bluuebunny/crossref_metadata_2025_split huggingface dataset:
47-OR: OPA1 Reprograms Macrophage Metabolism to Enforce Tolerance of Inflammation in Obesity
Authors: WANG DAIXI , HU CHENG , YAN JING 
Published: June 2024

Introduction & Objective: Adipose tissue macrophages (ATMs) are key players orchestrating metabolic homeostasis through regulating metabolic inflammation. Mitochondrial dynamics and metabolic remodeling are pivotal for the function of macrophages. The aim of our study is to explore the role of the macrophage mitochondrial fusion protein, optic atrophy 1 (OPA1) in metabolic disorders and elucidate the underlying mechanisms.
Methods: We generate myeloid cell-specific OPA1 knockout and transgenic mice, subject them to a NCD or HFD to evaluate metabolic and inflammatory phenotypes. By using immunoblot analysis, flow cytometry, seahorse metabolic assays, metabolism assessment, combined with culturing bone marrow derived macrophages to reveal the molecular mechanisms of OPA1 in regulating metabolic reprogramming in macrophages.
Results: Myeloid-specific KO of OPA1 induces M2-like to M1-like macrophages shift in AT, thus promoting metabolic inflammation and exacerbating HFD-induced systemic insulin resistance, glucose dysregulation and liver steatosis in mice. In vitro studies show OPA1 loss impairs mitochondrial oxidative metabolism and inhibits JAK1/STAT6 pathway, resulting in decreased M2 polarization upon IL-4 stimulation. Mechanistically, OPA1 KO impairs the activity of itaconate transporter-Slc25a11 locating in the inner membrane of mitochondrial, leading to itaconate accumulation within the mitochondrial to suppress JAK1/STAT6. Further, mice with transgenic overexpression of OPA1 exhibit improved inflammation and metabolic homeostasis.
Conclusion: We reveal a novel role of OPA1 as a positive regulator of M2 macrophages polarization by governing metabolic reprogramming. Targeting macrophage OPA1 could represent a therapeutic target for AT inflammation and metabolic diseases.

Disclosure
D. Wang: None. C. Hu: None. J. Yan: None.

Funding
the National Science Foundation of China (82370879); Shanghai Rising-Star Program (23QA1407400)
485-P: Alternate-Day Fasting and the 5:2 Diet Alleviate Distal Symmetric Polyneuropathy by Regulating Gut Microbiota and Metabolites
Authors: YUAN HUIJUAN 
Published: June 2024

Objective: Intermittent fasting (IF) regimens such as alternate-day fasting (ADF) and the 5:2 diet have shown promise in mitigating diabetes mellitus (DM). We aimed to investigate whether IF by altering the gut microbiota and related metabolites promotes distal symmetric polyneuropathy (DSPN), which is the most common neuropathy in patients with DM.
Methods: Male db/db mice were subjected to ad libitum feeding, ADF, or the 5:2 diet to observe peripheral nerve function with or without an antibiotics cocktail treatment. Then we further verified the causality of the above symptoms by fecal microbiota transplantation.
Results: Both ADF and the 5:2 diet improved DSPN, fortified gut barrier function and reduced inflammatory factor levels while causing changes in microbiota. Lactobacillus, etc were enriched in ADF diet-treated mice, Mucispirillum, etc increased in 5:2 diet-treated mice. Furthermore, ADF increased levels of metabolites such as gamma-tocopherol while the 5:2 diet increased levels of n-acetylhistamine and asparagine, and both diets decreased levels of n-acetylputrescine and phenylacetic acid. However, depletion of gut microbiota via antibiotics negated the neuroprotective effects of ADF and the 5:2 diet. Pseudo germ-free mice that received fecal transplants from ADF or 5:2 diet-treated mice exhibited improved peripheral nerve function and reduced inflammatory factor levels. Similarly, the stools from ADF increased the abundances of gamma-tocopherol, while the 5:2 diet decreased N-acetylputrescine, both repaired gut barrier in colonic epithelium of pseudo germ-free mice.
Conclusion: Gut microbiota plays a significant role in the onset and progression of DSPN. Both ADF and the 5:2 diet appear to ameliorate DSPN by regulating gut microbiota, altering gut metabolites, reducing inflammatory factor levels and restoring gut barrier function.

Disclosure
H. Yuan: None.

