bluuebunny/crossref_metadata_2025_split huggingface dataset:
246-LB: Stimulation of Hepatic Lipid Secretion by Glucocorticoid Action in the Nucleus of the Solitary Tract
Authors: VASILEV BOYAN , GREWAL MANTASH S. , LUM BRYAN , YUE JESSICA T. 
Published: June 2023

Dysregulated lipid metabolism is a characteristic of diabetes, insulin resistance, and obesity. Increased glucocorticoid (GC) levels and/or action is associated with elevated levels of circulating triglyceride (TG)-rich very low-density lipoproteins (VLDL-TGs). Lipid metabolism is heavily affected by GCs via its direct actions on peripheral organs, e.g. liver, adipose tissue. However, how GCs modulate hepatic VLDL-TG secretion via their actions in the brain is less known. The nucleus of the solitary tract (NTS) in the hindbrain is responsive to various hormones and is an important region involved in whole-body metabolism. Here, we aimed to assess how GC action in the NTS affects hepatic TG secretion and hypothesized that GC receptor (GR) agonism in the NTS stimulates hepatic TG secretion.
Sprague-Dawley rats underwent stereotaxic NTS bilateral cannulation and vascular catheterizations to enable simultaneous direct NTS infusions, intravenous injections, and blood sampling. Hepatic TG secretion rates were measured in 10h-fasted rats after intravenous poloxamer injection with concurrent NTS infusions. NTS GC infusion stimulated TG secretion compared to NTS vehicle controls, but this effect was negated with pharmacological and genetic GR antagonism, suggesting that NTS GCs are mediated via its receptor. The NTS GC-induced increase in VLDL-TG was not associated with changes in liver lipogenic gene expression and protein levels or plasma ApoB48/100. However, plasma FFAs were increased in NTS GC infused rats, and this was associated with increased pHSL:HSL protein levels in white adipose tissue.
We herein provide evidence that acute GC action in the NTS stimulates hepatic VLDL-TG secretion and affects adipose tissue lipid metabolism. Increased circulating FFA availability may contribute to the hyperlipidemic effects of NTS GCs. Future studies to assess the role of NTS GC action in diabetic and obesity-related metabolic disease dyslipidemic models are warranted.

Disclosure
B. Vasilev: None. M. S. Grewal: None. B. Lum: None. J. T. Yue: None.

Funding
Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-06657); Canada Foundation for Innovation (37267); Canada Research Chairs Tier 2 in Brain Regulation of Metabolism
248-LB: Aging of Tanycytes Abolishes the Dynamic Regulation of Blood–Brain Barrier Permeability in the Hypothalamus
Authors: PHAM VIANA , XU ALLISON , BACHOR TOMAS P. 
Published: June 2023

Aberrant metabolic regulation and blood-brain barrier (BBB) dysfunction are two well-known phenomena of aging. The hypothalamus is the main brain region that controls food intake and body weight. It contains a specialized BBB that allows for the free flow of blood through fenestrated capillaries in the median eminence (ME), which places a portion of neurons critical to feeding unprotected by the BBB. Aging's pernicious effect on the traditional BBB throughout the brain is well studied, however how the specialized BBB in the hypothalamus is altered with age is unknown. To study the effects of aging on hypothalamic injury and repair, we injected monosodium glutamate (MSG) into young and old mice to ablate neurons located outside the BBB. We found that in the hypothalamus of young animals, MSG led to tightening of the BBB imparted by a reduction in the number of fenestrated capillaries. In contrast, aged mice were unable to dynamically alter the BBB permeability or modulate fenestrated blood vessels in response to MSG injury. We show that hypothalamic tanycytes, radial glial-like cells lining the wall of the third ventricle, show a higher degree of physical contact with fenestrated blood vessels than with non-fenestrated blood vessels. Tanycytes in young mice following MSG exposure, modified their expression of pleiotrophin, a growth and angiogenic factor, and robustly proliferated. In comparison, tanycytes in aged mice lacked in these responses to injury, which indicate these cells undergo functional decline with aging. Moreover, aged mice following MSG lost a greater number of neurons outside the BBB and experienced severe weight loss weeks after treatment, whereas young mice showed no change in their body weight. These findings uncover that aging leads to loss of hypothalamic BBB plasticity and defective tanycytes, which increase hypothalamic vulnerability to injury and morbidity development in aged animals.

