bluuebunny/crossref_metadata_2025_split huggingface dataset:
23-OR: Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization
Authors: SHANG RUI , SYNG LEE CHAE , HUSSEIN BAHIRA , RODRIGUES BRIAN 
Published: June 2023

VEGFB is known to up-regulate FA delivery through its effect on EC FA transporters. In its absence, intracellular lipid accumulation was reduced. Paradoxically, cardiac-specific overexpression of VEGFB demonstrated a lowered heparin-releasable lipoprotein lipase (LPL) activity with reduced FA utilization in vivo. Currently, the mechanism behind this in vivo metabolic effect of VEGFB on cardiac LPL is unclear. In transgenic (Tg) hearts, the vectorial transfer of LPL from myocytes to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes. Given that insulin is known to inhibit LPL translocation and thus FA metabolism in the heart, this observation is likely a secondary effect of VEGFB on vascular development with its associated augmentation of insulin delivery. We tested whether lowering of insulin by fasting would validate our hypothesis. WT fasted hearts enhanced their heparin-releasable LPL activity in an attempt to switch substrate utilization to FA. Intriguingly, this increase in LPL activity following fasting was even more dramatic in Tg hearts. Thus, with insulin deficiency following fasting, VEGFB works unimpeded to facilitate LPL movement. This effect occurred through the activation of p38 MAPK. PET imaging using 18FTHA revealed augmented LPL-derived FA and impaired FDG glucose uptake in the Tg fasted heart. Additionally, this increased delivery of LPL-derived FA correlated to augmented mitochondrial oxidation determined by high resolution oxygraphy. We examined whether this property of VEGFB on FA uptake and oxidation could be useful following diabetes, with its attendant loss of metabolic flexibility. Unexpectedly, in Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling. Our data suggests that following diabetes, loss of VEGFB action may contribute towards the metabolic inflexibility, lipotoxicity and diabetic cardiomyopathy.

Disclosure
R.Shang: None. C.Lee: None. B.Hussein: None. B.Rodrigues: None.

Funding
Canadian Institutes of Health Research (PJT180558); Diabetes Canada (OG3215585BR)
230-LB: A Composite Capsule Strategy Support Longevity of Microencapsulated Pancreatic ß Cells
Authors: QIN TIAN , SMINK ALEXANDRA M. , DE VOS PAUL 
Published: June 2023

Microencapsulation of islets in immunoprotective membranes offers an alternative treatment for type 1 diabetes in absence of systemic immunosuppression. However, periods of survival of transplanted islets are still limited. A factor that might be involved in a limited duration of survival is permanent damage to the extracellular matrix (ECM) during enzymatic islet-isolation which enhances susceptibility of islets for inflammatory stress. Here we investigated whether a combination of inclusion of ECM components (collagen IV and RGD), necroptosis inhibitor necrostatin-1 (Nec-1), amino acids (AA), and inclusion of the immunomodulatory polymer pectin in microcapsules can enhance the functionality of β-cells. The impact of these factors individually or combined was tested on MIN6 β-cells and human islet-cells. Viability, function, and immune activation via danger-associated molecular patterns (DAMPs) release and NF-κB activation in THP1-reporter cells were determined. Also, impact on mitochondrial dynamics was tested. Our data show that composite capsules of pectin/ECM/Nec-1/AA improve insulin secretion and enhance the mitochondrial activity of β-cells in vitro till day 7 after encapsulation. The alginate-pectin based microcapsules also showed immunomodulatory effects with decreased DAMPs release and lower NF-κB activation. After cytokine exposure, pectin/ECM/Nec-1/AA prevented the cytokine-induced decrease of mitochondrial activity and prevented viability loss until day 5. The rescuing effects were accompanied by modulation of mitochondrial fusion and fission gene expression, similar to that of untreated controls. Our data suggest that this composite capsule strategy using pectin/ECM/Nec-1/AA supports survival of microencapsulated β-cells and lowers susceptibility of β-cells for inflammatory stress. This strategy to create a better intracapsular microenvironment is a potentially promising way to preserve islet function and enhance graft survival time.

Disclosure
T. Qin: None. A. M. Smink: None. P. De vos: None.

