.001) reductions in the expression of all genes examined with two exceptions: both HNF1A and ABCC8 were significantly upregulated (P<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<0.001) compared to -15.2± 7.8 lbs. (-6 % ± 0.3%) in PP (p<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<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 <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 <0.001), WC (p =0.002), trunk fat % (p <0.001), whole-body fat % (p <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 <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<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<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<0.001) and dialysis (<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.
29-LB: Exercise Effects on ?3-AMPK Activity, Akt Substrate of 160 kDa Phosphorylation, and Glucose Uptake in Muscle of Normal and Insulin-Resistant Female Rats
Authors: WANG HAIYAN , ARIAS EDWARD B. , ZHENG AMY , KWAK SEONGEUN , ZHAO JIAHUI , DONG GENGFU , CARTEE GREGORY D.
Published: June 2021

Background: Previous studies demonstrated that exercise can enhance insulin-stimulated glucose uptake (ISGU) concomitant with greater Akt Substrate of 160 kDa (AS160) phosphorylation in muscles from normal or insulin resistant, male rats. However, little is known about exercise effects on ISGU in insulin-resistant muscle from female rats. Our goal was to assess exercise effects on ISGU and key signaling proteins in muscles from female rats fed a low-fat or high-fat diet.

Methods: Female rats were randomly assigned to 2 diet-groups: standard chow (low-fat diet, LFD: 14% kCal fat) or high-fat diet (HFD: 60% kCal fat). After 2 weeks, rats from each diet-group either remained sedentary (LFD-SED or HFD-SED) or exercised (2h duration swim). At 3h post-exercise (3hPEX), paired epitrochlearis muscles were isolated and incubated with [3H]-2-deoxyglucose ±insulin to measure GU. Muscles were also assessed for γ3-AMPK activity and phosphorylated AS160 (pAS160; Ser588 and Thr642).

Results: HFD-SED vs. LFD-SED rats had lower ISGU. At 3hPEX in each diet group, ISGU exceeded their diet-matched, sedentary controls. ISGU for LFD-3hPEX was greater than HFD-3hPEX. LFD-3hPEX vs. LFD-SED had greater γ3-AMPK activity and insulin-stimulated pAS160 (Ser588 and Thr642). For HFD-3hPEX vs. HFD-SED, insulin-stimulated pAS160 Thr642 was increased. However, γ3-AMPK activity was not different between HFD-SED and 3hPEX. Insulin-stimulated pAS160 Ser588 and Thr642 at 3hPEX did not differ between diet-groups, but γ3-AMPK for LFD-3hPEX exceeded HFD-3hPEX.

Conclusions: These results indicated that prior exercise can enhance ISGU for LFD and HFD female rats, and suggested that the exercise-increase in ISGU for each diet-group may be related to greater pAS160. The elevated γ3-AMPK activity for LFD-3hPEX vs. LFD-SED, but not HFD-3hPEX vs. HFD-SED, raises the possibility that this difference may be relevant for the greater ISGU in LFD-3hPEX vs. HFD-3hPEX.

Disclosure

H. Wang: None. E. B. Arias: None. A. Zheng: None. S. Kwak: None. J. Zhao: None. G. Dong: None. G. D. Cartee: None.

Funding

National Institutes of Health (DK71771)
293-OR: IFN-a Evokes a Heterogeneous, Rapid ROS Response from a Subset of Human Islet Beta Cells in Situ
Authors: ARVIN MATTHEW , MURALIDHARAN CHARANYA , CONTEH ABASS M. , IRIZARRY MICHELLE M. MARTINEZ , ORR KARA , DUNN KEN W. , LINNEMANN AMELIA K.
Published: June 2021

A large body of evidence reveals a web of complex, multifaceted genetic, and environmental factors that influences incidence of T1D. Among these, viral infection has been discussed as a factor implicated in onset. Production of type 1 interferons (IFN) is the archetypal immune response to viral infection. Indeed, at-risk children exhibit IFN-associated transcriptional profiles and IFN-stimulated genes are elevated in new onset T1D patients. IFN-α induces ER stress, substantial overexpression of HLA class 1, and insulitis in the islet. β-cells are known to be sensitive to reactive oxygen species (ROS) accumulation which may contribute to autoimmunogenicity in the IFN response. In order to detect the in vivo effects of IFN-α on the physiology of human islets, we conducted intravital microscopy studies of human islets transplanted in the mouse kidney - following transduction with a ratiometric fluorescent redox biosensor. These studies revealed that intravenous IFN-α elicited a mild overall accumulation of ROS in human islets, but rapid and pronounced accumulation of ROS in a subset of islet β-cells - a population of cells we termed, “ROSponders." Interestingly, the percentage of β-cells categorized as ROSponders was variable between donors (ranging from ~1% to 6% of all β-cells). Recent observations have drawn attention to the importance of β-cell expression and functional heterogeneity within the islet. Furthermore, recent work suggests that blockade of IFN-α signaling prior to clinical T1D manifestation may intercept autoimmunity and abort onset. Altogether, this work identifies novel heterogeneity of response to an inflammatory cytokine implicated in T1D onset and may inform future approaches to the treatment of T1D.