Disclosure
V. Pham: None. A. Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company. T. P. Bachor: None.

Funding
National Institutes on Aging (1R01AG063506-01)
248-OR: Diabetes Remission after Gastric Bypass Is Characterized by Upregulation of LXR and Antioxidant-Related Pathways in Jejunum
Authors: STEFATER-RICHARDS MARGARET A. , GOURASH WILLIAM F. , COURCOULAS ANITA 
Published: June 2023

We have previously shown that intestinal adaptation precedes and relates to metabolic improvement in humans after Roux-en-Y gastric bypass surgery (RYGB). Based on this, we hypothesized that persistence of this adaptation at the one-year postoperative timepoint occurs selectively in patients with persistent postoperative metabolic improvement, versus those without Type 2 diabetes (T2D) remission. RNA-seq was used to determine gene expression in jejunum collected before and 12 months (± 1 month) after RYGB. T2D was defined as HbA1c &gt;6.5% or requiring T2D medications prescribed for prior diagnosis of diabetes. Remission was defined as HbA1c &lt;6.5% off any T2D medications. Nine of 17 patients with T2D failed to achieve remission by 12 months. After sample quality control, jejunal biopsies from 7 patients with T2D without remission (NR), 8 patients with diabetes remission (R) and 13 patients without diabetes (ND) were analyzed via RNA-seq. Significance was defined by an FDR cutoff of 0.05. Unsupervised principal components analysis (PCA) showed no significant differences across PC1 or PC2 among the 3 groups. However, among top pathways expressed in samples from patients with T2D remission (R), LXR/RXR pathway activation was upregulated (pathway z-score= 0.333, p= 4.85E-06) but downregulated in patients without diabetes (ND, z-score= -1.508, p=.01) and in patients without remission (NR, z-score=-1.0, p=2.07E-07). Antioxidant action of vitamin C exhibited a similar pattern of activation uniquely in R and not in NR or ND (R: p=.02, z-score=0.816; NR: p=0.33, z-score=0.816; ND: p=0.03, z-score=-1.0). In summary, although jejunal remodeling may occur in patients without T2D remission, lipogenic (LXR-driven) and antioxidative pathways are uniquely upregulated in biopsies from those with remission. We hypothesize that these processes may underlie mechanisms for T2D improvement after RYGB.

Disclosure
M.A.Stefater-richards: None. W.F.Gourash: None. A.Courcoulas: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R56DK125816, R01DK108642, K08DK125878)
251-LB: Association of Plasma Sphingolipids with Insulin Secretion and Insulin Sensitivity in Healthy Black and White Adults
Authors: ASUZU PEACE , MANDAL NAWAJES , WAN JIM Y. , STENTZ FRANKIE B. , DAGOGO-JACK SAMUEL 
Published: June 2023