Funding
National Natural Science Foundation of China under Grant (81970705, 82270865)
488-P: Phosphatidate Phosphatase Lipin1 Is Involved in the Development of Diabetic Encephalopathy by Regulating the Homeostasis of Mitochondria-Associated Endoplasmic Reticulum (MAMs)
Authors: CHEN SHIHONG , ZHUANG XIANGHUA , YU SHUYAN , HUANG SHAN , HAN XIAOLIN 
Published: June 2024

Introduction & Objective: Diabetic encephalopathy (DE) is a common chronic central nervous system complication without clear elucidation of pathogenesis as well as effective therapy currently. Mitochondria-associated endoplasmic reticulum membrane is a dynamic contact site connecting mitochondrial membrane with endoplasmic reticulum (ER) membrane, where phospholipid components are exchanged to each other. Our previous work has revealed that Lipin1, a critical enzyme related to phospholipid synthesis, involves in the pathogenesis of DE. However, it needs further investigation whether Lipin1 affects cognitive function via regulating the homeostasis of MAMs in neurons of DE.
Methods: We used C57BL/6J mice in vivo and HT-22 neuronal cells in vitro to construct DE models and Lipin1-targeted regulation models to detect any changes in MAMs, ER stress, mitophagy, dendritic structure and cognitive function. Statistics were analyzed by using t-test and one-way ANOVA.
Results: Here, we demonstrate that Lipin1 is significantly reduced in hippocampus of DE mice. Knockdown of Lipin1 within hippocampus or neurons induces significant structural and functional impairment of MAMs with the enhancement of ER stress and mitophagy, and then leads to impaired dendritic structure and cognitive dysfunction, similar to that observed in DE. In contrast, up-regulation of Lipin1 within hippocampus or neurons in the DE model ameliorates this cascade of dysfunction.
Conclusion: Lipin1 deficiency in response to chronic hyperglycemia contributes to the imbalance of MAMs homeostasis in hippocampal neurons, accompanying the enhancement of ER stress and mitophagy, and finally leads to cognitive deficits observed in DE.

Disclosure
S. Chen: None. X. Zhuang: None. S. Yu: None. S. Huang: None. X. Han: None.

Funding
National Natural Science Foundation of China (82170828,82070847, 82270869) and the Natural Science Foundation of Shandong Province (ZR2021LSW016).
50-PUB: Maternal Apolipoprotein C3 and Diabetes in Pregnancy in a High-Risk Cohort
Authors: VAZQUEZ LAURA , VAZQUEZ ARREOLA ELSA , LOOKER HELEN C. , HANSON ROBERT L. , WASAK DOROTA , CABALLERO RACHEL , SINHA MADHUMITA 
Published: June 2024

Introduction & Objective: Apolipoprotein C-III (ApoC3) regulates lipid metabolism by inhibiting lipoprotein lipase and reducing hepatic triglycerides uptake, higher levels associate with insulin resistance (IR). The role of ApoC3 in pregnancy is unclear. We study if apolipoprotein levels differ in women with diabetes in pregnancy.
Methods: Among 66 pregnant women (Hispanic and Indigenous American) in the Early Tracking of Childhood Health Determinants (ETCHED) study (April 2022-September 2023), 22 (33%) had diabetes. Baseline maternal prenatal lipids (triglycerides, total cholesterol, HDL-C, ApoA1, ApoB, and ApoC3 measured by immunoenzymatic assay) and glycemic markers (fasting glucose and insulin, HbA1c, C-peptide) were compared by diabetes status; IR was estimated by HOMA IR. Cord blood fructosamine, C-peptide, and apolipoproteins were analyzed in a subset (n=40).
Results: Table 1 contrasts measures in pregnancies by diabetes. In women with diabetes, pregestational BMI, glycemic markers, HOMA IR, and ApoC3 were higher. Cord-blood fructosamine levels were higher in offspring of mothers with diabetes. In similar analyses by hypertension in pregnancy the only difference between groups was higher pregestational BMI (p&lt;0.001) in hypertensive women.
Conclusion: Women with diabetes in pregnancy had higher levels of ApoC3 and increased insulinemia, compared to those without it; ApoC3 may be a marker of IR in pregnancy.

