bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &lt; 0.001). GI symptoms were experienced mainly within first 60 minutes of meal study in all 4 groups (P &lt; 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 &lt; 0.01 for group factor). Likewise, autonomic symptoms were most prevalent during the early phase of the meal (P &lt; 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 &lt; 25Kg/m2. 2) NMu (n=3765): MD and 22≤BMI &lt; 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) &lt;1.0 mmol/L (male) and &lt;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&lt;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&gt;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&lt;0.05). Surprisingly, GSIS was elevated in Pex5Pdx1-/- mice compared to littermate controls both in vivo (n=15; AUC p&lt;0.05) and ex vivo in isolated islets as measured by perifusion analysis (n=12; AUC p&lt;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 &gt; 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&lt;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)