Objective: Sphingolipid (SPL) are associated with glucose dysregulation. Here, we examined plasma SPL profiles in relation to insulin action and secretion in Black and White adults.
Methods: Baseline plasma levels of 58 SPLs (ceramides {CER}, monohexosyl-ceramides {MHC}, sphingomyelins {SM}, sphingosine {SO} and dihydro-SO-1-phosphate {DHS1P}) were assayed using LC-MS/MS. Insulin sensitivity was assessed by euglycemic clamp (ISI) and HOMA-IR; insulin secretion by IVGTT (AIR), HOMA-B and disposition index (DI, i.e, AIR × ISI).
Results: We enrolled healthy offspring of parents with T2DM (75 Black, 65 White; mean age 47.7 ± 9.01 y, BMI 30.4 ± 6.12 kg/m2, FPG 92.9 ± 6.86 mg/dl and 2-hrPG 130 ± 28.8 mg/dl. Total SPLs showed no association with ISI or HOMA-IR but was significantly associated with insulin secretion (AIR, r=0.19, P=0.031; DI r=0.21, P=0.038). There were differential associations between individual SPLs and insulin secretion/sensitivity, but 5 of 58 SPLs (SM C16:0, SM C28:0, SM C28:1, SM C30:1 and SM C34:0) showed concurrent associations with both measures (r=0.16-0.37, P=0.04-&lt;0.0001). Four SPLs were significantly associated with insulin secretion corrected for insulin sensitivity: MHC C14:0 (r=0.24, P=0.016); MHC C26:0 (r=0.23, P=0.025); SM C22:0 (r=0.26, P=0.009); DHS1P (r=0.27, P=0.006). Very long chain SMs correlated with BMI, waist circumference, body fat and lean mass (r=0.19-0.25, P=0.03-0.0004). Plasma CERs and SMs showed significant associations with 2hrPG (r=0.17-0.25, P=0.04-0.003) but not FPG.
Conclusion: Circulating SPLs associate differentially with indices of insulin sensitivity, secretion, and adiposity. Of the 58 individual SPLs assayed, MHC C14:0 and C26:0, SM C22:0 and DHS1P showed the strongest association with insulin secretion corrected for insulin sensitivity.

Disclosure
P. Asuzu: None. N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. S. Dagogo-jack: None.
252-LB: Dectin-2 Deficiency Promotes Proinflammatory Cytokine Release from Macrophages and Impairs Glucose-Stimulated Insulin Secretion
Authors: FUJITA MASAMICHI , MIYAZAWA TAKASHI , UCHIDA KEIICHIRO , UCHIDA NAOHIRO , HATAYAMA TOMOMI , NAKAMURA SHINTARO , TAKEICHI YUKINA , MIYACHI YASUTAKA , OGAWA YOSHIHIRO 
Published: June 2023

Pancreatic islet inflammation plays an important role in the pathogenesis of diabetes mellitus. Islet macrophages, which have emerged as a key player in islet inflammation, express Dectin-2 (D2), one of the C-type lectin receptors recognizing α-mannans, while endocrine cells such as α-cells and β-cells lack the expression of D2. To elucidate the role of D2 in glucose metabolism and β-cell function, we analyzed the phenotype of D2 knockout (D2KO) mice. D2KO mice exhibited significantly impaired glucose tolerance compared to wild-type (WT) mice, although there were no significant differences in insulin sensitivity. Glucose-stimulated insulin secretion (GSIS) was significantly reduced in isolated islets from D2KO mice compared to WT mice. Comprehensive analysis of RNA-seq in isolated islets from D2KO and WT mice revealed that D2 deficiency induced immune cell infiltration and inflammation in pancreatic islets. Furthermore, RNA-seq analysis in peritoneal macrophages from D2KO and WT mice showed that macrophages from D2KO mice acquired an inflammatory phenotype and exhibited enhanced NF-κB signaling compared to those from WT mice. Next, to determine whether humoral factors secreted from macrophages affect GSIS, we examined GSIS using the culture supernatants of macrophages from D2KO and WT mice. The culture supernatants of macrophages from D2KO mice suppressed GSIS compared to WT mice. Furthermore, the multiplex cytokine assay revealed that IL-1α and IL-6 were significantly increased in the culture supernatants from macrophages of D2KO mice. Finally, we found that the stimulation of IL-1α and IL-6 reduced GSIS in β-cells. These findings suggest that macrophages from D2KO mice suppress GSIS by increasing IL-1α and IL-6 production. This study provides new insights into the mechanism by which D2 is involved in the pathogenesis of pancreatic islet inflammation.

