bluuebunny/crossref_metadata_2025_split huggingface dataset:
145-LB: Regional Grey Matter Volume and Cerebral Blood Flow in Obese Youth With and Without Type 2 Diabetes
Authors: BRADY RYAN , SHAH AMY S. , DIFRANCESCO MARK W. 
Published: May 2022

Neurocognitive decline, dementia and stroke are associated with obesity and type 2 diabetes (T2D) in adults. Volumetric brain changes and cerebral vascular impairment, which may mediate these outcomes, have been demonstrated in youth-onset T2D and obesity. A key to understanding the brain pathophysiology in obesity and T2D in youth requires the integration of brain structure and brain perfusion analysis. In 20 youth with T2D (mean age 16.7 years, BMI 98.5%, 75% female) and 19 obese age, sex, race, and BMI similar controls (mean age 17.4 years, BMI 98.5%, 79% female) we examined the relationship between grey matter volume (GMV) and cerebral blood flow (CBF) by MRI and how this might differ by group (T2D vs. obese controls) . Voxel-wise analysis after adjusting for multiple comparisons demonstrated a statistically significant positive relationship between GMV and CBF in the occipital, fusiform, lingual, and right posterior insula with adjustment for socioeconomic status (p&lt;0.05, see Figure) . No difference in the relationship between GMV and CBF by group was discerned. CBF was positively related to GMV mainly in the posterior regions of the brain in obese youth with and without T2D. Whether vascular impairment due to obesity or T2D leads to structural changes and subsequent impaired cognitive function requires further investigation.

Disclosure
R. Brady: None. A. S. Shah: None. M. W. Difrancesco: None.

Funding
Shared Discovery Award CCHMCNational Institutes of Health (R01NS125316)
145-OR: Selenite Treatment Impacts Adipocyte Metabolism and Counteracts Detrimental Effects of Diet-Induced Insulin Resistance
Authors: HAUFFE ROBERT , RATH MICHAELA , KLEINRIDDERS ANDRE 
Published: May 2022

The loss of insulin receptor (IR) in white adipose tissue (WAT) is a feature of type 2 diabetes. Previously, we have demonstrated that feeding mice a preventive selenium rich HFD (SRHFD) , while not influencing obesity development, counteracted diet-induced downregulation of IR and insulin resistance. This was caused by selenite-induced Glutathione peroxidase 3 (GPx3) , which enhanced IR expression and concomitant whole-body insulin sensitivity. The positive correlation between GPX3 and IR levels was also present in humans. In the current study, we investigate A) which selenite (Se) transporter is responsible for the beneficial Se-induced metabolism of WAT using of 3T3-L1 cells, and B) the potential therapeutic effect of selenite supplementation in diet-induced obese mice. We find that LDL Receptor Related Protein (LRP) 8 is necessary for Se-induced upregulation of GPx3 and IR expression to modulate insulin action, as siRNA mediated LRP8 knockdown in 3T3-L1 cells abrogates Se-induced insulin-sensitizing effects with e.g. reduced GPx3 and IR expression. To assess the metabolic effect of selenite supplementation in diet-induced obese mice, C57BL/6N mice received a HFD for 6 weeks, which was followed by a SRHFD for further 12 weeks. Unexpectedly, feeding obese mice a SRHFD resulted in a 10% increase in body weight gain compared to the HFD-fed control group. Nevertheless, these mice exhibited signs of improved metabolism with a shift towards smaller adipocytes, as indicator of improved adipocyte metabolism, and decreased plasma insulin levels. Yet, this was accompanied by unaltered inflammation, GPx3 and IR expression.
In conclusion, our data suggest that LRP8 represents a novel Se-transporter in adipocytes controlling insulin sensitivity and that established obesity precludes the beneficial increase of Se-induced GPx3 and IR regulation in WAT, highlighting the potential importance of GPx3 as a mediator of adipose tissue insulin sensitivity.

Disclosure
R.Hauffe: None. M.Rath: None. A.Kleinridders: Other Relationship; Novozymes.

