bluuebunny/crossref_metadata_2025 huggingface dataset:
281-LB: The Association between Pericardial Fat Volume and Mortality—The Multi-Ethnic Study of Atherosclerosis
Authors: SHIL HONG EUN , BRUMBACK LYNDIA , ALLISON MATTHEW
Published: June 2023

Background: Pericardial fat, a specific measure of ectopic fat, is associated with incident cardiovascular disease (CVD). Both coronary artery calcium (CAC) and body mass index (BMI) may modify the effect of ectopic fat on mortality. However, there are few studies on the association between pericardial fat and mortality and if this association can be modified by CAC and BMI.

Objective: We examined the association between pericardial fat volume (PFV) and all-cause and CVD mortality.

Methods: This study ascertained PFV using cardiac computed tomography in 6,785 participants without pre-existing cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA). Cox proportional hazards regression was used to evaluate the association between PFV and mortality. We tested for effect modification in these associations by CAC and BMI categories.

Results: The mean age of the analytic sample was 62.1 ± 10.0 years and 53% were female. The mean PFV was 79.6 ± 42.0 cm3. Over a 16.9-year median follow-up, there were 1,701 (25%) all-cause deaths and 411 CVD-related deaths (6%). In unadjusted model, every 1-SD (42 cm3) increase in PFV was associated with a 2-fold higher rate of all-cause mortality (HR=1.99, 95% CI=1.81-2.20). After adjusting for demographics, CV risk factors, income, and waist-to-hip ratio, this association was attenuated but remained significant (HR=1.20, 95% CI=1.06-1.36). Similarly, PFV was associated with CVD mortality in unadjusted model (HR=2.38, 95% CI=1.95 - 2.91) but was no longer statistically significant after multivariable adjustment (HR=1.26, 95% CI=0.97-1.62). There were no significant interactions by CAC. However, a significant interaction by BMI was found (p value for interaction = 0.013); the HR of BMI≥35kg/m2 was 2.4-times higher than the HR of BMI<25kg/m2.

Conclusions: In this large, community-based, prospective cohort study, pericardial fat was associated with a higher risk of all-cause mortality especially among obese participants.

Disclosure

E. Hong: None. L. Brumback: None. M. Allison: None.
282-LB: Analysis of Cell-Free Mitochondrial DNA in Obese Patients With and Without Type 2 Diabetes after Bariatric Surgery
Authors: YUZEFOVYCH LARYSA , PASTUKH VIKTOR M. , RICHARDS WILLIAM , RACHEK LYUDMILA
Published: June 2023

While the improvement of mitochondrial function after bariatric surgery was shown, there is limited evidence about the metabolic effects of bariatric surgery on circulatory cell-free (cf) mitochondrial DNA (mtDNA). Therefore, the goal of this study was to compare plasma levels of cf-mtDNA in the association to the metabolic changes before and after surgery in obese patients. Plasma was isolated from 13 morbidly obese bariatric surgery patients with and without type 2 diabetes (T2D) and 8 healthy controls (HC). From each obese patient, blood was collected at baseline, 2 weeks, 3 and 6 months after surgery. QRT-PCR was used to quantify short cf-mtDNA (~100 bp) in isolated plasma within the ND6 region. At baseline, plasma level of short cf-mtDNA fragments was significantly higher in obese patients compared to HC. Additionally, when obese patients were grouped by presence or absence of T2D and compared to HC patients, plasma ND6 levels were significantly higher in obese T2D but not in non-T2D group. Bariatric surgery reduced BMI and improved insulin sensitivity and other whole-body metabolic parameters in all obese patients. No significant variation in mean ND6 values over time was observed post-surgery in all obese patients or when we plotted the data according to the T2D and non-T2D. Importantly, significant positive correlation was observed between plasma ND6 level and HOMA-IR but only 2 weeks post-surgery. Interestingly, plasma from both HC and obese groups at all time points post-surgery contain long (~8 kb) cf-mtDNA fragments, suggesting the presence of near intact and/or whole mitochondrial genomes. Overall, bariatric surgery decreased weight and improved insulin sensitivity and other metabolic parameters in obese patients without significant change in plasma cf-mtDNA levels. Further studies need to test potential determinants, characteristics and origin of cf-mtDNA associated with postoperative metabolic improvements following surgery.

Disclosure

L. Yuzefovych: None. V. M. Pastukh: None. W. Richards: Research Support; Ethicon, Inc. L. Rachek: None.

Funding

University of South Alabama (807 to L.R., W.R.)
283-LB: The Differential Effect of Gastric Bypass vs. Sleeve Gastrectomy on Prandial Symptoms of Hypoglycemia and Dumping Syndrome
Authors: HONKA HENRI , AL-RIFAIE SAMAR , GASTALDELLI AMALIA , SALEHI MARZIEH
Published: June 2023

Gastric bypass surgery (GB), and to lesser degree sleeve gastrectomy (SG), predispose to prandial hypoglycemia. Diagnosis is challenging since hypoglycemic symptoms overlap with those of dumping syndrome. Here, we sought to determine whether symptoms distribution after meal challenge differ among GB vs. SG or non-operated controls (CN), and between GB with and without documented hypoglycemia syndrome as per Whipple's triad. Plasma glucose and prandial symptoms were obtained every 15 min during a 3-h mixed-meal test in matched, non-diabetic groups of 11 hypoglycemic-GB (HGB), 18 asymptomatic-GB (AGB), 24 SG and 5 CN. Symptoms were stratified into autonomic (breathlessness, fatigue, sleepiness, palpitation, restlessness, dizziness, shaking, sweating, feeling warm) and neuroglycopenic (fainting or syncope, impaired cognition, irritability, seizure), and gastrointestinal (GI) symptoms. Peak-to-nadir glycemic excursion was higher in GB vs. SG vs. CN (137±8.0 vs. 86.6±6.0 vs. 48.6±9.1 mg/dl, respectively, P < 0.001). GI symptoms were experienced mainly within first 60 minutes of meal study in all 4 groups (P < 0.001 for time factor), and their average score was higher in GB compared with SG (by 2-fold) and CN subjects (by 14-fold, P < 0.01 for group factor). Likewise, autonomic symptoms were most prevalent during the early phase of the meal (P < 0.05), and their average score tended to be higher in GB compared with SG (by 2-fold) and CN subjects (by 5-fold, P = 0.06 for group factor). Neither GI nor autonomic symptom scores differed among HGB and AGB. Given the low rate of chemical hypoglycemia, neuroglycopenic symptoms were rare and not different among the groups. We conclude that the majority of autonomic symptoms, often mistaken for hypoglycemia, occur in early prandial phase and are not different among GB with and without documented hypoglycemia syndrome. Thus, presence of neuroglycopenia is critical in diagnosis of clinical hypoglycemia in this population.