Disclosure
L. Vazquez: None. E. Vazquez Arreola: None. H.C. Looker: None. R.L. Hanson: None. D. Wasak: None. R. Caballero: None. M. Sinha: None.
507-P: Human Liver-Specific Regulation of Lipogenesis by Long Noncoding RNA hLMR1
Authors: JASO VERA MARCOS E. , TAKAOKA SHOHEI , RUAN XIANGBO 
Published: June 2024

Hepatic de novo lipogenesis (DNL) significantly contributes to circulating triglycerides in the presence of high carbohydrate diets, making liver-specific inhibition of DNL an attractive strategy for relieving hypertriglyceridemia to control coronary artery disease (CAD) risk. We recently identified a human lncRNA, hLMR1 (Gene symbol: LOC100507389), which promotes hepatic cholesterol synthesis. Our unpublished follow-up studies demonstrated that genetic variants associated with elevated blood triglyceride levels predispose carbohydrates-induced hLMR1 expression, and hLMR1 positively regulates the expression of glycolytic and lipogenic genes. The aim of this work is to define how hLMR1 regulates glycolysis and lipogenesis. ChiRP-Seq, a high-throughput sequencing method to discover regions of the genome that are bound by a specific RNA, was performed using hLMR1 targeting probes in human liver tissues. hLMR1 target genes were measured in cultured human hepatocytes and a humanized liver mouse model upon knocking down of hLMR1. One-way ANOVA is being used for the statistical analysis. We found that hLMR1 is robustly upregulated by carbohydrates and knocking down of hLMR1 in humanized livers resulted in decreased expression of genes in the glycolysis and lipogenesis pathway. Furthermore, hLMR1, and its interacting protein, PTBP1, positively regulate the expression and interact with an enhancer region of ChREBP-β, a known transcription factor strongly associated with hepatic lipogenesis and blood triglyceride levels in humans. As a human liver-specific lncRNA, hLMR1 positively regulates glycolysis and lipogenesis, likely by inducing the expression of ChREBP-β. Our future work will further explore the role of this hLMR1-ChREBP-β signaling pathway in high carbohydrate diet-induced fatty liver diseases and hypertriglyceridemia using the humanized liver mouse model.

Disclosure
M.E. Jaso Vera: None. S. Takaoka: None. X. Ruan: None.
51-OR: Vascular Sorbs2 Deficiency Is an Independent Risk of Vascular Complications in Diabetes
Authors: XIONG XIAOWEI , SUN XIAOJING , LEE HON-CHI , LU TONG 
Published: June 2024

Introduction & Objective: We have recently reported that Sorbs2 (sorbin and SH3 domain-containing 2) proteins are abundantly expressed in vasculature and linked to BK channelopathies in Sorbs2 null mice. However, the role of Sorbs2 on vascular physiology is unknown.
Methods: We created the vascular smooth muscle cell (SMC)-specific Sorbs2 KO (SMC-Sorbs2 KO) mice. We examined BK channel activity and BK channel-mediated vasodilation in the coronary arteries of these animals as well as db/db and high-fat diet (HFD) diabetic mice.
Results: SMC-Sorbs2 KO mice at 6-7 months of age has normal body weights and blood glucose levels, but their coronary vasodilation to NS-1619 (a BK channel activator) was diminished by 41.52% * (n=7-12), which was associated with a 30% reduction of BK channel current density (defined as the iberiotoxin-sensitive K+ components) in freshly isolated coronary SMCs, compared to those of age-matched WT mice. Importantly, vascular Sorbs2 expression was downregulated by 58.82% * (n=6) and 51.12% * (n=4) in db/db mice and HFD mice, compared to nondiabetic controls. This was accompanied by decreased BK-α and BK-β1 protein levels by 76.0% and 69.74% in db/db mice and by 55.35% and 66.24% in HFD mice (n=6 for both), and by impaired BK channel activity and BK channel-mediated vasodilation in the coronary arteries of diabetic mice.
Conclusion: Sorbs2 is a key determinant of vascular BK channel physiology. Lack of vascular Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetes. Vascular Sorbs2 deficiency should be considered an independent risk of diabetic cardiovascular complications. *: p&lt;0.05.

Disclosure
X. Xiong: None. X. Sun: None. H. Lee: None. T. Lu: None.
516-P: High-Fat Feeding Alters Circulating Triglyceride Profile by Decreasing SCD Activity and Depleting n-3 Fatty Acids
Authors: OH YOUNGTAEK , SHEN TONG , JEONG SHINWU , CHO SUENGMOK , FIEHN OLIVER , YOUN JANG 
Published: June 2024