Disclosure
M. Fujita: None. T. Miyazawa: None. K. Uchida: None. N. Uchida: None. T. Hatayama: None. S. Nakamura: None. Y. Takeichi: None. Y. Miyachi: None. Y. Ogawa: None.
254-OR: Effects of Roux-en-Y Gastric Bypass on Postprandial Glucose Turnover Assessed through the Single-Tracer Oral Minimal Model
Authors: BRUNASSO ALESSANDRO , DALLA MAN CHIARA , HERZIG DAVID , BALLY LIA , SCHIAVON MICHELE 
Published: June 2023

Rearrangements of gastrointestinal anatomy after Roux-en-Y gastric bypass (RYGB) surgery alter postprandial glucose metabolism. However, the impact on different components of glucose homeostasis remain incompletely understood.
Here, we aim to evaluate the effects of RYGB on postprandial glucose turnover, production (P) and disposal (D) glucose effectiveness (GEP, GED) and production and disposal sensitivity to insulin (SIP, SID).
Ten RYGB (2M, age=39.2±3.1 y, BMI=28±1 kg/m2- mean±SE) subjects and 10 healthy controls (5M, age=36.4±3.2 y, BMI=26±1 kg/m2) ingested 60g of glucose (G) labelled with [6,6-2H2]-glucose. Plasma samples were frequently drawn to measure G, insulin (I) and tracer concentrations in the following 180 min. The Single-Tracer Oral Minimal Model was used to estimate meal glucose rate of appearance (Ra), endogenous glucose production (EGP), glucose disposal (Rd), GEP, GED, SIP and SID.
Incremental area under the G curve (iAUC(G)) was not different in the two groups, while iAUC(I) was significantly higher in RYGB (8346±803 vs. 5451±602 μU/mL*min, p=0.011); iAUC(Ra) normalized to the G dose was significantly higher in the first 60 min after the meal (0.72±0.04 vs. 0.28±0.03, p&lt;0.001) while, throughout the experiment, EGP suppression (EGPs) normalized to basal (EGPb) was significantly lower (0.31±0.06 vs. 0.55±0.05, p=0.006) and iAUC(Rd) normalized to basal (Rdb) was higher (3.46±0.10 vs. 2.82±0.08, p&lt;0.001) in RYGB than controls. Model predicted SIP was significantly lower in RYGB than controls (2.0±0.5 vs. 5.1±1.2 10-4 dL/kg/min per μU/mL, p=0.033) while no differences were observed in GEP, GED and SID.
We concluded that the abnormally high I concentration in RYGB was responsible for the higher iAUC(Rd) in the operated individuals, while the reduced SIP likely works as a protective mechanism against postprandial hypoglycaemia by reducing EGPs despite the high circulating I.

Disclosure
A.Brunasso: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. D.Herzig: None. L.Bally: Research Support; Dexcom, Inc., Ypsomed AG. M.Schiavon: None.

Funding
Italian Minister for Education (Law 232/2016); Swiss National Science Foundation (PCEGP3_186978)
256-LB: An OGT–TFF2 Axis in the Pathogenesis of Nonalcoholic Steatohepatitis
Authors: ZHANG LEI , WANG QI , DESROULEAUX REINA , YANG XIAOYONG 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a global metabolic disease that comprises a broad spectrum of liver dysfunction ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) with fibrosis. It is largely unknown how the communication between hepatocytes and non-parenchymal cells dictates the disease progression from NAFL to NASH and fibrosis. Dysregulation of protein O-GlcNAcylation in hepatocytes has been implicated in a wide range of liver diseases. In this study, we demonstrate the role of O‑GlcNAc transferase (OGT) in mediating intercellular crosstalk between hepatocytes and immune cells in NASH-fibrosis development. RNA-sequencing analysis of wildtype and hepatocyte-specific OGT knockout mice was performed and trefoil factor 2 (TFF2) was identified as one of the highly induced genes encoding secreted proteins in OGT-deficient hepatocytes. Immunohistochemistry and western blot were performed to reveal decreased OGT and increased TFF2 expression in the liver of NAFLD patients. Mechanically, OGT was found to repress TFF2 transcription in hepatocytes by modifying forkhead box protein A2 (FOXA2). Recombinant TFF2 along with NASH stimuli was applied to a 3D spheroid culture system comprised of hepatocytes and non-parenchymal cells and TFF2 was shown to promote NASH stimuli-induced triglyceride secretion and elevate the expression of pro-inflammatory and fibrogenic genes. ELISA and RT-qPCR were performed to further show that TFF2 treatment induced the expression of Th1-type cytokines (IFN-γ and TNF-α) and Th17-type cytokine (IL17) in CD4 T cells, promoting Th1 and Th17 differentiation. Collectively, these results identify an OGT-TFF2 axis that mediates the crosstalk between hepatocytes and CD4 T cells during NASH pathogenesis, revealing a potential therapeutic target for the treatment of chronic liver disease.