Funding
JDRF (2-SRA-2018-523-S-B); China Scholarship Council (201906230339)
230-OR: Hybrid Continuous Glucose Monitoring Protocols in the Intensive Care Unit—Multicenter Experience
Authors: FAULDS EILEEN R. , BADAKHSHI YASAMAN , BOUTSICARIS ANDREW , EXLINE MATTHEW C. , HESTER JOI , JONES LAUREEN G. , MCNETT MOLLY , MILLER JOSHUA D. , SHAH ROHAN , GARCIA MARLENE , CHANDRA SUVRAT , PASQUEL FRANCISCO J. , DUNGAN KATHLEEN M. 
Published: June 2023

There is limited experience with continuous glucose monitoring (CGM) in intensive care units (ICUs). We assessed the effectiveness, safety, and accuracy of real-time CGM use in COVID-19 ICUs. We pooled data from three academic centers using hybrid protocols combining point of care (POC) blood glucose (BG) with non-adjunctive CGM. At hospitals A and B, CGM was used non-adjunctively with POC at least every 6 hours. At hospital C, POC BG was performed every two hours. We also examined CGM performance during lowest pAO2, oxygen saturation, pH, and mean arterial pressure. Of 169 patients, mean age was 60.9±12.2 years, and 82%, 93%, and 62% received corticosteroids, mechanical ventilation, and vasopressors respectively. Median duration of IV insulin was 118, 156, and 50 hours at hospitals A, B, and C respectively. Mean POC BG frequency was 10.2±6.1, 7.0±5.2, and 16±6.5 times/day on day 1 of IV insulin and 6.7±3.1, 6.0±3.5, and 12.2±5.8 times/day thereafter. The median percent CGM time in range (TIR, 70-180mg/dl) was 72%, 70% and 46% during IV insulin. Median time &lt;70mg/dl was &lt;0.1% for all hospitals. The absolute relative difference between CGM and POC did not correlate with hemodynamic instability, Figure. This data indicates hybrid monitoring can reduce POC frequency while safely maintaining glucose. Sensor-meter agreement was not associated with abnormal physiologic parameters and requires further study.

Disclosure
E.R.Faulds: Advisory Panel; Dexcom, Inc., Other Relationship; A1Control, LLC, Research Support; Dexcom, Inc., Speaker's Bureau; Dexcom, Inc., Medscape. M.Garcia: None. S.Chandra: None. F.J.Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies. K.M.Dungan: Board Member; Elsevier, Consultant; Eli Lilly and Company, Dexcom, Inc., Other Relationship; UpToDate, Research Support; Dexcom, Inc., Abbott, ViaCyte, Inc., Sanofi, Speaker's Bureau; Academy for Continued Healthcare Learning, Cardiometabolic Health Congress, Medscape, Integritas. Y.Badakhshi: None. A.Boutsicaris: None. M.C.Exline: Other Relationship; Abbott Nutrition. J.Hester: None. L.G.Jones: None. M.Mcnett: Research Support; Dexcom, Inc., National Institutes of Health. J.D.Miller: Advisory Panel; MannKind Corporation, Employee; Medtronic, Research Support; Dexcom, Inc. R.Shah: None.
231-LB: Prolactin Modulates the Differentiation of Pancreatic Ductal Cell to Islet-Like Cell
Authors: WANG YI 
Published: June 2023

Objective: Pancreatic ductal cells will be differentiated into islet-like cell with the activation of PRL-PRLR signaling pathway in vitro.
Methods: Primary mouse and human pancreatic ductal cells were obtained by CK-19 labelling and MACS sorting of digested pancreatic tissue, and selected cells were cultured with recombinant mouse prolactin and recombinant human prolactin. Subsequently, the cell clusters formed by the pancreatic ductal cells were stained by anti-insulin, anti-GCK, anti-GLUT2, anti-PC1/3 Abs. In vitro, glucose stimulated insulin secretion (GSIS) was quantified. Prolactin related signaling pathway, glucose transportation and insulin secretion related proteins were assessed by immunoblotting. Lastly, the in vitro formed islet-like cells were transplanted under the kidney capsule of diabetic mice. To assess the role for blood glucose regulation of transplanted islet-like cells, blood glucose, c-peptide and intravenous glucose tolerance tests were performed and immunofluorescence staining for insulin and glucagon was performed on the grafts.
Results: At day 7, the pancreatic ductal cells, also called progenitor cells, expressed CK-19; at day 14, the ductal cells were aggregated and formed sphere-shaped cell clusters. At day 21, the cell clusters stained positive for insulin and etc. By in vitro GSIS test, we measured a 2.58±0.32-fold increase of insulin secretion in response to a 16.7 mM glucose stimulation. Immunoblotting demonstrated that PDX-1, MafA and other genes were expressed. At day 21, the cell clusters expressed PDX-1, insulin and glucagon. In vivo studies showed that diabetic mice transplanted with islet-like cells, maintained blood glucose levels below 300 mg/dL with c-peptide detected in the serum. Further tissue staining indicated that the transplanted islet-like cells contained both β-cells and α-cells.
Conclusion: Out study shows that in vitro stimulation by prolactin might differentiate pancreatic ductal cells into islet-like cells.

