bluuebunny/crossref_metadata_2025_split huggingface dataset:
1638-P: Oxidized Lipids Cause Ceramide Accumulation and Insulin Resistance in Skeletal Muscle
Authors: ZEMSKI BERRY KARIN , BERGMAN BRYAN C. 
Published: June 2023

Accumulation of muscle lipids promotes insulin resistance and type 2 diabetes (T2D). Ceramides are important muscle lipids that decrease insulin sensitivity and it was previously shown that accumulation of ceramides in the sarcolemma negatively impacts insulin sensitivity in humans. The mechanisms explaining accumulation of lipids in specific compartments in skeletal muscle are unknown, but one possibility is through circulating oxidized lipids. POVPC, a major circulating oxidized phospholipid, was exposed to rat myotubes (1-50 μM) for 4h and the total cellular ceramide levels in myotubes measured by LC-MS/MS. Total ceramide content increased dose dependently at POVPC doses in the physiological range (5 μM, p &lt;0.05). To determine the mechanism of POVPC induced ceramide accumulation, ceramide was measured in myotubes after treatment with POVPC (25 μM) in the presence of inhibitors of neutral and acid sphingomyelinase (GW4869 and ARC39), ceramide synthase (fumonisin B1) and serine palmitoyltransferase (myriocin). The individually administered inhibitors in the presence of POVPC each showed a decrease (41-55%) in ceramide accumulation. When all of inhibitors were administered together along with POVPC, an almost complete inhibition of ceramide accumulation (95%) was observed indicating that the sphingomyelinase, de novo, and salvage pathways of ceramide synthesis are activated by POVPC. The role of oxidized lipids on insulin sensitivity was examined after treatment of rat myotubes with 1-25 μM POVPC. Increasing doses of POVPC at doses as low as 1 μM significantly decreased insulin sensitivity in vitro (p &lt;0.05). These results reveal circulating oxidized lipids promote ceramide accumulation and insulin resistance in muscle cells and may help explain variability in total and localized muscle ceramide levels between individuals. These data also suggest that therapies designed to lower circulating oxidized lipids could be beneficial for the treatment and prevention of T2D.

Disclosure
K.Zemski berry: None. B.C.Bergman: Research Support; Eli Lilly and Company.

Funding
National Institutes of Health (P30DK048520); University of Colorado (25N0350)
1639-P: Meroterpenoid-Rich Fraction of the Ethanol Extract from Sargassum Serratifolium Suppressed Muscle Atrophy Induced by Dexamethasone in C2C12 Myotubes and C57BL/6 Mice
Authors: LEE MIN-KYEONG , RYU HEEYEON , HAK JEONG HYEON , LEE BONGGI 
Published: June 2023

Decline in muscle mass and strength impairs the ability to perform normal daily functions and increases the risk of falls and fractures, significantly reducing the quality of life. In addition, as the muscle is considered a major regulator of systemic glucose homeostasis, maintaining muscle mass is important for glycemic control. Although dexamethasone (DEX), a synthetic glucocorticoid, is a well-known anti-inflammatory drug, high doses or long-term use induces side effects such as skeletal muscle atrophy. Sargassum serratifolium is a brown alga that contains high concentrations of meroterpenoids and exhibits antioxidant, anti-inflammatory, anti-obesity, anti-atherosclerosis, and hepatoprotective activities. However, its effects on DEX-induced muscle atrophy remain unknown. Here, we investigated the beneficial effects of the meroterpenoid-rich fraction of the ethanol extract from S. serratifolium (MES) on DEX-induced muscle atrophy in C2C12 myotubes and C57BL/6 mice. In the in vitro study using C2C12 myotubes, DEX (5 μM) treatment reduced cell viability, myotube diameter, and glucose uptake, whereas MES treatment reversed these effects. In addition, in DEX-stimulated C2C12 myotubes, MES treatment not only increased the phosphorylation of Akt and p706SK but also decreased the mRNA and protein expression of protein degradation factors such as MAFbx/Atrogin-1, MuRF1, and FoxO3a. In the in vivo study, MES suppressed DEX-induced decrease in body weight, ability to exercise, lean body mass, calf thickness, muscle weight, and cross-sectional area of the gastrocnemius muscle. Taken together, MES ameliorated DEX-induced muscle atrophy and maintained glucose homeostasis. Therefore, MES can be used as a potential therapeutic agent for the treatment of muscle atrophy.