Funding
Deutsche Forschungsgemeinschaft (KL 2399/4-1) German Ministry of Education and Research BMBF (82DZD00302)
1455-P: The Loss of Pancreatic ß-Cell Complement 1q-Like-3 Secreted Protein Increases Insulin Secretion in Lean and Obese Mice
Authors: RAHMAN MOSTAFIZUR , ALSHARIF HAIFA , BHATNAGAR SUSHANT 
Published: May 2022

Previously, we identified complement-1q like-3 (C1ql3) secreted protein as a hub gene affecting pancreatic islet function in obese mice using network biology. We demonstrated that the recombinant C1ql3 protein inhibits insulin secretion stimulated by exendin-4 (an agonist for GLP-1 receptor) from human and mouse islets. Our goal is to investigate the role of β-cell C1ql3 in pancreatic β-cell function in physiological and pathophysiological states. We generated mice with β-cell-specific deletion of C1ql3 (βKO) by crossing C1ql3fl/fl and RIP-Cre+ mice. C1ql3 βKO mice showed significantly improved glucose clearance after oral glucose challenge than control mice, whereas no difference in insulin action was observed. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. C1ql3 βKO islets significantly increased insulin secretion stimulated by cAMP and Exendin-4 than control islets. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. Obesity increases the expression-coupled secretion of C1ql3 from mouse islets. Adenovirus mediated overexpression of C1ql3 in islets showed increased ER stress - a key trigger for β-cell dysfunction in obesity- as well as decreased expression of genes involving β-cell function and maintenance. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased glucose stimulated insulin secretion from islets of C1ql3 βKO Leptinob/ob compared to Leptinob/ob control mice. These findings identify that the loss of β-cell C1ql3 maintains ER stress to compensate β-cell workload during obesity and increases insulin secretion to maintain glucose homeostasis. Our work shows that an autocrine regulation of the C1ql3-signaling pathway contributes to β-cell dysfunction in obesity and type 2 diabetes.

Disclosure
M.Rahman: None. H.Alsharif: n/a. S.Bhatnagar: None.

Funding
American Diabetes Association (1-18-PDF-103) ; 1R01DK120684-01
1458-P: Lipophagy Is Constitutively Active in Pancreatic Beta Cells and Maintains Insulin Secretion
Authors: LIU SIMING , BRENNECKE BRIANNA R. , YANG USEONG , ANKRUM JAMES A. , IMAI YUMI 
Published: May 2022

Lipid droplets (LDs) , organelles important for intracellular lipid metabolism, are actively formed in rat and human adult beta cells and affect islet function and health. Acute mobilization of LDs by adipose triglyceride lipase in beta cells is known to support insulin secretion. As LD degradation by lysosomal acid lipase (LIPA) through lipophagy is an alternative pathway for LD catabolism, we addressed whether LIPA regulates beta cell function. LDs in human beta cells are associated with autophagy (LC3) and lysosomal (LAMP1) markers. LIPA suppression via siRNA and LIPA inhibitor (lalistat2) in INS1 cells increased LD size (DMSO 0.5 vs. Lali2 1.5 µm2/cell, p&lt;0.05, p value by Student’s t test unless specified otherwise) and number (Scr 2/cell vs. siLIPA 14/cell, p&lt;0.05; DMSO 4.5/cell vs. Lali2 16/cell, p&lt;0.05) . Rat and human beta cells treated with Lali2 also showed increased in LD area and/or number of LDs per cell (p&lt;0.05) . In all three models, LIPA suppression increased TG contents confirming constitutively active lipophagy. While acute inhibition of LIPA by Lali2 had little effect on glucose-stimulated insulin secretion (GSIS) , chronic (over 48 h) LIPA suppression by Lali2 or siRNA reduced GSIS from INS1 cells, rat islets, and human islets. Lentiviral shRNA transduction in human pseudoislets decreased insulin secretion in response to glucose (41 ± 10.5% of Scr, p&lt;0.05) and to KCl (61.3 ±16.1% of Scr, p&lt;0.05) in vitro. When Scr and shLIPA human pseudoislets were transplanted under kidney capsules of NSG mice on Western diet, human insulin secretion in response to intraperitoneal glucose load was blunted in mice carrying shLIPA islets compared with shScr control (2-Way ANOVA, p&lt;0.05) .
In summary, lipophagy is constitutively active in human and rat beta cells and serves as a pathway for LD catabolism that is acutely insensitive to glucose. However, LIPA mediated LD catabolism is needed for beta cell function in a long-term.