Disclosure

H. Honka: None. S. Al-rifaie: None. A. Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp & Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. M. Salehi: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)
284-LB: From Metabolically Healthy Obesity (MHO) to Metabolically Unhealthy Obesity (MUHO)—Decreased Thyroid Hormone Sensitivity
Authors: ZHANG NING , WANG GUANG
Published: June 2023

Background: To explore the difference of thyroid hormone sensitivity between metabolically healthy and metabolically unhealthy obesity patients and its influence on obesity phenotype.

Methods: 10927 euthyroid adults were enrolled, 4 groups based on the presence/absence of metabolic disorders (MD) and BMI were divided: 1) NC (n=1441): no MD and 22≤BMI < 25Kg/m2. 2) NMu (n=3765): MD and 22≤BMI < 25Kg/m2. 3) MHO (n=148): obese with no MD (BMI≥28Kg/m2). 4) MuHO (n=1981): obese with MD (BMI≥28Kg/m2). MD was defined as meeting none of the following criteria: fasted blood glucose ≤6.1 mmol/L; triglycerides ≥1.7 mmol/L; high density lipoprotein (HDL) <1.0 mmol/L (male) and <1.3 mmol/L (female); elevated SBP (≥130 mmHg) or/and DBP (≥85 mmHg). Thyroid hormone central sensitivity indices were calculated by thyroid feedback quantile-based index (TFQI), TSH index (TSHI), Chinese-referenced parametric TFQI (PTFQI) and thyrotropin thyroxine resistance index (TT4RI). Peripheral thyroid hormone sensitivity was evaluated by FT3/FT4 ratio.

Results: Compared with MHO group, TFQI, PTFQI and TT4RI elevated in MuHO group, and the trend still existed after adjusting for confounding factors. High FT3/FT4 ratio was an independent risk factor for MuHO (OR = 1.22, 95%CI: 1.13, 1.37, P<0.001). In euthyroid obese patients, decreased TFQI was a protective factor for MHO (OR=0.71, 95%CI 0.51, 0.83, P=0.036), while TSHI (OR= 1.27, 95%CI: 1.11, 1.38, P =0.027) and TT4RI (OR= 1.08, 95%CI: 1.03, 1.16, P =0.022) were significantly correlated with the occurrence of MuHO.

Conclusions: Thyroid hormone sensitivity is impaired with elevated BMI. Impaired thyroid hormone sensitivity associated with the development of metabolically unhealthy obesity in patients with similar BMI.

Keywords Metabolically Healthy Obesity, Thyroid Hormone Sensitivity

Disclosure

N. Zhang: None. G. Wang: None.

Funding

National Natural Science Foundation of China (81770792)
285-LB: LEAP2 Reduces Preprandial and Postprandial Glucose Levels and Ad Libitum Food Intake in Obese Men
Authors: ENGLUND ANDERS , HAGEMANN CHRISTOFFER A. , GASBJERG LÆRKE S. , KNOP FILIP K.
Published: June 2023

The naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP2) has gained interest as a ghrelin receptor antagonist. Recently, we reported food intake and plasma glucose-lowering effects of exogenous LEAP2 in lean healthy males. Here, we investigated the effects of LEAP2 infusion on ad libitum food intake and postprandial glucose tolerance in obese men. Twenty obese men (mean (SEM) age 44.2 (2.2) years; BMI 36.3 (0.8) kg/m2; body fat percentage 37.4 (0.9)%) were enrolled in this randomized, double-blind, placebo-controlled, crossover study comprising two experimental days. Experimental days involved a ~5-hour intravenous (iv) infusion of LEAP2 or placebo during which a liquid mixed meal test (MMT) and a subsequent ad libitum meal test were performed. Plasma glucose measures included fasted (preprandial), Cmax and Tmax values as well as area under the curve (AUC) during MMT. Ad libitum food intake was measured in kilojoule (kJ) and kJ/kg body weight. Compared to placebo, LEAP2 infusion lowered preprandial plasma glucose (mean (SEM): 5.03 (0.08) vs. 5.19 (0.06) mmol/L, P=0.0095) as well as Cmax (6.58 (0.18) vs. 6.98 mmol/L (0.18), P=0.0001) and AUC for plasma glucose during MMT (1,506 (33.4) vs. 1564 (30.4) min×mmol/L, P=0.0005), but not Tmax. Ad libitum food intake was reduced by ~13% during LEAP2 infusion compared to placebo (2,939 (266) vs. 3,378 (258) kJ, P=0.0118; 25.0 (2.4) vs. 28.4 (2.0) kJ/kg body weight, P=0.0140). We conclude that a continuous iv LEAP2 infusion reduces pre- and postprandial plasma glucose concentrations as well as ad libitum food intake in obese men.