Disclosure
Y. Wang: None.

Funding
National Natural Science Foundation of China (81802504); Sichuan Science and Technology Bureau (2022YFH0005, 2023YFH0010)
232-LB: Transcriptional Regulation of Adipocyte Insulin and Inflammatory Signaling by Early B-Cell Factor-1 (Ebf1)
Authors: GUTIERREZ ALEX , MARTINEZ YADIRA , IBARRA KIMBERLY , BAILEY ZACHARY , GRIFFIN MICHAEL 
Published: June 2023

Overnutrition is causally associated with many chronic diseases, including insulin resistance and diabetes, heart disease, hypertension, and cancer. Chronic activation of the innate immune system may lie at the heart of a majority of T2DM cases; the bulk of the evidence suggests that a litany of inflammatory cytokines and toxic lipid species released from irritated adipocytes contribute significantly to disrupted insulin signaling in metabolic tissues and may eventually lead to frank type 2 diabetes. However, the molecular mechanisms that initiate these inflammatory events in adipocytes remain unknown, particularly at the transcriptional level. Our previous work showed that the transcription factor Ebf1 regulates insulin signaling and promotes inflammation in adipocytes; however, the precise molecular mechanisms through which Ebf1 regulates the expression of inflammatory loci remain unknown (as evidence had suggested Ebf1 regulates these genes indirectly). We have recently discovered that Ebf1 can physically interact with multiple subunits of the well-known inflammatory transcription factor NF-κB, and many of the critical inflammatory loci showing impaired expression in Ebf1-deficient 3T3-L1 adipocytes also happen to be well-established NF-κB target genes. This striking result likely explains our paradoxical observations that EBF1 directly (and positively) regulates several core insulin signaling genes (Pik3r1, Akt, etc.) but also promotes insulin resistance in adipocytes—apparently without directly occupying inflammatory loci. We are currently working on physically and functionally characterizing these interactions and propose a model to explain the previously-mentioned paradox. If our hypothesis is correct, we anticipate that the eventual development of pharmaceutical agents designed to interfere with EBF1-NF-κB protein-protein interactions may represent a viable treatment for overnutrition-associated diabetes.

Disclosure
A. Gutierrez: None. Y. Martinez: None. K. Ibarra: None. Z. Bailey: None. M. Griffin: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
233-LB: Role of SUMO-Specific Protease 2 (SENP2) in Modulating Brown Adipose Tissue Activity
Authors: JEE CHOE HUN , SEON LEE JI , PARK JONGYOEN , LEE SEUNG-AH , SOO CHUNG SUNG , SOO PARK KYONG 
Published: June 2023

Brown adipose tissue (BAT) is a metabolically active endocrine organ. Activation of BAT contributes to increased energy expenditure through systemic glucose and lipid utilization. SUMO-specific protease 2 (SENP2) is a post-translational protein modifier that is involved in regulation of metabolism in different tissues. We had previously showed that while SENP2 suppresses browning of white adipose tissues, morphologic defect in BAT was observed in adipose specific SENP2 deficient mice fed with high fat diet. How SENP2 may modulate BAT activity has not been elucidated yet. BAT-specific Senp2 knockout (Senp2-BKO, Ucp1-Cre;Senp2f/f) mice were more insulin resistant in response to high fat diet than controls. They were also intolerant to acute cold exposure. Mechanistically, knockdown of Senp2 in brown adipocytes resulted in reduced levels of Ucp1 and Cidea through SUMOylation of ERRα. SUMOylation of ERRα interrupted binding of ERRα to ERRα response element (ERRE) in the Ucp1 promoter, and deSUMOylation of ERRα via SENP2 enhanced the synergistic effect of ERRα/PGC-1α complex required for the transcription of Ucp1. Collectively, these results suggest that SENP2 is intimately involved in modulating the activity of Ucp1 in BAT through deSUMOylation of ERRα/PGC-1α complex, especially ERRα.

Disclosure
H. Choe: None. J. Lee: None. J. Park: None. S. Lee: None. S. Chung: None. K. Park: None.