Disclosure
L. Zhang: None. Q. Wang: None. R. Desrouleaux: None. X. Yang: None.

Funding
American Diabetes Association (1-19-IBS-119 to X.Y.); National Institutes of Health (R01DK089098, P30DK34989)
259-LB: Loss of AMPK Induces Elongation of Preexisting Hepatic Fatty Acids, without Affecting DNL, during Fasting–Refeeding
Authors: FLETCHER JUSTIN A. , DEJA STANISLAW , BURGESS SHAWN C. , FU XIAORONG , INIGO MELISSA MAE R. , BROWNING JEFFREY , KUCEJOVA BLANKA 
Published: June 2023

AMP-activated protein kinase (AMPK) is a cellular energy sensor that conserves energy by inhibiting anabolic processes, such as de novo lipogenesis (DNL). Paradoxically, fructose metabolism activates AMPK by reducing the energy state (elevated AMP/ATP ratio), yet also promotes DNL. However, the comprehensive effects of fructose metabolism and AMPK activity on hepatic DNL has not been thoroughly investigated. Here, we examine how loss of AMPK function impacts DNL in response to fasting followed by refeeding a fructose or chow diet. After a 16 hour fast, 12 liver-specific AMPKα1α2 knock-out mice (AMPK-KO) and 12 AMPK α1α2 lox/lox mice (control) were fed either high fructose or chow diets (6 per a group) and administered D2O drinking water for 7 hours prior to blood collection and tissue harvest. After Folch extraction, fatty acids in liver triglyceride (TG-FA) were analyzed by proton and deuterium NMR spectroscopy to determine 2H incorporation and estimate DNL, elongation and re-esterification fluxes. Body water enrichment (~3.5%) was similar between groups. After correcting for food intake and body weight, preliminary data indicates that the AMP/ATP ratio was greater in AMPK-KO liver compared to controls, but neither chow nor fructose diets affected the energy state. Overall, neither hepatic steatosis nor DNL differed between groups. Furthermore, loss of AMPK function did not affect the amount of various FA species (i.e. saturated, unsaturated, DHA and ω3, linoleic, and non-essential). Instead, AMPK-KO liver had increased TG-FAs that were elongated compared to controls. This effect also tended to be greater in fructose fed mice (AMPK-KO and controls) compared to chow fed mice, even though fructose fed mice consumed fewer calories.
In conclusion, loss of AMPK function resulted in increased elongation of hepatic TG-FAs, but not DNL, or the amount of FAs in the liver in response to fasting and refeeding with either fructose or chow diets.

Disclosure
J. A. Fletcher: None. S. Deja: None. S. C. Burgess: None. X. Fu: None. M. R. Inigo: None. J. Browning: None. B. Kucejova: None.