Disclosure
S.Liu: None. B.R.Brennecke: None. U.Yang: None. J.A.Ankrum: None. Y.Imai: None.

Funding
National Institute of Diabetes andDigestive and Kidney Diseases (R01=DK090490) U.S. Department of Veterans Affairs (IBX005107)
146-LB: Impact of the COVID-19 Pandemic on Quality of Life in Youth with Type 1 Diabetes
Authors: COBRY ERIN C. , PYLE LAURA , VIGERS TIMOTHY B. , GEISER LUKE , MELTZER LISA J. 
Published: May 2022

Diabetes is a risk factor for COVID-19 infection-related complications, increasing fear in this population. The effect of the pandemic on quality of life for youth with type 1 diabetes (T1D) has not been evaluated.
Youth with T1D (n=108, mean age 11.6±4.0 yrs, mean T1D duration 5.3±3.9, 57.4% male) and a parent completed surveys at baseline (September to November 2020) and every 3 months for 12 months. Measures included the COVID-19 Exposure and Family Impact Survey ([CEFIS], exposure (range 0-25) , family impact (range 0-4, scores &gt;2.5 indicate negative impact) , distress (range 1-10)) , the PedsQL Diabetes Module (higher score indicates higher quality of life) , and the PROMIS Sleep Disturbance and Sleep-Related Impairment surveys (higher score indicates more problems) .
CEFIS impact score remained above 2.5 over 12 months. Parent Proxy PedsQL decreased from 3 to 6 months (p=0.019) and 3 to 12 months (p=0.017) . Parent Proxy PROMIS Sleep-Related Impairment increased from 6 to 12 months (p=0.03) and 9 to 12 months (p=0.004) . PedsQL (parent and child) significantly decreased with increased exposure (p&lt;0.001 and p=0.011) and impact (p&lt;0.001 and p=0.016) .
Families of youth with T1D were negatively impacted by the pandemic. Parents reported worsening child quality of life and sleep-related impairment during this time. As the pandemic continues, it is important for health care providers to be mindful of mental health in youth with T1D.

Disclosure
E. C. Cobry: None. L. Pyle: None. T. B. Vigers: None. L. Geiser: None. L. J. Meltzer: None.

Funding
National Institutes of Health (K12DK094712)
1469-P: Inhibition of the Integrated Stress Response Increases PD-L1 in Islet ß-Cells and Protects against Autoimmune Diabetes
Authors: HUANG FEI , KULKARNI ABHISHEK , SYED FAROOQ , MALONEY DAVID J. , TERSEY SARAH A. , MIRMIRA RAGHAVENDRA G. 
Published: May 2022

Type 1 diabetes (T1D) has become viewed as an autoimmune disease initiated and propagated by stress responses in islet β cells. The integrated stress response (ISR) is activated upon inflammatory signaling and delimits protein production through the actions of phospho-eIF2α. We hypothesized that inhibition of the β cell ISR will protect against β cell immunogenicity and development of T1D. To test this hypothesis, we studied the effect of ISR inhibition using ISRIB (p-eIF2α inhibitor) and VLX-10 (human 12-lipoxygenase inhibitor) on the response of isolated human islets and EndoC-βH1 cells to inflammatory cytokines (IFN-γ+IL-1β) and studied the effect of ISR inhibition on T1D outcomes in NOD mice. Human islets exposed to cytokines exhibited an increase in p-eIF2α and suppression of mRNA translation initiation (by polysome profiling) , consistent with activation of the ISR. Inhibition of the ISR with ISRIB or VLX-10promoted production of PD-L1, an immune checkpoint protein that suppresses the immune response, in human islets and EndoC-βH1 cells. This finding suggested that blockade of the ISR in β cells might thwart immune attack. To assess if inhibition of the ISR using the human-specific 12-lipoxygenase inhibitor VLX-10modifies T1D progression, we generated mice in which the gene encoding mouse 12-lipoxygenase gene was replaced by the corresponding human gene. These “humanized” mice were subsequently backcrossed onto the NOD background, then treated in the prediabetic phase with VLX-1005. Male and female humanized mice developed T1D at the expected frequency, but those receiving VLX-10showed significant delay of T1D onset. Consistent with the suppression of autoimmunity, insulitis was significantly reduced and β cell mass was significantly increased in treated animals. Our results support the targeting of the ISR through inhibition of the 12-lipoxygenase enzyme provides an opportunity for the modification of T1D disease progression.