Disclosure

A. Englund: None. C. A. Hagemann: Employee; Gubra ApS. L. S. Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. F. K. Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.
285-OR: Surveying Specific and Shared Responses of Human Islets to T2D-Associated Stressors
Authors: SOKOLOWSKI EISHANI K. , BHUIYAN REDWAN M. , KURSAWE ROMY , STITZEL MICHAEL L. , UCAR DUYGU
Published: June 2023

Endoplasmic reticulum (ER) and inflammatory stress in islets is linked to Type 2 Diabetes (T2D). We hypothesize that a subset of non-coding T2D-associated genetic variants (T2D SNPs) modulate these pathophysiologic responses in human islets. To test this, we compared chromatin accessibility and gene expression in human islets before and after exposure to ER stress (thapsigargin) or pro-inflammatory cytokines (IL-1β+IFN-γ) to identify specific and shared stress-responsive cis-regulatory elements (CREs) and their target genes. Approximately 13% of CREs (n=14,966) and 30% of genes (n=5,131) are modulated by ≥1 stressor (ER stress-specific: ~41% CREs & ~33% genes, inflammation-specific: ~52% CREs & ~42% genes, shared: ~7% CREs & ~25% genes), implying that changes in accessibility and expression in islets are stress-specific. For example, ER stress-specific genes (ex: DDIT3 & ATF4) are involved in unfolded protein response, and ER stress-specific CREs enrich for 157 transcription factor (TF) binding sites (ex: CHOP & ATF4). Many genes nearest to stress-responsive CREs are also stress-responsive genes (ER stress-specific: n=596, inflammation-specific: n=827, shared: n=91) suggesting a context-specific modulation of gene expression by CREs. Of these CREs, 92 (ER stress: n=53, inflammation: n=39) harbor 114 T2D SNPs, of which 19 T2D SNPs become accessible only upon ER stress. For example, rs6444081 (A>G) overlaps an ER stress-specific CRE and resides downstream of ETV5 (ER stress-responsive gene). The T2D risk allele (G) is predicted to be bound by ER stress-specific TF ETV1. In a separate cohort, ETV5 expression is higher in T2D vs non-T2D beta cells, suggesting that ETV5 is a putative target gene of rs6444081 and that its activity is genetically modulated in islets. Our results nominate T2D SNPs that we propose modulate stress-specific islet responses. Further study of these CREs and their target genes should help to functionally compartmentalize T2D risk variants.

Disclosure

E.K.Sokolowski: None. R.M.Bhuiyan: None. R.Kursawe: None. M.L.Stitzel: None. D.Ucar: None.

Funding

National Institutes of Health (R01DK118011-01A1); U.S. Department of Defense (W81XWH-18-0401)
286-LB: A Trailblazing Approach to Target Mitochondrial Dysfunction in Diabetic Beta Cells
Authors: JANKAUSKAS STANISLOVAS , KANSAKAR URNA , NIEVES GARCIA CRYSTAL , GAMBARDELLA JESSICA , MONE PASQUALE , TOMER YARON , SANTULLI GAETANO , LOMBARDI ANGELA
Published: June 2023

Rationale: Currently no curative treatment exists to reverse or prevent autoimmune destruction of pancreatic islets in type 1 diabetes (T1D), and the disease can only be managed with insulin replacement therapy. We propose to leverage the therapeutic properties of ketone bodies to prevent and/or improve diabetes-associated ailments of beta cells. Of note, although excessive production of ketones leads to life-threatening ketoacidosis in diabetic patients under glucose lowering treatment, emerging lines of evidence suggest that modest levels of ketone bodies play adaptive and beneficial roles. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body. However, therapeutic applications of BHB have never been considered in T1D.

Results: In NOD mice BHB treatment significantly increased survival and delayed diabetes onset, protecting pancreatic islets from apoptosis, reducing insulitis, and decreasing serum levels of pro-inflammatory cytokines. Furthermore, islet yield and total pancreatic insulin were markedly higher in BHB treated mice compared to controls. In addition, in NOD pancreatic islets and in human islets isolated from healthy donors treated with a cocktail of pro-inflammatory cytokines (i.e. IL-1β, TNF-α, and IFN-γ) BHB had a protective effect on oxidative stress, significantly reducing the production of ROS. Finally, in both systems BHB significantly increased the mitophagy flux improving mitochondrial fitness and preserving mitochondrial functions.

Conclusion: The proposed studies are highly significant and are attempting for the first time to dissect the role of ketones in pancreatic beta cell death and dysfunction during T1D. Indeed, if our preliminary studies are confirmed BHB might emerge as a glucose-lowering agent that, acting synergistically with pharmacotherapy, could be able to improve the quality of life in patients with T1D.

Disclosure

S. Jankauskas: None. U. Kansakar: None. C. Nieves garcia: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.
29-LB: Multicenter, Randomized Controlled Clinical Investigation Evaluating a Unique Micro Water Jet Technology Device vs. Standard Debridement in the Treatment of Diabetic Foot Wounds
Authors: ARMSTRONG DAVID G. , GALIANO ROBERT , CARTER MARISSA J. , ZELEN CHARLES M.
Published: June 2023

Background: Proper debridement of the wound base is critical to facilitate wound granulation and closure in non-healing diabetic foot ulcers(DFUs). A unique micro water jet device has been developed and recently granted breakthrough designation for treatment of DFUs by the Foot and Drug Administration(FDA) that precisely cleans acute and chronic wounds in a tissue-preserving manner while performing a precise mechanical cleaning and stimulation of the wound base to enhance granulation and healing.

Methods: 170 patients were screened, and 96 patients were enrolled for the analysis, in a two arm randomized controlled trial. DFUs that were non-healing for at least 4 weeks, with adequate blood flow and were void of clinical infection or osteomyelitis were entered into 2 weeks of screening. Those that met all the qualifications were randomized to receive either weekly micro jet wound debridement or standard sharp debridement along with SOC wound dressing and offloading. Both groups were followed for 16 weeks. The primary study endpoint was healing at 16 weeks and the secondary endpoints included a safety analysis.

Results: At 16 weeks 65%(28/43) of the Micro Water jet treated DFUs healed compared with 42%(22/53) treated with standard sharp debridement p=0.021 (unadjusted). Further, at 16 weeks, the safety analysis showed with regard to wound related adverse events (AE) and serious adverse events (SAE); 4 AEs and 1 SAE occurring in the Micro Water jet group versus 12 AEs and 4 SAEs in the standard sharp debridement group.