Funding
National Institutes of Health (K01AA030327)
264-OR: Incorporating Shared Decision-Making to Facilitate Equitable Insulin Pump Use among Pediatric Patients with Type 1 Diabetes
Authors: TURNER JOEL , NELSON GRACE , ADAMS BLAKE V. 
Published: June 2023

Background: Insulin pumps, CGMs, and other technologies have shown to improve outcomes for patients with T1D. However, various obstacles prevent some patient groups from utilizing these technologies. This was evident by the discrepancy in non-Hispanic black patients on insulin pumps (9%) vs non-Hispanic white patients (23%) in our clinic. Our goal is to identify and overcome these obstacles in order to safely increase the total number of patients that utilize insulin pumps while also creating equity in pump use between groups.
Methods: We identified a group of non-Hispanic black patients who were not candidates for starting insulin pumps based on our clinic’s “typical” practice, but showed interest in pumps. By focusing on this group, we continued to adjust pump prescriptions and processes. After demonstrating efficacy and safety of pump use in this group, we began expanding to all patients as appropriate. Beyond continued education for nurse educators and changing pump start criteria, we also started using shared decision-making to be sure all patients were learning about technology on a regular basis.
Results: As of December 2022, we have helped &gt;35% of our interested patients navigate the process of obtaining an insulin pump. Equity was also improved, with 20% of our non-Hispanic black patients now using pumps vs 25% of non-Hispanic white patients. Some of these patients would not typically be candidates for pumps but were able to safely begin using this technology because of the interventions we initiated.
Conclusions: Utilizing shared decision-making can help to identify patients who might not initially be considered for insulin pumps and other technology. We have demonstrated that many interested patients can safely initiate pumps which will help improve management of their diabetes. We are continually adjusting our processes to improve equity in pump use and increase the overall number of patients utilizing pumps in our clinic.

Disclosure
J.Turner: None. G.Nelson: None. B.V.Adams: None.
266-LB: SGLT2 Inhibition Improved Endurance Performance of db/db Mice Accompanied by an Increased Endogenous AMPK Activator in Skeletal Muscles
Authors: NAKAMURA SHINTARO , MIYACHI YASUTAKA , YOKOMIZO HISASHI , OTSUKA HIROKO , SAKAMOTO RYUICHI , TAKAHASHI MASATOMO , IZUMI YOSHIHIRO , MIYAZAWA TAKASHI , BAMBA TAKESHI , OGAWA YOSHIHIRO 
Published: June 2023

Background: Diabetes is associated with loss of skeletal muscle mass and function. Specifically, diabetes may affect the function of oxidative muscle fibers with lower fatigability and higher oxidative capacity in skeletal muscle. The effects of SGLT2 inhibition on skeletal muscle metabolism and function in patients with type 2 diabetes remain unclear.
Methods: Male db/db (diabetic) and db/+ (non-diabetic) mice at 8 weeks of age were fed a normal chow diet or a diet containing canagliflozin (CANA) for 4 weeks. Grip strength and running distance were assessed during CANA treatment. At the end of CANA treatment, we measured muscle weight and analyzed metabolites in skeletal muscle.
Results: The weights of the oxidative soleus and glycolytic extensor digitorum longus muscles were reduced by approximately 50% in the diabetic group compared to the non-diabetic group, but neither was altered by CANA treatment. Grip strength did not differ between the CANA-treated diabetic, diabetic, and non-diabetic groups. However, the running distance decreased in the diabetic group compared to the non-diabetic group (89 ± 60 m vs. 1980 ± 276 m). This was partially restored by CANA treatment (89 ± 60 m vs. 415 ± 140 m). Metabolomic analysis revealed that long-chain acyl-CoA increased and medium-chain and short-chain acyl-CoA decreased in diabetic soleus muscle. In contrast, CANA treatment increased medium-chain and short-chain acyl-CoA. Furthermore, CANA increased 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5’-monophosphate (AICARP), an endogenous AMPK activator, by approximately 3-fold in diabetic soleus muscle with increased levels of AMPK phosphorylation (Thr172).
Conclusion: These results suggest that SGLT2 inhibitors may activate the AICARP/AMPK pathway and improve impaired oxidative muscle function in patients with type 2 diabetes.

Disclosure
S. Nakamura: None. Y. Miyachi: None. H. Yokomizo: None. H. Otsuka: None. R. Sakamoto: None. M. Takahashi: None. Y. Izumi: None. T. Miyazawa: None. T. Bamba: None. Y. Ogawa: None.