Disclosure
M.Lee: None. H.Ryu: None. H.Jeong: None. B.Lee: None.
1640-P: Meroterpenoid-Rich Ethanolic Extract of Sargassum serratifolium (MES) Alters Macrophage Transcriptome and Secretion Profile toward Improving Muscle Atrophy and Glucose Intolerance
Authors: RYU HEEYEON , LEE BONGGI 
Published: June 2023

Skeletal muscle plays an essential role in glucose homeostasis. Of many cell types in the skeletal muscle, recent studies indicate that secretion factors derived from macrophages are important for glucose metabolism in the skeletal muscle. Here, RNA Sequencing analysis showed that Lipopolysaccharide (LPS) treatment broadly altered the transcriptome of macrophages, of which signaling related to secretion factors was markedly altered toward elevating unfavorable cytokines to maintain skeletal muscle metabolism. On the other hand, the treatment of the Meroterpenoid-Rich Extract of Sargassum Serratifolium (MES), a strong anti-inflammatory and antioxidant extract found in our previous studies, reversed the LPS-induced signaling pathways. We further tested whether the treatment of conditioned media (CM) derived from LPS-macrophage (LPS-CM) or CM derived from LPS-macrophage treated with MES (MES-CM) affects glucose homeostasis in differentiated C2C12 myotube cells. LPS-CM treatment notably increased mRNA levels of muscle atrophy-associated genes including MuRF1, MAFbx, and Myostatin, and decreased glucose uptake, and MES-CM treatment reversed these characteristics, indicating that secretion factors induced by LPS or MES either impair or improve muscle glucose homeostasis, respectively. We further analyzed secretion factors inside by proteome array and data showed that LPS-CM includes GDF-15, IL-1 α/β, RAGE, etc related to muscle atrophy and glucose intolerance, which were significantly reduced in MES-CM. These data indicate that LPS- or MES-induced changes in the transcriptome in macrophages are closely related to the alteration in secretion factors toward either impairing or improving glucose metabolism in the skeletal muscle respectively. Of many, the decrease in macrophage-derived cytokine mentioned above may be important for glucose homeostasis in the skeletal muscle.

Disclosure
H.Ryu: None. B.Lee: None.
1668-P: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist
Authors: CHAE YUNA , JUNG IL-HUN , KIM TAE-HYOUNG , JIN LEE SU , KIM MI-KYUNG , HEON KIM HYUNG 
Published: June 2023

DA-1726 is a novel oxyntomodulin analogue preparing for phase I clinical trials for obesity. In this study, the pharmacological effect of DA-1726 compared to other competitor peptides was evaluated. DA-1726 showed superior efficacy compared to other glucagon-like peptide-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist (Cotadutide; COTA) in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. DIO control at 30 nmol/kg, p&lt;0.05) and improving plasma glucose, insulin, and HOMA-IR (-91% for DA-1726 vs. -52% for COTA) in diet-induced obese mice. In addition, superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA were confirmed by DA-1726. These data suggested that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Meanwhile, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. Thus, DA-1726 was injected for 3 weeks and glucose tolerance test was performed at 72-h after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72-h after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist (Tirzepatide; TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p&lt;0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control.

Disclosure
Y.Chae: None. I.Jung: None. T.Kim: None. S.Lee: None. M.Kim: Employee; Dong-A ST. H.Kim: None.
167-LB: Knowledge Retention and Glycemic Control in Participants of Kids in Control of Food (KICk OFF) Program—Virtual vs. On-Site
Authors: ALMATROOK REEM , TAHA NEHAD , RAHME ZAHRAA , ALQABANDI ALGHALIA 
Published: June 2023