Introduction and Objective: Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD), and plasma triglyceride (TG) is considered as a major component in the assessment of diabetes or CVD risk. However, previous lipidomics studies demonstrated that not all TG molecules behave similarly, and that individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased (TGs with lower carbon number [C#] and double-bond number [DB#]) or decreased (TGs with higher C# and DB#) diabetes risk. In the present study, we examined the effects of high fat feeding in rats on plasma lipid profiles with special attention to TG profiles.
Methods: Wistar rats were maintained on a low-fat (control) or high-fat (HFD) diet for 2 weeks, and plasma samples were obtained before and 2.5 h after a meal (n = 10 each) and subjected to a lipidomics analysis.
Results: High fat feeding had significant impacts on circulating lipid profiles with most significant effects observed on TG profile. The effects of HFD on individual TG species depended on DB# in their fatty acid chains; HFD increased TGs with low DB#, known to be associated with increased diabetes risk, but decreased TGs with high DB#, known to be associated with decreased diabetes risk. These changes in TGs with HFD were associated with decreased hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profile. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, HFD selectively depleted n-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#.
Conclusion: HFD had profound impacts on circulating TG profile, and some of these changes are explained, at least in part, by decreased SCD activity and depleted n-3 PUFA.

Disclosure
Y. Oh: None. T. Shen: None. S. Jeong: None. S. Cho: None. O. Fiehn: None. J. Youn: None.

Funding
National Institutes of Health (HL146570)
527-P: How Stressed Are Feet? Novel Methods for Quantifying the Daily Cumulative Stress Imparted on Diabetic Foot Ulcers
Authors: CREWS RYAN T. , JHAVERI SANAM , YALLA SAI V. , FLEISCHER ADAM E. , MILLER STEVEN A. , BOULTON ANDREW J. , ROSENBLATT NOAH J. 
Published: June 2024

Introduction: Physical stress is a key factor in diabetic foot ulcer (DFU) formation and healing. However, knowledge on the association of stress with DFU is still limited due to the complexities in quantifying the magnitude of stress imparted on feet over 24hr periods. This project utilized novel methods to quantify the daily cumulative stress (CS) applied to active DFU.
Methods: Plantar pressures were measured in participants with DFU while walking offloaded with a removable cast walker and while walking unshod (Figure 1). Similar measurements were made while participants stood still. Pressure values (pressure time integral) were paired with steps/day & standing time/day over a one-month period during which adherence with the cast walker was objectively monitored via accelerometry.
Results: For a sample of 5 DFU patients the following median and ranges were found for the 4 components to CS: offloading adherent walking 80.9 MPa*s/day (9.9 - 126.7); non-adherent walking 69.0 MPa*s/day (28.5 - 156.5; offloading adherent standing 313.8 MPa*s/day (25.5 - 649.6); non-adherent standing 341.8 MPa*s/day (165.6 - 500.2).
Conclusion: The methodology developed is the most comprehensive assessment of foot loading in patients’ daily lives to date. In accordance with past work showing DFU patients spend more time standing than walking each day, standing contributed more to the daily CS than walking.

Disclosure
R.T. Crews: Other Relationship; OPED Medical. S. Jhaveri: None. S.V. Yalla: None. A.E. Fleischer: None. S.A. Miller: None. A.J. Boulton: None. N.J. Rosenblatt: None.

Funding
National Institutes of Health Award Number (R01DK131303)
53-OR: Individual Sources of Diabetes Distress—A Precision Mental Health Approach Combining Ecological Momentary Assessment and Continuous Glucose Monitoring
Authors: EHRMANN DOMINIC , KULZER BERNHARD , SCHMITT ANDREAS J. , HERMANNS NORBERT 
Published: June 2024

Using n-of-1 analyses, we aimed at identifying individual sources of diabetes distress. Using ecological momentary assessment (EMA) and CGM, subjective EMA-based experiences of glucose management (hypoglycemia, hyperglycemia and glucose variability distress) and objective CGM-based markers of glucose management (time in hypo- and hyperglycemia, glucose variability) were assessed on a daily level for 17 days. Mixed-effect regression analysis with daily diabetes distress as dependent variable and daily subjective and objective markers of glucose management as random factors was performed, controlled for gender, diabetes type and study day. Individual estimates of the associations between subjective and objective markers and diabetes distress were extracted per person to identify individual sources of diabetes distress. Associations of these individual sources and psychosocial well-being 2 months later were examined. Data from 379 participants were analyzed (50.9% type 1 diabetes, 92.9% insulin therapy). Subjective experiences of glucose variability (t=14.4, p&lt;.0001) and hyperglycemia (t=13.6, p&lt;.0001) were the strongest predictors of daily diabetes distress while CGM-based glucose variability was not significantly associated with daily distress (t=1.13, p=0.26). Individuals for whom subjective markers were a more significant source of diabetes distress had more depressive symptoms (DS: r=0.32), more diabetes distress (DD: r=0.39), and more hypoglycemia fear (FoH: r=0.34) at follow-up (all p&lt;.001). Individuals for whom objective markers were a more significant source of diabetes distress had more favorable psychosocial well-being at follow-up (DS: r=-0.31; DD: r=-0.33; FoH: r=-0.27; all p&lt;.001). N-of-1 analyses demonstrated the differential effects of objective and subjective sources of diabetes distress on psychosocial well-being highlighting the need for individualized approaches.