Disclosure

M. Arvin: None. C. Muralidharan: None. A. M. Conteh: None. M. M. Martinez irizarry: None. K. Orr: None. K. W. Dunn: None. A. K. Linnemann: None.

Funding

Human Islet Research Network (RRID:SCR_014393; UC4 DK104162); National Institutes of Health (3T32DK064466-18S1)
298-OR: Lipid Pattern in Men with Hypogonadism and Type 2 Diabetes Improves during Long-Term Treatment with Testosterone Undecanoate Injections (TU) in Comparison with an Untreated Control Group: Update of Real-World Registry Data
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2021

Background: Previous studies reported inconsistent effects of testosterone therapy on the lipid profile in men with hypogonadism.

Methods: Of 361 men with hypogonadism and T2DM, 183 received TU 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups.

Results: Mean follow-up 8.7±3.1, baseline age: 61.8±5.3 years. Total cholesterol (mmol/L for all lipids) decreased by 2.9±0.1 (unadjusted from 8.3±1.1 to 5.2±0.3) at 12 years in T-group and increased by 1.3±0.1 (7.1±1.2 to 8.2±1.4) in CTRL. (p<0.0001 for both). HDL increased by 0.5±0.0 (1.0±0.4 to 1.6±0.4) in T-group and decreased by 0.3±0.0 (1.1±0.5 to 0.1±0.4) in CTRL (p<0.0001 for both). The total cholesterol:HDL ratio decreased by 5.6±0.3 (9.7±4.3 to 3.4±0.7) in T-group and increased by 5.5±0.3 (8.0±3.9 to 12.1±6.1) in CTRL. (p<0.0001 for both). LDL decreased by 1.9±0.1 (4.7±0.9 to 2.6±0.2) in T-group and increased by 1.0±0.1 (4.1±1.4 to 4.9±1.5) in CTRL (p<0.0001 for both). Triglyceride decreased by 1.1±0.0 (3.5±0.6 to 2.2±0.1) in T-group and increased by 0.6±0.0 (3.1±0.6 to 3.7±0.5) in CTRL (p<0.0001 for both). Non-HDL decreased by 3.4±0.1 (7.3±1.2 to 3.6±0.3) in T-group and increased by 1.6±0.1 (6.0±1.4 to 7.4±1.5) in CTRL (p<0.0001 for both). Remnant cholesterol decreased by 1.5±0.1 (2.6±1.0 to 0.9±0.3) in T-group and increased by 0.6±0.1 (2.0±1.0 to 2.4±0.7) in CTRL (p<0.0001 for both). The triglyceride:HDL ratio decreased by 5.3±0.4 (9.4±4.4 to 3.2±0.8) in T-group and increased by 5.7±0.4 (8.0±4.1 to 12.5±6.0) in CTRL (p<0.0001 for both).

Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM progressively improved the lipid profile, which worsened in controls.

Disclosure

F. Saad: Consultant; Self; Bayer AG, Stock/Shareholder; Self; AbbVie Inc., Bayer AG, Novo Nordisk. K. S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Other Relationship; Self; Bayer AG.

Funding

Bayer AG
31-OR: ACSL1 in Smooth Muscle Cells Regulates High-Fat Diet-Induced Obesity and Thermogenesis in Mice
Authors: REN GUANG , YOUNG MARTIN , KIM JEONGA
Published: June 2021

Long-chain acyl-CoA synthetases (ACSL) are the enzymes that convert long-chain fatty acids to long-chain fatty acyl-CoAs that are utilized for various cellular processes, including triglyceride synthesis, energy metabolism, sphingolipid formation, and modification of lipids and proteins. Among five common isotypes (ACSL1, 3, 4, 5, and 6), ACSL1 is the predominant isotype in adipose tissue and essential for fatty acid oxidation during the cold adaption in brown adipose tissue. However, it is unknown whether ACSL1 is involved in brown adipocyte differentiation. Since the smooth muscle-like cells (mural cells) are the progenitors of brown adipocytes, we hypothesize that the ACSL1 in smooth muscle cells contributes to brown adipocyte differentiation and energy metabolism. We generated a smooth muscle-specific ACSL1 knockout mouse (ACSL1SM-/-) by breeding SM22α-cre mouse with ACSL1flox/flox mouse. ACSL1 deficiency in smooth muscle cells protected from high-fat diet (HFD)-induced obesity without changes in food intake and physical activity. Furthermore, HFD-fed ACSL1flox/flox mice were more glucose tolerant and insulin sensitive compared to HFD-fed wild-type mice. We also observed that cold adaptation, thermogenesis, was significantly impaired in ACSL1SM-/- mice. We isolated stromal vascular cells (SVCs) from inguinal and brown adipose tissues and then subjected them to adipocyte differentiation. We found that the adipocyte differentiation was impaired, and the expression of UCP1 was significantly reduced in the absence of ACSL1. These results suggest that ACSL1 in smooth muscle cells contributes to energy metabolism and glucose homeostasis by regulation of brown fat differentiation.