Funding
National Research Foundation of Korea (2015R1D1A1A09059551, 2016R1A2B3010373, 2019R1A2C3009517)
234-LB: Cell-State Dependent Regulation of PPARg Signaling by Zbtb9 in Adipocytes
Authors: XU XUAN , BUCHNER DAVID 
Published: June 2023

The discovery of new genes involved in adipocyte development and function can shed light on the pathophysiology of obesity and T2D and provide new therapeutic targets for these disorders. Towards this end, GWAS and rare variant association studies in the T2D Knowledge Portal revealed associations between ZBTB9 and T2D, BMI, and hip circumference. However, the function of ZBTB9 in organismal physiology was not known. We found that Zbtb9 plays a key role in adipocyte biology and differentiation via cell-state dependent regulation of PPARγ signaling. Zbtb9 directly interacts with the PPARγ/RXRα complex as shown by co-IP, and acts as a positive regulator of PPARγ transcriptional activity as shown by a PPARγ reporter assay, together establishing Zbtb9 as a new PPARγ cofactor. In line with these findings, endogenous PPARγ target gene expression was decreased in the context of Zbtb9 deficiency in adipocytes. Given the central role of PPARγ in adipogenesis, we also sought to investigate the role of Zbtb9 in this process. Surprisingly, loss of Zbtb9 in preadipocytes increased adipogenesis and the expression of adipogenic genes, including PPARγ. Transcriptome analysis prior to and during adipogenesis revealed enhanced expression of E2F target genes prior to the initiation of differentiation and later induction of adipogenic gene expression. Treatment of Zbtb9 deficient preadipocytes with an E2F1 inhibitor (HLM006474) blocked the effects of Zbtb9 deficiency on adipogenic gene expression and adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of PPARγ expression via altered E2F1 signaling. We further demonstrated that E2F1 activation by Zbtb9 is associated with increased phosphorylation of Rb, which is known to cause dissociation of the Rb/E2F complex, and activation of E2F. Our findings revealed cell-state dependent roles of Zbtb9 in adipocytes, identifying a new molecule that may be important in the pathogenesis and treatment of obesity and T2D.

Disclosure
X. Xu: None. D. Buchner: None.

Funding
National Institutes of Health (DK119305)
235-LB: Incretin-Linked Adipose Tissue Microvascular Blood Flow in Healthy People With and Without a Family History of Type 2 Diabetes
Authors: ROBERTS-THOMSON KATHERINE , PARKER LEWAN , KESKE MICHELLE 
Published: June 2023

Adipose tissue microvascular blood flow (ATMBF) increases in response to a mixed meal challenge (MMC) to promote nutrient storage. This vascular action is impaired in apparently healthy people with a parent with type 2 diabetes (FH+). The mechanisms for this vascular impairment in FH+ are unknow. We aimed to investigate whether incretins [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)] are associated with ATMBF responses to a MMC. Thirteen healthy (FH-, no parents or grandparents with type 2 diabetes) and fourteen FH+ underwent a 2-hr MMC after an overnight fast. Age, BMI, fasting and peak postprandial blood glucose and plasma insulin concentrations were similar between FH- and FH+ (Table 1). Baseline ATMBF, assessed by contrast ultrasound, was similar between groups, but was impaired in FH+ in response to the MMC (Table 1). Peak plasma GLP-1 and GIP concentrations, but not their ratio (GLP-1:GIP), were higher in FH+ in response to the MMC (Table 1). GLP-1 and GIP concentrations were not associated with ATMBF, however, GLP-1:GIP was significantly associated with postprandial ATMBF at 1-hr (p=0.025, r=0.46). We conclude that impaired postprandial ATMBF in FH+ is not exclusively linked to incretin levels. However, lower GLP-1:GIP ratios may be linked to impaired ATMBF responses in the postprandial state.

Disclosure
K. Roberts-thomson: None. L. Parker: None. M. Keske: None.
245-OR: Impaired Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Is Associated with Increased Obesity Classified by Waist-to-Hip Ratio in Nondiabetes EGAT Population
Authors: ATTACHAIPANICH TANAWAT , SRIWICHAIIN SIRAWIT , APAIJAI NATTAYAPORN , KERDPHOO SASIWAN , THONGMUNG NISAKRON , VATHESATOGKIT PRIN , KITIYAKARA CHAGRIYA , SRITARA PIYAMITR , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C. 
Published: June 2023

This study aimed to determine the impact of waist-to-hip ratio (WHR)-classified obesity and diabetes (DM) status on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) using a large cohort from the Electricity Generation Authority of Thailand (EGAT) during 2017-2018. The 1954 participants were included in this study with an average age of 67.1±7.7 years old. The mitochondrial respiration in PBMCs obtained from fresh blood samples was analyzed by the Seahorse Flux Analyzer. The participants were classified based on DM status and WHR including 1) non-DM non-obese, 2) non-DM obese, 3) DM non-obese and 4) DM obese. We found that the non-DM obese group had lower basal respiration (BR), maximal respiration, spare respiratory capacity (SRC), and proton leak (PL), compared to those of the non-DM non-obese group (Figure 1). The BR, SRC, and PL of non-DM obese group were not significantly different from those of the DM group with or without adjusting with age. All of these findings suggest that WHR-classified obesity in people with non-DM is associated with impaired mitochondrial respiration in PBMCs at a level comparable to that in people with DM. Thus, not only DM, but also obesity, may play an important role on impaired mitochondrial respiration in PBMCs.