Conclusion: The micro water jet device was able to statistically significantly close more refractory DFUs over 16 weeks, without the need for any advanced biologic or graft. Further, the number of wound related infections and hospitalizations were 75% less in those patients treated in the Micro Water jet group. Further evaluation is warranted to validate these initial promising findings.

Disclosure

D. G. Armstrong: Research Support; Medaxis LLC. R. Galiano: Advisory Panel; Medaxis LLC, Research Support; 3M/KCI, Speaker's Bureau; Musculoskeletal Transplant Foundation. M. J. Carter: Research Support; Medaxis LLC. C. M. Zelen: Research Support; Medaxis LLC.
291-OR: CREG1 Regulates Hepatic Insulin Sensitivity and Insulin Receptor Trafficking
Authors: QI YANMEI , LIU JIE , CHAO JOSHUA C. , RAHIMI SAUM A. , LEE LEONARD Y. , LI SHAOHUA
Published: June 2023

CREG1 is a small glycoprotein in the endosomal-lysosomal system involved in endocytic trafficking. It contains 3 N-linked glycosylation sites and is highly expressed in the liver. To elucidate its physiological functions, we generated Creg1fl/fl mice using CRISPR technology. Whole-body and hepatocyte-specific deletion of Creg1 was achieved by crossing Creg1fl/fl with UBC-cre-ERT2 and Albumin-cre mice, respectively. Both knockout mice developed elevated glycemia, glucose intolerance, and resistance to the blood glucose-lowering effect of insulin. Loss of hepatic CREG1 also aggravated high-fat diet-induced insulin resistance and hyperinsulinemia. This is likely caused by impaired insulin receptor (IR) trafficking because IR expression on the hepatocyte surface was significant reduced in hepatocyte specific Creg1 knockout mice. In in vitro studies using cultured hepatocytes, CREG1 overexpression increased IR recycling to the cell surface and enhanced insulin signaling, whereas its knockdown had the opposite effect. These findings indicate a cell autonomous role of CREG1 in hepatocyte IR trafficking and insulin signaling. Furthermore, SNP database survey identified 3 missense mutations of CREG1 at the N216 glycosylation site (N216I, N216K, and N216Y). When overexpressed in human hepatocytes, the N216I mutant inhibited insulin signaling in a dominant negative fashion. Taken together, these results suggest CREG1 regulates hepatic insulin sensitivity and signaling likely through its effect on IR trafficking. CREG1 glycosylation at N216 may be required for its function in these processes.

Disclosure

Y.Qi: None. J.Liu: None. J.C.Chao: None. S.A.Rahimi: None. L.Y.Lee: Speaker's Bureau; Abbott. S.Li: None.

Funding

Rutgers Biomedical and Health Sciences
295-LB: Pancreatic Peroxisomes Are Required for Physiological Regulation of Insulin Secretion and Maintenance of Normal Glucose Tolerance in Male Mice
Authors: BURKE SUSAN , GHOSH SUJOY , BURK DAVID , NOLAND ROBERT , COLLIER JASON
Published: June 2023

The regulation of glucose-stimulated insulin secretion (GSIS) is central to maintenance of glucose disposal. The role of lipid storage and lipid oxidation to regulate pancreatic islet β-cell insulin secretion is not completely understood. Peroxisomes are enriched in insulin-producing β-cells, but their contribution to β-cell function and maturity is lacking. Therefore, we generated a novel model of peroxisomal dysfunction to test the hypothesis that peroxisomal lipid metabolism is required to prevent a hyperlipidemic environment that interferes with β-cell function and maturity. Pex5 plays a critical role in importing the majority of peroxisomal proteins into the peroxisomal matrix; thus, deletion of the Pex5 gene creates a cellular environment with reductions in function of this organelle. In this study, we bred Pex5 mice on a C57BL/6J background containing ‘floxed’ alleles to Pdx1-cre mice to generate offspring with a pancreas-wide deficiency in Pex5 expression and abundance. Glucose tolerance was impaired by 12 weeks in male mice (n=20; AUC p<0.05). Surprisingly, GSIS was elevated in Pex5Pdx1-/- mice compared to littermate controls both in vivo (n=15; AUC p<0.05) and ex vivo in isolated islets as measured by perifusion analysis (n=12; AUC p<0.01). We further found that a subset of β-cells from Pex5Pdx1-/- mice expressed the de-differentiation marker Aldh1a3, while a subset of β-cells showed reductions in MafA and Nkx6.1 staining compared to controls. Perilipin-1 staining showed increased presence of lipid droplets in pancreatic tissue of Pex5Pdx1-/- mice versus controls. Thus, pancreatic deletion of peroxisomal function results in increased lipid storage in pancreatic tissue that is correlated with exaggerated insulin secretion. Collectively, these data are in support of a model whereby peroxisomal function supports β-cell insulin secretion and maintenance of the fully differentiated state.

Disclosure

S. Burke: None. S. Ghosh: None. D. Burk: None. R. Noland: None. J. Collier: None.
30-LB: Study on the Mechanism of Calycosin in Promoting Wound Healing in Diabetic Foot Ulcers
Authors: XU YONGSONG , KE JING , YANG LONGYAN , ZHAO DONG
Published: June 2023

Objective: To investigate the effect of calycosin in promoting wound healing of foot ulcers and explore the regulation on vascular endothelial growth factor (VEGF).

Methods: 8-week-old male C57BL/6J mice were injected intraperitoneally with 1% streptozotocin 120 mg/kg for 3 consecutive times, and the mice with random blood glucose > 16.7 mmol/L were used and randomly divided into model group and calycosin suspension groups (30 mg/kg, 60 mg/kg, 90 mg/kg). Mice were pretreated for 30 days at a dose of 10 mL/kg of the corresponding drugs once a day, and the control group was given the same dose of 0.5% sodium carboxymethyl cellulose solution. At the end of administration, the animals were anesthetized with isoflurane and the whole layer of skin with diameter 10 mm was removed on the back to establish the wound model of diabetic foot ulcer as day 0. The wound healing was observed and photographed with a camera on the day 0, 2, 4, 6, 8, 10 and 12, respectively. At the end of the day 12, the new tissues around the wound were taken for the detections of the growth of new granulation tissue, VEGF, CD31 and the content of sorbitol.