Disclosure
F.Huang: None. A.Kulkarni: None. F.Syed: None. D.J.Maloney: Employee; Veralox Therapeutics. S.A.Tersey: n/a. R.G.Mirmira: None.

Funding
NIH (UDK127786-02)
147-LB: Effects of the COVID-19 Pandemic on Type 1 Diabetes Outcomes
Authors: GEISER LUKE , PYLE LAURA , VIGERS TIMOTHY B. , MELTZER LISA J. , COBRY ERIN C. 
Published: May 2022

As the COVID-19 pandemic has disrupted daily life, it is important to understand its effects on youth with T1D. The COVID-19 Exposure and Family Impact Survey (CEFIS) was used to examine COVID-19 effects on diabetes metrics in a pediatric T1D population.
Parents of youth with T1D (n=108; mean age 11.6±4 yrs, mean T1D duration 5.3±3.9yrs, 57.4% male) completed the CEFIS (score ranges: Exposure 0-25, Impact 0-4 with &gt;2.5 indicating negative impact, and Distress 1-10) . CEFIS measures and diabetes metrics (A1c, average glucose, in-person visits vs. telemedicine, and number of cancelled visits) were obtained at baseline, 3, 6, 9, and 12 months. Changes in diabetes metrics and correlations with CEFIS scores were analyzed by anova.
Cancelled visit frequency per person decreased from baseline to 3 months and was maintained for the duration of the study (p&lt;0.001) . For every one point increase in CEFIS Impact, A1c increased by 0.3 (0.1%) (p=0.04) . For every one point increase in CEFIS Exposure, average glucose increased by 2.3 (0.7mg/dL) (p=0.002) .
High perceived stress from the COVID-19 pandemic from CEFIS Impact and Exposure scores may worsen glycemic outcomes for youth, suggesting that the pandemic had a negative affect regardless of COVID-19 infection. Further studies on perceived stress and effects on diabetes management are needed to determine long term impacts of the COVID-19 pandemic on this population.

Disclosure
L. Geiser: None. L. Pyle: None. T. B. Vigers: None. L. J. Meltzer: None. E. C. Cobry: None.

Funding
NIH (K12DK094712)
147-OR: Glucose Intolerance of Hereditary Progeria Werner Syndrome and Cellular Senescence in Their Adipose Tissue
Authors: SAWADA DAISUKE , KATO HISAYA , MAEZAWA YOSHIRO , KINOSHITA DAISUKE , FUNAYAMA SHINICHIRO , KANEKO HIYORI , MINAMIZUKA TAKUYA , KOSHIZAKA MASAYA , SHIOHAMA TADASHI , TAKATANI TOMOZUMI , HAMADA HIROMICHI , YOKOTE KOUTARO 
Published: May 2022

