bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &lt; 0.05) and a gain of the rhythm of serum glucose level (Control [Ctr], adjP &gt; 0.05; HF, adjP &lt; 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 &gt; 0.05; HF, adjP &lt; 0.05). Consistently, maternal HF induced a rhythm gain of serum and liver acetate in the juvenile offspring (Ctr, adjP &gt; 0.05; HF, adjP &lt; 0.05). Meanwhile, maternal HF resulted in a gain of the rhythm of hepatic G6pc (Ctr, adjP &gt; 0.05; HF, adjP &lt; 0.05), a marker of gluconeogenesis metabolism. G6pc rhythmic expression was significantly correlated with serum acetate (R = 0.58, P &lt; 0.05) and liver acetate (R = 0.64, P &lt; 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% (&lt;35yrs - 1.5%, 35-54 yrs - 2.9% and &gt;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% (&lt;35yrs - 16.5%, 35-54 yrs - 22.4% and &gt;54 yrs - 24.8%) achieved control on HbA1c, 23.7% (&lt;35yrs- 30.8%, 35-54 yrs - 23.7% and &gt;54 yrs - 22.8%) on BP, and 44.8% (&lt;35yrs - 34.6%, 35-54 yrs - 42.7% and &gt;54 yrs - 47.6%) on LDL-C.
Conclusion: The achievement of goals A and C (HbA1C&lt;7% and LDL-C&lt;100 mg/dL) increases by age and subjects with age≥54 years have significantly better control of HbA1c and LDL-C. Younger (&lt;34 Years) patients diagnosed with diabetes are at a much higher risk of cardiovascular disease as compared to older (&gt;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&lt;0.01, respectively). IENFD was significantly decreased in DM compared to nDM (p&lt;0.05) and further decreased in DM+HT (p&lt;0.05 vs DM). The infiltration of M1 was significantly increased in DM (p&lt;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&lt;0.05). MNFD was comparable between DM and DM+HT. MNFD was inversely correlated with M1/M2 ratio (r=0.37, p&lt;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&lt;.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.