Disclosure
D. Ehrmann: Advisory Panel; Dexcom, Inc. Speaker's Bureau; Dexcom, Inc., Sanofi-Aventis Deutschland GmbH. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care, Berlin-Chemie AG. B. Kulzer: Advisory Panel; Abbott Diagnostics, Berlin-Chemie AG, Dexcom, Inc., Sanofi, embecta, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Bayer Inc., Insulet Corporation, Lilly Diabetes. A.J. Schmitt: None. N. Hermanns: Speaker's Bureau; Berlin-Chemie AG, Sanofi-Aventis Deutschland GmbH. Research Support; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Speaker's Bureau; Dexcom, Inc. Advisory Panel; Abbott Diagnostics, Ypsomed AG.

Funding
German Centre for Diabetes Research (DZD; FKZ 82DZD01102)
532-P: Comprehensive Analysis of Cardiovascular and Metabolic Health in Type 2 Diabetes Mellitus—Insights from the UDF Study on ABI, BMI, and Neuropathy Across Diverse Population
Authors: ROHATGI RAGINI M. , SHAH PRANJALI K. , PADHYE DAKSHATA , KOVIL RAJIV R. , SOWANI ALPANA , METHIL VINOD , PATANGE SONALI A. , TANNA SNEHAL R. , KARKHANIS SHEFALI A. , GONSALVES BENSLEY L. , ASHTEKAR CHANDRASHEKHAR , DESHMANE RAJESH 
Published: June 2024

Studies link T2DM with obesity, poor glucose control, CV risk, peripheral arterial disease, and prevalent neuropathy in diverse populations. We analyzed 537 T2DM patients, across 18 centres (UDF Study), aged 12-89 for BMI, HbA1C, LDL, ABI, and neuropathy to assess obesity, cardiovascular, and circulatory health. Ankle-brachial index (ABI) was categorised as normal (0.9 to 1.4), &lt;0.9 strong indicator of CV risk, &gt;1.4 stiff peripheral arteries associated with CV disease. Ages ranged from 12 to 89 years with a mean age of 56 ± 12 years. The median age was 58, with most (50%) between 49 and 65 years. The 95% confidence interval for the mean age was 55 to 57 years. The BMI ranged from 12 to 49 with a mean of 27 ± 4.7. Half had BMIs between 24 and 30. 95% CI for the mean BMI was 27 to 28. HbA1C levels varied from 4 to 15, with a mean of 8.4 ± 1.8. The median was 7.9, and the 95% CI for the mean was 8.2 to 8.5. The LDL levels ranged from 15 to 221 mg/dl, with a mean of 92 ± 35 mg/dl. The median LDL level was 89 mg/dl, with a 95% CI for the mean between 89 and 95 mg/dl. Neuropathy assessments in right and left feet show no significant difference (P=0.9764) with similar distribution across normal, mild, moderate, and severe categories. ABI values. Right foot: (0.9 to 1.4): (n=418), &lt;0.9 (n=81), &gt;1.4 (n=38). Left foot: (0.9 to 1.4) (n=428), &lt;0.9: (n=71), &gt;1.4 (n= 38). Moderate correlations observed between right and left metatarsals (0.343-0.429) and heels (0.349), indicating symmetrical pressure change patterns in diabetic feet. The UDF Study's comprehensive analysis of 537 T2DM patients highlighted a significant spectrum of metabolic health challenges linked to varied BMI, HbA1C, and LDL levels. ABI categorization underscored the prevalent cardiovascular risks and arterial stiffness. Despite the diverse age range, foot neuropathy showed uniformity, with moderate correlations in foot pressures suggesting consistent patterns of diabetic foot complications.

Disclosure
R.M. Rohatgi: None. P.K. Shah: None. D. Padhye: None. R.R. Kovil: None. A. Sowani: None. V. Methil: None. S.A. Patange: None. S.R. Tanna: None. S.A. Karkhanis: None. B.L. Gonsalves: None. C. Ashtekar: None. R. Deshmane: None.