Background: Werner syndrome (WS) is a hereditary premature aging disorder in which various signs of accelerated aging develop after puberty. These signs include gray hair, cataracts, diabetes, myocardial infarction, and malignant tumors. Patients with WS frequently show severe insulin resistance, visceral fat accumulation, and subcutaneous fat atrophy, leading to myocardial infarction due to atherosclerosis. However, the mechanism of accelerated aging and its effect on adipose tissue dysfunction and glucose intolerance remain unclear.
Materials and Methods: We evaluated visceral fat area and insulin resistance using the glucose clamp method in four Japanese patients with WS. Stromal vascular fraction (SVF) was obtained from the subcutaneous adipose tissue of WS patients (WSVF) . Healthy individuals and phenotypes were examined.
Results: The median glucose infusion rate (GIR) was 3.78 mg/kg/min (interquartile range 3.05, 4.25; insulin infusion rate=1.25 mU/kg/min; normal range &gt;6 mg/kg/min) . All Japanese patients showed severe insulin resistance, sarcopenia, and visceral fat accumulation. The visceral fat area and GIR were inversely correlated (R2=0.72) . In vitro analysis of WSVF revealed early replicative senescence and an increase in SAβgal staining. A significant increase was observed in the expression of senescence-associated secretory phenotypes (SASP) , such as IL1B, IL6, and CXCL8 (p&lt;0.01) , and the senescence marker CDKN2A (p=0.094) . RNA-seq analysis showed that genes related to cell adhesion and cell structure were upregulated in WSVF, whereas genes related to chromosomes, nuclear division, and cell cycle were downregulated. Adipose differentiation was suppressed in WSVF.
Conclusions: SVF from the adipose tissue of WS patients exhibited cellular senescence and increased inflammatory cytokine production. Cellular senescence and chronic inflammation of adipose tissue induced by SASP may exacerbate insulin resistance in WS patients.

Disclosure
D.Sawada: None. T.Takatani: None. H.Hamada: None. K.Yokote: None. H.Kato: n/a. Y.Maezawa: None. D.Kinoshita: None. S.Funayama: None. H.Kaneko: None. T.Minamizuka: None. M.Koshizaka: None. T.Shiohama: None.

Funding
JSPS (20K17485) , AMED (21bm0804016h0005)
1473-P: Combination Therapy with Dual-Function Peptide S1K and Insulin Reduces Blood Glucose Levels in Mouse Models of Type 1 Diabetes through Beta-Cell Regeneration and Immunosuppression
Authors: LEE YOUNG-HOON , KIM HYEON-JEONG , KIM JI AE , JANG YUNSIL , MOON EUN-JOUNG , KIM HAE-JIN 
Published: May 2022

β cell regeneration is necessary to cure patients with type 1 diabetes (T1D) whose β cells are destroyed by immune cells. Although insulin therapy can control blood glucose levels, it must be administered throughout life and occurs several side effects such as hypoglycemia. New β cell can be generated through neogenesis, β cell replication or transdifferentiation from other cells in diabetic animals. In addition to β cell regeneration, immunosuppression is another important mechanism to prevent β cell destruction, but currently any drugs haven’t been approved as immunosuppressants for T1D treatments yet. A novel 9-mer peptide, Shiloah 1000 (S1K) , has dual functions of β cell regeneration and immunosuppression. In streptozotocin-induced hyperglycemic mouse model, the number of mice recovered to normoglycemia was increased by the combined treatment of S1K and insulin compared to S1K or insulin alone. In addition, the combined treatment more increased the number of β cells than S1K or insulin alone. Interestingly, insulin/glucagon double-positive cells were increased by both combined and S1K alone treatments. The increase in the number of mice recovered to normoglycemia is considered to be due to β cell regeneration through α- to β-cell transdifferentiation by S1K. In the NOD mouse model, the combined treatment of S1K and insulin suppressed hyperglycemia more than insulin alone. In addition, the serum C-peptide levels were increased by both combined and S1K treatments, but not by insulin treatment. The increase in the serum C-peptide level suggest that β cells remain undestroyed by immunosuppression. Taken together, our data show that S1K, as a drug candidate for T1D treatment in combination with insulin reduces blood glucose levels in the T1D mouse models through β cell regeneration and immunosuppression, suggesting a potential role in preventing and curing T1D.