Introduction: Kids In Control Of Food (KICk OFF) is a structured educational program for children with T1D from ages 11 to 16 years old. Due to the COVID-19 pandemic, the program was adapted and delivered virtually to accommodate regulations. It is unclear whether the virtual adaptation provides the same learning experience and effect on glycemic control as the original on-site version.
Objectives: To compare both HbA1c and knowledge retention between participants who completed the program virtually versus on-site.
Methods: A knowledge retention test of 15 questions was developed addressing the main diabetes concepts explained during KICk OFF: diabetes, insulin, carbohydrate counting, etc. This test was distributed to all the participants (virtual/on-site) 6 months after the completion of the course. Their knowledge retention tests were scored as a percentage of correct answers to total questions. HbA1c was recorded at baseline and 6 months. A t-test was used for statistical analysis.
Results: A total of 43 participants attended KICk OFF (23 on-site, 20 virtual). A significantly higher knowledge retention test score was achieved in the on-site group (p-value=0.015) (Table 1). An insignificant reduction of HbA1c of 0.3% was observed in the on-site group after 6 months, and no reduction in the virtual group (Table 2). Table 1: Mean retention test scores for the on-site and virtual participants.
Table 2: Mean HbA1c for the on-site and virtual participants.
Discussion: Although virtual KICk OFF was necessary during COVID-19, the results indicated a superiority in the on-site KICk OFF course in terms of knowledge retention, as well as HbA1c reduction. Further research is recommended.

Disclosure
R. Almatrook: None. N. Taha: None. Z. Rahme: None. A. Alqabandi: None.
1670-P: Sex-Dependent Effects of PERK Deletion in Thermogenic Adipocytes
Authors: JENA JAYASHREE , GARCÍA-PEÑA LUIS M. , PEREIRA RENATA 
Published: June 2023

Brown and beige adipocytes dissipate chemical energy as heat through thermogenic respiration, thereby playing important roles in adaptive thermogenesis and energy homeostasis in mice. The Protein Kinase R (PKR)-Like Endoplasmic Reticulum Kinase (PERK) has been shown to be required for mitochondrial thermogenesis in cultured brown adipocytes, and in mice lacking PERK in white and brown adipose tissues. Here, we tested the hypothesis that PERK expression specifically in thermogenic adipocytes is required for adaptive thermogenesis and to regulate energy homeostasis in mice, by selectively deleting PERK in Ucp1-expressing cells (brown and beige adipocytes) of male and female mice. At baseline conditions, mitochondria oxygen consumption rates (OCR) were significantly reduced in brown adipocytes isolated from male, but not from female KO mice. After being housed at thermoneutrality for 7 days (30 °C), wild type (WT) and KO mice were exposed to 4 °C for 3 days. Surprisingly, both male and female KO mice were able to properly adapt to cold exposure, as demonstrated by preserved core body temperatures relative to WT mice. Interestingly, age-induced weight gain, fat mass expansion and impairments in glucose homeostasis were all attenuated in KO males, while weight gain was exacerbated in KO females. This correlated with increased energy expenditure (EE) in male mice, while EE was reduced in female mice. We, next, tested the hypothesis that male KO mice would be resistant to diet-induced obesity. After 12 weeks of high-fat feeding (60% calories from fat), male KO mice became as obese, glucose intolerant and insulin resistant as WT mice. In conclusion, our data suggest that PERK expression in thermogenic adipocytes reduces mitochondrial OCR in male mice, but is dispensable for thermoregulation after short-term cold exposure in both male and female mice. Furthermore, our data reveal a sex-dependent effect of PERK in thermogenic adipocytes in the regulation of energy homeostasis, which is dependent on changes in EE.

Disclosure
J.Jena: None. L.M.García-peña: None. R.Pereira: None.

Funding
National Institutes of Health (DK125405, 2T32DK112751-06)
1672-P: Isoxanthohumol Improves Obesity and Glucose Metabolism via Regulation of Gut Barrier and Intestinal Lipid Absorption with a Bloom of Akkermansia muciniphila
Authors: WATANABE YOSHIYUKI , FUJISAKA SHIHO , WATANABE SHIRO , NISHIMURA AYUMI , KADO TOMONOBU , RAHIL ASLAM MUHAMMAD , BILAL MUHAMMAD , MORINAGA YOSHITOMO , TOBE KAZUYUKI 
Published: June 2023