Results: Compared with the model group, the wound healed faster in calycosin groups. It closed on the 12th day, but the wound in the model group did not heal completely. However, there was no obvious dose-effect relationship between different dose groups. The mice in treatment groups showed a better structural integrity of epidermis, and a more expression of VEGF and CD31 in the newborn tissue. And the protein level of VEGF of the calycosin (60 mg/kg) group increased. And the sorbitol content in calycosin (90 mg/kg) group reduced significantly (P<0.05), while in 30 mg/kg and 60 mg/kg changed slightly.

Conclusion: Calycosin could promote the wound healing of diabetic foot ulcer, which may be related to the effect of increasing the level of VEGF and reducing the accumulation of sorbitol in tissues. And further research was needed for fully exploration on the mechanism.

Disclosure

Y. Xu: None. J. Ke: None. L. Yang: None. D. Zhao: None.

Funding

Tongzhou District Science and Technology Plan Project (KJ2022CX024)
30-OR: Sirtuin 1 Dysfunction Underlies the Pathological Upregulation of NETosis in Diabetes
Authors: DE WANG LIANG , DALAN RINKOO , LING WONG SIU
Published: June 2023

Activated neutrophils can release their chromatin, forming neutrophil extracellular traps (NETs). Being highly procoagulant and pro-inflammatory, NETs are implicated in conditions that are prevalent in diabetes, such as thrombosis, stroke, and delayed wound healing. While diabetes is found to prime neutrophils for NET formation (NETosis), a knowledge gap persists for years as to its underlying mechanism. Here, we report an important role of Sirtuin 1 (SIRT1) in the modulation of NETosis. We found that Ex-527 (a SIRT1 inhibitor), and SIRT1 knockdown using siRNA, predisposed blood neutrophils isolated from healthy mice and humans, as well as HL-60-derived neutrophils (dHL-60 cells), to NETosis. While neutrophils from mice and humans with diabetes and dHL-60 cells primed in high glucose naturally generated more NETs when compared to their healthy or basal glucose-cultured counterparts, Ex-527 failed to further exacerbate NETosis in these cells, implicating that SIRT1 is dysfunctional in hyperglycemia and diabetes, leading to maximal NETosis even without Ex-527. Cell-based assays reflected that SIRT1 acts upstream of peptidylarginine deiminase 4 (PAD4, an enzyme critical for NETosis), and suppresses NETosis via PAD4 inhibition in healthy neutrophils and basal glucose-cultured dHL-60 cells, but not neutrophils isolated from mice and humans with diabetes, nor dHL-60 cells primed in high glucose. Remarkably, acute treatment using resveratrol (a polyphenol known to activate SIRT1) normalized NETosis in neutrophils from mice and humans with diabetes, alongside a concomitant reduction in PAD4 activity. To conclude, SIRT1 serves as an endogenous suppressor of NETosis in health and becomes defective in hyperglycemia and diabetes, resulting in excessive NETosis. Reactivation of SIRT1 using resveratrol effectively abrogated NETosis by inhibiting PAD4 activity. Revitalizing SIRT1 could be a novel therapeutic strategy in alleviating NET-mediated inflammation and diabetic complications.

Disclosure

L.Wang: None. R.Dalan: None. S.Wong: None.

Funding

Nanyang Assistant Professorship; Singapore Ministry of Education Academic Research Fund Tier 1 (RG25/20); Nanyang President's Graduate Scholarship
303-OR: Maternal High-Fat Diet Alters the Gut Microbiota–Liver Circadian Rhythms and Results In Metabolic Dysfunction in Offspring
Authors: DING LU , LIU JIEYING , ZHANG QIAN , XIAO XINHUA
Published: June 2023

Maternal high-fat diet (HF) disturbs the gut microbiota-liver interactions and induces negative effects in the offspring, but its impact on metabolic, gut microbial, and hepatic circadian rhythms in the offspring (F1) are unknown. Here, we tested whether maternal HF could disrupt the metabolic rhythm in the juvenile (postnatal day [PND] 28) and adult offspring (PND112). Metagenomics, transcriptome, and metabolomics throughout the gut microbiota-liver axis were used to investigate the mechanism underpinning metabolic changes in the juvenile offspring. eJTK_Cycle was applied to characterize rhythmic patterns. Both juvenile and adult offspring of HF dams exhibited deteriorated glucose tolerance (P < 0.05) and a gain of the rhythm of serum glucose level (Control [Ctr], adjP > 0.05; HF, adjP < 0.05). Maternal HF altered the compositional and functional circadian rhythms of gut microbiota in the juvenile offspring. The rhythm of capacity for gut microbial synthesis of the short-chain fatty acid acetate was significantly gained in the juvenile offspring of HF dams (Ctr, adjP > 0.05; HF, adjP < 0.05). Consistently, maternal HF induced a rhythm gain of serum and liver acetate in the juvenile offspring (Ctr, adjP > 0.05; HF, adjP < 0.05). Meanwhile, maternal HF resulted in a gain of the rhythm of hepatic G6pc (Ctr, adjP > 0.05; HF, adjP < 0.05), a marker of gluconeogenesis metabolism. G6pc rhythmic expression was significantly correlated with serum acetate (R = 0.58, P < 0.05) and liver acetate (R = 0.64, P < 0.05) in the juvenile offspring. Taken together, we show that maternal HF disrupted the metabolic rhythm and the gut microbiota-liver rhythms, increasing susceptibility to metabolic dysfunction in the offspring.

Disclosure

L.Ding: None. J.Liu: None. Q.Zhang: None. X.Xiao: None.