Disclosure
Y. Lee: Employee; Ensolbiosciences. H. Kim: Employee; Ensolbiosciences. J. Kim: Employee; Ensol Bioscience. Y. Jang: Employee; Ensolbiosciences.
150-OR: The Use of Luminescent Cell-Based Assays for Studying Insulin and Glucagon Secretion and Activity
Authors: HAUPT KIM , LEIPPE DONNA M. , VIDUGIRIENE JOLANTA 
Published: May 2022

The complex nature of metabolic diseases often relies on the use of animal models for drug development and testing. However, recent advances in disease-relevant cellular models and cell-based assays offer opportunity for more rapid and cost-effective studies. Here, we describe the development and implementation of luminescent cell-based assays to study insulin and glucagon secretion and measure their control of diverse metabolic pathways. To measure insulin and glucagon secretion, we developed no-wash immunoassays using luciferase complementation technology. Immunoassays have sensitive detection from 10pM to 8nM (insulin) and 0.5pM to 1nM (glucagon) . They have broad utility for measuring hormone secretion from cells and islets. Furthermore, they can be scaled to 384-well plates, which enables the rapid, cost-effective measurement of large numbers of samples, such as from perifusion or high-throughput screening experiments. To investigate hormone action on glucose and lipid metabolism, we developed a core luminescent technology that couples specific metabolite dehydrogenases to the production of NAD (P) H and the generation of light. Assays can be used in cellular models, reducing the need for animal studies. Luminescent glucose uptake assay was validated as insulin potency assay: insulin-stimulated glucose uptake in 3T3-L1 MBX adipocytes was measured within the expected pharmacology and a 10-fold assay window. The utility of a glucose assay for measuring insulin effect on gluconeogenesis was demonstrated using iPS-derived hepatocytes, and triglyceride assays provided rapid tool for lipogenesis studies in liver microtissues. All assays were scalable and amenable to automation, making them well-suited for high-throughput screening and new drug development.

Disclosure
K.Haupt: None. D.M.Leippe: None. J.Vidugiriene: None.
151-OR: 27-Hydroxycholesterol Inhibits Food Intake through ERa-Mediated Activation of POMC Neurons
Authors: YE HUI , FENG BING , LUO PEI , IBRAHIMI LUCAS , PATEL NIRALI , KOTA MAYA , DIXIT DEVIN , HE YANLIN , XU PINGWEN , ANTONY NIMISHA , CARRILLO-SÁENZ LESLIE , IRIZARRY VALERIA C. TORRES , SCHAUL SARAH 
Published: May 2022

Oxysterols are metabolites of cholesterol produced in peripheral tissues as a means to eliminate cholesterol. 27-hydroxycholesterol (27HC) is the most abundant oxysterols and can cross the blood-brain barrier. Interestingly, 27HC has recently been identified as an endogenous selective estrogen receptor modulator (SERM) for both estrogen receptor α and β (ERα/β) . Considering the regulatory effects of brain estrogen/ERα signaling on energy metabolism, we hypothesize that the endogenous SERM 27HC binds with ERα in the arcuate nucleus of hypothalamus (ARH) of brain to modulate energy homeostasis.In supporting this point of view, we found that a single acute intracerebroventricular (ICV) injection of 27HC inhibited food intake in both male and female mice. The reduced food intake was attributed to decreased meal size and increased intermeal intervals. This anorexigenic effect was also associated with the increased c-fos expression in the pro-opiomelanocortin neurons in ARH (POMCARH) . Using brain slice patch-clamp recording, we consistently showed that 27HC dose-dependently actives POMCARH in an ERα-dependent manner, suggesting a mediating role of ERα expressed by POMCARH neurons. Notably, we further revealed that the inhibitory effects of 27HC on food intake were blocked by antagonists for ERα or POMC downstream melanocortin 3/4 receptors. In addition, chemogenetic inhibition of POMCARH neurons also blunted the anorexigenic effects of 27HC in mice. Collectively, these results support a model that 27HC acutely inhibits food intake by acting on ERα to stimulate POMCARH neuronal activity. This 27HC/ERα/POMC signaling pathway may serve as a critical defending mechanism against high-fat diet-induced obesity.

Disclosure
H. Ye: None. B. Feng: None. D. Dixit: None. Y. He: None. P. Xu: None.