Dysbiosis is an important factor that leads to metabolic disorders via disruption of the gut barrier function. A decrease in Akkermansia muciniphila (AM) is a phenotype of obesity-induced disruption of the gut barrier. Although interventions to increase AM have been reported to improve glucose metabolism, the underlying mechanism has not been fully understood. The administration of IX suppressed weight gain and steatohepatitis and improved glucose metabolism in diet-induced obese mice. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption via decreased expression of the lipid absorption transporter, CD36, in the jejunum. Moreover, IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the observed effects of IX were cancelled by antibiotics and reproduced by fecal microbiota transplantation to GF mice. 16S rRNA sequencing revealed that the microbial community structure changed with a significant increase in AM in the IX-administration group. An anaerobic chamber study showed that IX promoted the growth of AM, while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct impact of AM on lipid and glucose metabolism in monocolonized mice, we transplanted either AM or Bacteroides thetaiotaomicron to GF mice. AM monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism with decreased multiple classes of fatty acids in plasma metabolomics analysis. In summary, IX contributes to metabolic improvement by decreasing CD36 and lipid absorption in the small intestine which is associated with a bloom of AM, suggesting an important interaction between food ingredients and AM abundance in controlling metabolism.

Disclosure
Y.Watanabe: None. S.Fujisaka: None. S.Watanabe: None. A.Nishimura: None. T.Kado: None. M.Aslam: None. M.Bilal: None. Y.Morinaga: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care.

Funding
Japan Society for the Promotion of Science (21K20896, 22K16424); Lotte Foundation; Yakult Bio-Science Foundation
1676-P: A Novel GLP1R/GCGR Dual Agonist, DA-1726 Elicits Weight Loss Superior to Semaglutide in Diet-Induced Obese Rats
Authors: CHAE YUNA , KIM TAE-HYOUNG , JUNG IL-HUN , HEON KIM HYUNG , KIM MI-KYUNG 
Published: June 2023

DA-1726 showed superior weight loss efficacy compared to Semaglutide (SEMA) in DIO mice. In this following study, a dose-response of DA-1726 was evaluated to determine the maximum efficacy in DIO rats that are known to have good translatability to human studies. The half-life of DA-1726 was longer in rats compared to mice, however the in vitro activity of DA-1726 against rat glucagon receptor was less potent than in the mouse, and plasma protein binding was approximately 10-fold higher in rats. Therefore, we set the effective dose for rats higher than for mice. DA-1726 was injected twice a week for about 4 weeks, a dose-dependent and significant weight loss effect was observed. The minimum effective dose in DIO rats was found to be 250 nmol/kg. Then, the maximum body weight loss effects of DA-1726 (500 and 1000 nmole/kg) and SEMA were compared in the DIO rat. In this study, DA-1726 showed an excellent weight loss effect than SEMA (32.6% for DA-1726 at a high dose vs. 24.0% for SEMA, p&lt;0.05). The low-dose DA-1726 group showed a similar effect compared to SEMA even though they consumed more food. The high-dose DA-1726 group showed similar food intake as SEMA, but led to a higher weight loss effect. After repeated dosing, the high-dose DA-1726 significantly increased the expression of energy metabolism-related genes (Ucp1, Ppargc1a) in white adipose tissues (WAT), supporting increased energy expenditure. So then, in order to confirm whether this increased gene change was a direct effect leading to weight loss or an indirect effect caused by weight loss, we assessed the changes in gene expression after single dosing. DA-1726 (250 and 500 nmol/kg) induced small but significant weight loss 3 days after a single injection (-7.6% and -9.5% vs. control). However, the genes expression (Ucp1, Ppargc1a) in WAT was significantly increased only in the 500 nmol/kg-treated group suggesting a direct effect. Therefore, DA-1726 is expected to elicit excellent weight loss effects in humans with a new mechanism.