Disclosure

G. Ren: None. M. Young: None. J. Kim: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079626); National Heart, Lung, and Blood Institute (HL128695); National Institute on Aging (AG058078)
311-OR: Predicting Inadequate Early Glycemic Control among Adults with Younger-Onset Type 2 Diabetes
Authors: MISHRA PRANITA , ALEXEEFF STACEY , GRANT RICHARD W. , GOPALAN ANJALI
Published: June 2021

The prevalence of type 2 diabetes (T2D) is increasing among individuals younger than 45 years, who are at an increased risk of T2D-related complications, making the lasting benefits conferred by early glycemic control particularly critical. The ability to proactively identify these younger-onset individuals at increased risk of inadequate early glycemic control could support more targeted and tailored initial care. The study sample was randomly split into training (70%) and validation (30%) sets to develop and test the model. We used logistic LASSO (Least Absolute Shrinkage and Selection Operator) regression to identify predictors of inadequate glycemic control (HbA1c ≥8%) at 1-year following diagnosis among adults ages 21-44. Potential predictors were assessed at diagnosis. We used terciles of predicted risk to stratify our cohort into low (LR), intermediate (IR) and high-risk (HR) groups and compared characteristics between them using chi-square and ANOVA tests. Of the 10,897 individuals with new T2D, the mean age was 37.9 ± 5.3 years and 33% were Latinx. The LASSO model selected 46 out of 97 candidate variables. The resulting model yielded a c-statistic of 0.73 and had good calibration. We observed differences in socioeconomic, clinical, and care utilization characteristics between the risk groups. Those in high-risk group were more likely to be Latinx (45% HR vs. 30% IR vs. 27% LR, p<0.01), residents of deprived neighborhoods (33% HR vs. 23% IR vs. 22% LR, p<0.01), and have an HbA1c ≥ 10% ( 74% HR vs. 9% IR vs. 0% LR, p<0.01) but less likely to have received a flu shot ( 22% HR vs. 37% IR vs. 42% LR, p<0.01) or be active users of the online patient portal (44% HR vs. 65% IR vs. 75% LR, p<0.01). Using a machine-learning developed predictive model, we characterized adults <45 years at low, intermediate or high risk for inadequate early glycemic control. Such models can support healthcare systems by leveraging EHR data to risk stratify younger-onset individuals and inform the intensity of initial T2D care.

Disclosure

P. Mishra: None. S. Alexeeff: None. R. W. Grant: None. A. Gopalan: None.
32-OR: Receptor-Mediated Gq Signaling in Adipocytes as a Critical Modulator of Systemic Glucose and Lipid Homeostasis
Authors: KIMURA TAKEFUMI , PYDI SAI PRASAD , WANG LEI , CUI YINGHONG , GAVRILOVA OKSANA , WESS JÜRGEN
Published: June 2021

Objective: In obesity, decreased insulin action leads to the accelerated breakdown of triglycerides stored in adipocytes, causing peripheral insulin resistance, a hallmark of type 2 diabetes. In this study, we investigated whether selective activation of Gq signaling in adipocytes might cause similar metabolic effects as insulin.

Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive, Gq-coupled designer G protein-coupled receptor (Gq DREADD = QGD) selectively in adipocytes (adipo-GqD mice). DREADDs are stimulated by an exogenous agent (e.g., CNO) that is otherwise pharmacologically inactive. We also made another mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Both mutant mouse strains underwent a series of metabolic tests.

Results: CNO-mediated activation of adipocyte Gq signaling in the adipo-GqD mice significantly improved glucose homeostasis and suppressed lipolysis. In contrast, adipo-Gq/11 KO mice showed the opposite metabolic phenotypes, impaired glucose metabolism and enhanced lipolysis. Consistent with these findings, in vitro studies with cultured adipocytes demonstrated that activation of Gq signaling enhanced glucose uptake and inhibited lipolysis in an AMPK-dependent manner. To test the hypothesis that activation of adipocyte Gq signaling might counteract impaired insulin signaling in adipocytes, we generated adipo-GqD mice that carried only one copy of the insulin receptor (IR) gene in adipocytes (adipo-GqD-IR+/- mice). Interestingly, activation of adipocyte Gq signaling by CNO ameliorated the metabolic deficits displayed by adipo-GqD-IR+/- mice maintained on a high-fat diet.

Conclusion: Our data indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis. This finding is likely to stimulate the development of novel drugs that can mimic the actions of insulin in the insulin-resistant state.

Disclosure

T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.