Funding

National Natural Science Foundation of China (81870579)
310-OR: FBF1 Deficiency Promotes Ciliary Cold-Sensing TRP Channel Activation in Thermogenesis
Authors: ZHANG YINGYI , LIU BRIAN , HAO JIELU , HUANG YAN , LING KUN , HU JINGHUA
Published: June 2023

Brown adipose tissue (BAT) dissipates energy as heat to maintain optimal thermogenesis and promotes metabolic health. Exposure to cold conditions strongly induces both hyperplasia and activity of brown fat by distinct but poorly understood mechanisms. The proliferation of preadipocytes and their subsequent differentiation is proposed to be a major contributor to BAT hyperplasia. Primary cilia are sensory organelles emanating from the surface of most eukaryotic cells. We previously discovered that primary cilia mediate hyperplasia and beiging of the white fat tissue in mice by FBF1-dependent manner. WAT preadipocytes transiently form primary cilia during induced differentiation. FBF1 deficiency promotes proliferation, differentiation, and beiging of WAT preadipocytes and thus leads to expansion of metabolically healthy fat tissue. Here, we discovered that BAT preadipocytes dynamically produce sensory cilia during differentiation. FBF1 deficiency enhances brown preadipocyte differentiation and expansion by stimulating PPARγ transcriptional activity. Consistently, Fbf1tm1a/tm1a mice exhibit BAT hyperplasia. We further discovered that FBF1 deficiency promotes the ciliary recruitment of cold-sensing TRP channels upon cold exposure, which likely explains the mechanism underlying cilia-mediated BAT hyperplasia. Collectively, our data provide molecular insights into coldness-induced BAT hyperplasia and highlight the importance of cilia-mediated TRP pathway in thermogenesis regulation.

Disclosure

Y.Zhang: None. B.Liu: None. J.Hao: None. Y.Huang: None. K.Ling: None. J.Hu: None.
311-OR: Role of Pcpe2 in Adipose Tissue Remodeling and Expansion
Authors: SORCI-THOMAS MARY G. , XU HAO , THOMAS MICHAEL J.
Published: June 2023

Prevalence of obesity in the US continues to drive greater risk for type 2 diabetes and cardiovascular disease. Excessive caloric intake stresses adipocytes into storing lipid in an unhealthy manner, directing lipid into existing adipocytes, or hypertrophy. Healthy adipose expansion occurs when adipose tissue precursor cells (PC) in the stromal vascular fraction (SVF) differentiate to create new pre-adipocytes which store lipid, called hyperplasia. Single cell sequencing of visceral adipose tissue (VAT) have identified two main types of PCs in the SVF, one called adipocyte precursor cells (APCs), while the other is a fibro-inflammatory progenitors (FIPs). APC are pre-adipocytes which differentiate into mature adipocytes, while FIPs, secrete cytokines inhibiting APC differentiation. Influencing APC and FIP lineage are the transforming growth factor beta (TGFb)-like signaling which inhibit adipogenesis, while bone morphogenetic protein (BMP)-like signaling promotes adipogenesis. Little is known about how signaling alters APCs and FIPs fate, especially during increased lipoprotein flux from high fat diet (HFD). Recently we discovered that both VAT PCs, APCs and FIPs express high levels of the extracellular matrix (ECM) protein, procollagen endopeptidase enhancer protein 2 (Pcpe2) whose expression decreases as APCs become committed adipocytes. We found that Pcpe2 is upregulated ~4-fold by both TGFb1, and HFD feeding suggesting that Pcpe2 plays a role in TGFb-like pathways in VAT PCs. Using PC-specific Pcpe2-hemagglutinin tagged (HA) over-expressor (ox) (PC-PcpeoxHA) and PC cell-specific Pcpe2 knockout (KO) (PC-Pcpe2KO) mice lines, show PC-Pcpe2KO mice have reduced (~35-40%) body and VAT weight, while PC-PcpeoxHA mice showed an increase (~40-45%) in body and VAT weight. In other studies we show APC rates of proliferation and differentiation are highly dependent on Pcpe2 expression. Overall, these studies reveal novel mechanistic insight into the mechanisms involved in dysfunctional fat storage.

Disclosure

M.G.Sorci-thomas: None. H.Xu: None. M.J.Thomas: None.
315-OR: Diabetes and Dyslipidemia in Young, a Hidden Pandemic—Real-World Multicentric Study from India
Authors: SAXENA ASHISH K. , LAKSHMANAN MEENAKSHISUNDARAM , PATIL AASHNA , SINGH NAGENDRA K. , MAHESHWARI ANUJ , GUPTA MUKULESH , PATNI BIJAY , KUMAR DINESH , HIREMATH VINAYAK S. , DARIYA S S. , PATRA SURAJEET K. , SHEOHARE RAKA , ASLAM MOHSIN , REGULLA RAMA , DANTU RAGHUNATH
Published: June 2023

Background: In people living with diabetes mellitus, dyslipidemia is one of the significant risk factors for cardiovascular disease. Achieving the ABC clinical targets (HbA1c, blood pressure, and low-density lipoprotein cholesterol) is a well-established method of managing cardiovascular disease related morbidity and mortality among diabetes patients. The management of diabetes disorders is ensured by specialized clinical care provided by diabetes experts, but pernicious risk factors for general cardiovascular health are still largely going unnoticed at the point of care.

Purpose: This EHR-based real-world study's objective was to determine which cohorts of people living with diabetes were more likely to experience cardiovascular disease, as determined by the ABC goals.

Methods: History of Type 2 diabetes mellitus for at least six months and presenting for routine treatment in one of the 14 centers across the country were included in the study. Data on medical history, comorbidities, diabetes complications, medicines, and laboratory values were gathered using an EMR (Medeva) integrated research proforma. The study started in March 2022 and completed in August 2022. (6 months).