Disclosure
Y.Chae: None. T.Kim: None. I.Jung: None. H.Kim: None. M.Kim: Employee; Dong-A ST.
1693-P: Association of Sleep and OSA Severity with Neurocognitive Function in the RISE Study
Authors: TEMPLE KARLA A. , TJADEN ASHLEY H. , EHRMANN DAVID , MANCHANDA SHALINI , EDELSTEIN SHARON , HANNON TAMARA S. , CRAFT SUZANNE , MOKHLESI BABAK ,   RISE CONSORTIUM
Published: June 2023

Poor sleep and obstructive sleep apnea (OSA) have both been associated with worsening neurocognitive function. In the Restoring Insulin Secretion (RISE) Study, we assessed the relationship between presence and severity of OSA and cognition in treatment-naïve adults (n=179) with prediabetes or early T2D. A cognitive battery (CogState™ and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Wrist accelerometers worn for 7 days measured average sleep duration and efficiency. Other sleep outcomes were measured during one night of laboratory polysomnography. Linear regression models were fit to assess independent relationships between cognition and sleep measures. The cohort consisted of 44% females, 56% males; 53% white, 33% black, 6% Hispanic; age 54.7±8.9 years and BMI 34.7±5.4 kg/m2 (mean±SD). Based on ADA criteria, 73% had prediabetes and 27% had T2D. Sleep duration was 6.5±1.0 h; sleep efficiency was 85.9±7.5%; 26% had moderate OSA, 40% had severe OSA. After adjustment for age, sex, race/ethnicity, education, and BMI, higher sleep efficiency was associated with better visual pattern separation (as measured by the One Card Learning Test; p=0.039) but not with any other neurocognitive assessment. In the RISE cohort, measures of OSA severity (apnea-hypopnea index, oxygen desaturation index, sleep duration below 90% oxygen saturation, microarousal index) were not associated with baseline cognition. This cross-sectional analysis shows a high prevalence of moderate/severe OSA in treatment-naïve adults with prediabetes or early T2D. Although higher sleep efficiency was associated with better visual pattern separation, it was not associated with other measures of cognitive function. Further, OSA severity was not associated with measures of neurocognition.

Disclosure
K.A.Temple: None. A.H.Tjaden: None. D.Ehrmann: None. S.Manchanda: Advisory Panel; Inspire. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.Craft: None. B.Mokhlesi: None. Rise consortium: n/a.

Funding
American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; U.S. Department of Veterans Affairs; Kaiser Permanente Southern California
1711-P: Assessment of Prediabetes in Patients with Morbid Obesity (MO)
Authors: BRIX JOHANNA , PARZER VERENA , HUBER SIMONE L. , LUDVIK BERNHARD 
Published: June 2023

The frequency of prediabetes as well as the optimal method to identify glucose abnormalities in morbid obesity (MO) is subject to debate. We, therefore, evaluated the frequency of prediabetes and the optimal method for its respective diagnosis in a large cohort with MO.
We included 1.626 patients with MO (age 34±10 years, BMI 44.6± 7.0 kg/m², 74.3% women). All patients without overt type 2 diabetes (T2D) underwent a 75g OGTT. Prediabetes was diagnosed according to ADA criteria. Demographic, cardiovascular risk-markers, insulin levels and renal parameters were assessed.
We excluded 421 (25.9%) patients due to T2D. Regarding prediabetes, 339 patients (28.1%) fulfilled the fasting glucose criterion, 240 the 2-hour postprandial criterion (19.9%), and 594 patients the HbA1c criterion (49.2%). 56 patients (4.6%) fulfilled all three criteria, 810 (67.2%) had at least one criterion. 933 (77.4%) patients fulfilled either the fasting glucose or the HbA1c criterion, and 834 (69.2%) either the 2h postprandial or HbA1c criterion. Patient's characteristics are depicted in table 1.
The results of our study suggest that fasting glucose or HbA1c are sufficient to diagnose prediabetes. This is particularly of interest since postoperative changes in gut anatomy following bariatric surgery might render a postoperative OGTT invalid for follow-up, whereas fasting glucose or HbA1c are not affected.

Disclosure
J.Brix: Advisory Panel; Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Novo Nordisk, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Novo Nordisk. V.Parzer: None. S.L.Huber: None. B.Ludvik: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Pharma GmbH&Co.KG, Amgen Inc., AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Pharma GmbH&Co.KG, Amgen Inc., AstraZeneca, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Pharma GmbH&Co.KG, Amgen Inc., AstraZeneca.