Results: Of the 2202 patients with Type 2 Diabetes Mellitus, at the overall level, 3.5% (<35yrs - 1.5%, 35-54 yrs - 2.9% and >54 yrs - 4.2%) of Type 2 Diabetes patients have achieved the ABC targets (HbA1c 7%, BP 130/80 mmHg, and LDL-C 100 mg/dL). On Individual goals, 23.3% (<35yrs - 16.5%, 35-54 yrs - 22.4% and >54 yrs - 24.8%) achieved control on HbA1c, 23.7% (<35yrs- 30.8%, 35-54 yrs - 23.7% and >54 yrs - 22.8%) on BP, and 44.8% (<35yrs - 34.6%, 35-54 yrs - 42.7% and >54 yrs - 47.6%) on LDL-C.

Conclusion: The achievement of goals A and C (HbA1C<7% and LDL-C<100 mg/dL) increases by age and subjects with age≥54 years have significantly better control of HbA1c and LDL-C. Younger (<34 Years) patients diagnosed with diabetes are at a much higher risk of cardiovascular disease as compared to older (>54 Years) diabetes patients.

Disclosure

A.K.Saxena: None. S.S.Dariya: None. S.K.Patra: None. R.Sheohare: None. M.Aslam: None. R.Regulla: None. R.Dantu: None. M.Lakshmanan: None. A.Patil: None. N.K.Singh: None. A.Maheshwari: None. M.Gupta: None. B.Patni: None. D.Kumar: None. V.S.Hiremath: None.
322-OR: Proinflammatory Macrophage Infiltration in Sural Nerve Is Associated with Reduction of Myelinated Nerve Fiber Density but Not IENFD in Human Diabetic Subjects
Authors: MIZUKAMI HIROKI , OSONOI SHO , TAKEUCHI YUKI , SASAKI TAKANORI
Published: June 2023

Background: The etiology of diabetic polyneuropathy (DPN) is multifactorial, and other than hyperglycemia, circulatory disturbance such as hypertension can be involved. Pro-inflammatory macrophages (M1) infiltration in the peripheral nerve is known to be the pathogenesis of DPN. However, it is still unclear how the inflammation and circulatory disturbance are involved in the pathological changes of human DPN.

Methods: Autopsied cases at Hirosaki University Hospital were evaluated: 7 nondiabetic cases (nDM), 11 nondiabetic cases with hypertension (nDM+HT), 6 diabetes cases (DM), 9 cases with hypertension and diabetes (DM+HT). Intraepidermal nerve fiber density (IENFD) was examined by immunofluorescent staining with the skin tissue 10 cm above external condyle. Dissected sural nerves were pathologically examined. Macrophage infiltration into the endoneurium of sural nerves was evaluated by double immunostaining using anti-CD68 and anti-CD163 antibodies.

Results: HbA1c level was significantly higher in DM and DM+HT than in nDM (p<0.01, respectively). IENFD was significantly decreased in DM compared to nDM (p<0.05) and further decreased in DM+HT (p<0.05 vs DM). The infiltration of M1 was significantly increased in DM (p<0.05). M1 infiltration was comparable between DM and DM+HT. Regression analysis showed that the M1/anti-inflammatory macrophages (M2) ratio was not significantly correlated with IENFD (r=0.3, p=0.09). Morphometric measurements of the sural nerve using semithin sections revealed that myelinated nerve fiber density (MNFD) was significantly decreased in DM compared with nDM (p<0.05). MNFD was comparable between DM and DM+HT. MNFD was inversely correlated with M1/M2 ratio (r=0.37, p<0.05).

Conclusions: Our results suggest that the factors other than sural nerve inflammation, such as hypertension, are possibly more involved in the loss of IENFD in DPN.

Disclosure

H. Mizukami: None. S. Osonoi: None. Y. Takeuchi: None. T. Sasaki: None.
327-OR: Smaller HDL Particles and ABCA1 Cholesterol Efflux Capacity Predict Incident Proliferative Retinopathy Only among Men with Type 1 Diabetes
Authors: COSTACOU TINA , MILLER RACHEL G. , ORCHARD TREVOR J.
Published: June 2023

Clinical studies have provided evidence for a potential role of dyslipidemia in the development of retinopathy in type 1 diabetes. Existing evidence, however, is generally based on conventional lipid analysis and/or cross-sectional study designs. We therefore assessed the prospective association of HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) with incident proliferative diabetic retinopathy (PDR) in a cohort of childhood-onset type 1 diabetes. HDL-P (calibrated differential ion mobility analysis) and total and ABCA1-specific CEC (validated cell-based assays) were quantified in 186 men and 185 women with type 1 diabetes free of PDR (stereo fundus photography) at baseline (mean age 25.6 years; diabetes duration, 17.1 years). Women had higher large HDL-P than men; the concentrations of extra-small, small and medium HDL-P as well as both total and ABCA1 CEC were similar by sex. During a median follow-up of 28 years, 108 men and 100 women developed PDR. In multivariable Cox models stratified by sex, HDL-C did not predict PDR incidence in either sex. However, in addition to increased HbA1c, non-HDL-C, white blood cell count and albumin excretion rate, increased extra-small (HR=0.25, 95% CI=0.09-0.67) and small (HR=0.72, 95% CI=0.55-0.94) HDL-P concentrations and ABCA1 CEC (HR=0.80, 95% CI=0.64-0.998) negatively predicted PDR in men but not women, among whom HbA1c, hypertension and white blood cell count were the only consistent significant predictors of PDR. In conclusion, while extra-small and small HDL-P concentrations and ABCA1 CEC did not differ by sex in type 1 diabetes, they only predicted incident PDR in men, a finding similar to our previously reported results for coronary artery disease. Further research is warranted to better understand the role of HDL in the pathophysiology of PDR and why this appears to differ by sex in type 1 diabetes.

Disclosure

T.Costacou: None. R.G.Miller: None. T.J.Orchard: None.

Funding

National Institutes of Health (R01HL130153, R01DK034818)
329-OR: Accuracy of Dietary Records (DR) Using a Smartphone App Is Greatly Improved by User’s Adjustments Compared with Artificial Intelligence (AI) Alone
Authors: KITAZAWA MASARU , HORIKAWA CHIKA , IKEDA IZUMI , TAKEDA YASUNAGA , FERREIRA EFREM D. , TAKEUCHI MIZUKI , MORIKAWA SAKIKO Y. , FUJIHARA KAZUYA , KODAMA SATORU , SONE HIROHITO
Published: June 2023

Although DR are important in managing diabetes, the traditional method, such as weighing foods and calculating nutrients, is burdensome to both patients and medical care providers. Although photo DR with smartphones using AI to identify the dish and calculate nutrients can be expected to reduce this burden, accuracy not been clarified. Furthermore, it is not clear to what extent accuracy improves when users and dietitians adjust the name of the dish and the portion consumed compared with AI only. In this study, photo DR taken with the smartphone app were analyzed by AI only, then adjusted by the users followed by further adjustments by a dietitian. We compared the nutrients calculated by AI, users, and dietitians to those by the traditional weighing method. Analyzed were 180 participants (mean age 58.7 y, BMI 26.7 kg/m2, 94/86 women/men, 22 with diabetes, energy intake [EI] 1640 kcal/day) The EIs (kcal/day) were calculated as 1502, 1619, and 1674 for AI, users, and dietitians, respectively, those were lower than that with the weighing method Spearman's rank correlation coefficients compared to the weighing method were 0.48, 0.88, and 0.88 for AI, users and dietitians, respectively, showing a weak correlation for AI and a strong correlation for users and dietitians. The user's adjustments greatly improved accuracy without increasing the burden on the dietitians.

Disclosure

M.Kitazawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. C.Horikawa: None. I.Ikeda: None. Y.Takeda: None. E.D.Ferreira: None. M.Takeuchi: None. S.Y.Morikawa: None. K.Fujihara: None. S.Kodama: None.

Funding

Grants-in-Aid for Scientific Research (21K17637)
33-LB: A Multidimensional Lifestyle Measure for Self-Assessment
Authors: FANCHIANG SHANPIN , BOUCHONVILLE MATTHEW F.
Published: June 2023

Lifestyle modification can help people manage many chronic diseases, including diabetes. Primary care practitioners should address patients' lifestyles, based on literature. Limited time per visit makes it challenging. It is person-centered using a lifestyle self-assessment for patients to prepare for clinic visits and if needed, to initiate focused lifestyle discussion. We explored if a multidimensional lifestyle measure can help people gain insight to prepare for their healthcare visits.

We used social media to disseminate this web-based multidimensional lifestyle measure. It has 11 dimensions with one to six items each. Some were positive actions, and some were negative to be avoided. Eleven additional dimension-specific questions asked if participants had gained insight through reflecting on the items. If the lifestyle self-assessment “helped me see the big picture of what I do” and “I could see myself doing a similar lifestyle reflection once a year” were also included. We tested the hypothesis that significant utility would be more than the “early majority” (34%) of participants had gained insight and supported the utility of lifestyle self-assessment.

Twenty-eight women and 10 men with a wide age range completed the online survey. Significantly more than 34% of the respondents indicated that they had gained insight into the following four dimensions: stress management (54.1%, p=.005), social support (47.4%, p=.041), nature connection (51.4%, p=.013), and sense of safety (54.1%, p=.005). About 54.1% (p=.005) agreed that doing lifestyle self-assessments helped them see the big picture of their actions. Twenty respondents could see themselves doing a similar lifestyle reflection once a year, with four more indicating they had done something similar, which summed up to 64.9% (p<.0001) supported this idea.

Periodic multidimensional lifestyle self-assessment appears to have positive utility. Analysis and redesign of the dimension-specific items are needed to enhance the utility of lifestyle self-assessment.

Disclosure

S. Fanchiang: None. M. F. Bouchonville: None.
332-OR: Association of Perceived Stress and Weight Loss in the National Diabetes Prevention Program (DPP)
Authors: CHICHMARENKO MARIYA , SAN DIEGO EMILY , SORIANO EMILY , SPIERLING BAGSIC SAMANTHA R. , ORENDAIN NATALIA , PHILIS-TSIMIKAS ATHENA , FORTMANN ADDIE L. , RUIZ MONICA
Published: June 2023

An estimated 96 million Americans over the age of 18 have prediabetes. The Centers for Disease Control and Prevention’s National Diabetes Prevention Program (DPP) aims to promote lifestyle changes and weight loss to prevent or delay the onset of type 2 diabetes. While stress can play a significant role in weight management, little is known about the association between participant stress and weight loss in this program. The Scripps Whittier Diabetes Institute delivers the DPP within a large healthcare system in Southern California and administers the Perceived Stress Scale (PSS-10) at baseline and month 6 as part of the program. This analysis was conducted to examine the association between changes in stress and weight over 6 months. During a five-year timeframe that spanned the onset of the COVID-19 pandemic, and the transition from in-person to virtual delivery (October 2016 - January 2020), N = 341 individuals participated in the Scripps DPP. The majority of the participants were female (80.2%), married (65.4%), and reported an annual household income ≥ $24,000 (82.5%); 48.8% were non-Hispanic White. Baseline M(SD) age = 59.9 ± 13.66 and BMI = 32.15 ± 6.16. In a linear regression model, controlling for attendance, sex, and household income, a 1-point decrease in perceived stress was associated with a 0.28 lb. decrease in weight (p=0.02). At 6 months, overall mean weight loss was 4.24%, 8.13 lbs. The DPP addresses stress in one session during the core phase, with two additional sessions related to coping and problem solving. Collecting data with the PSS-10 can help provide additional insights into the effects of the DPP intervention. These findings indicate that reduction of stress over time in the DPP is associated with greater weight loss, thus highlighting the importance of the focus on stress management and coping in the DPP curriculum.

Disclosure

M.Chichmarenko: None. E.San diego: None. E.Soriano: None. S.R.Spierling bagsic: None. N.Orendain: None. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. A.L.Fortmann: Employee; Dexcom, Inc. M.Ruiz: None.