Disclosure
T.Attachaipanich: None. S.C.Chattipakorn: None. S.Sriwichaiin: None. N.Apaijai: None. S.Kerdphoo: None. N.Thongmung: None. P.Vathesatogkit: None. C.Kitiyakara: None. P.Sritara: None. N.Chattipakorn: None.
247-LB: Link between Hyperglycemia and Cognitive Deficits in T2DM Animal Model
Authors: CHEN LI , NI JIANGXIA , FENG LINGGE , ZHANG XUEXIN , WANG QIUYAN , CHEN YELIN 
Published: June 2023

The Goto-Kakizaki (GK) rat is a model of spontaneously developing non-obese type 2 diabetes mellitus (T2DM). With age, GK rats exhibit insulin resistance, decreased pancreatic function, and hyperglycemia. Studies have shown that GK rats experience cognitive impairment concurrent with hyperglycemia, but the mechanisms is unclear. In this study, we aimed to elucidate the potential link between hyperglycemia and cognitive impairment in this unique T2DM model. Longitudinal assessments of fasting blood glucose (FBG) were performed in male GK rats and age-matched Wistar rats. Our results showed that FBG in GK group was significantly higher than that in the Wistar group starting from 6 weeks of age, and there was progressive fasting hyperglycemia in GK group. In the spatial probe test of Morris water maze (MWM) at 33 weeks old, the GK rats spent less time in the target quadrant (12.16 ± 2.18s vs. 22.17 ± 1.21, P&lt;0.001) and took more time to reach the location of the formerly hidden platform (36.78 ± 6.141 vs. 6.422 ± 0.8783s, P&lt;0.001) than Wistar rats, suggesting that GK rats showed spatial memory deficits. In mechanistic studies, insulin receptors (IR) and synaptic proteins were down-regulated and impaired insulin signaling pathways in the hippocampus of GK rats (Figure), suggesting impaired neuroplasticity and neuropathological processes may lead to cognitive dysfunction.

Disclosure
L. Chen: Board Member; Hua Medicine. J. Ni: None. L. Feng: Employee; Hua Medicine. X. Zhang: None. Q. Wang: None. Y. Chen: Stock/Shareholder; Silaiputai (Shanghai) Biopharmaceutical Company.

Funding
Hua Medicine Co., Ltd.
253-OR: Effect of Continuous Glucose Monitoring on Hypoglycemia, Diet Liberalization, and Quality of Life in Post-bariatric Hypoglycemia
Authors: RAMANUJAN SURUCHI , TURK NICOLE , AYHAN EKREM M. , CRAIG COLLEEN M. , MCLAUGHLIN TRACEY 
Published: June 2023

Post-bariatric hypoglycemia (PBH), affecting up to 39% of patients with Roux-en-Y gastric bypass (RYGB), is associated with episodes of disabling hypoglycemia, chronic diet restriction and reduced quality of life (QoL). We evaluated the effects of unblinded vs blinded CGM on hypoglycemia, dietary liberalization, and QoL. 15 RYGB patients with confirmed PBH wore in random order, a Dexcom G6 Pro for 10 days blinded and 10 days unblinded with alarm set to 65 mg/dL. The Hypoglycemia Fear Survey II (HFS-II) was administered after each phase to assess hypoglycemia-based worries and behaviors. The number of hypoglycemia events &lt;70, 54, and 40 mg/dL and proportion of time below each threshold was assessed (diurnal and nocturnal) and adjusted for meal intake. The number of diurnal hypoglycemic events &lt;40 and &lt;54 mg/dL were reduced by 66% and 25% respectively, and proportion of time was reduced by 71% and 50% respectively during unblinded vs blinded CGM use, though neither measure reached statistical significance. Diet liberalization was significantly greater during unblinded CGM use (54 vs 45 glucose spikes/10-day period, p=0.012). HFS-II showed improvement in 16/19 worry measures, reaching statistical significance in six. CGM use in patients with PBH enabled diet liberalization, reduced hypoglycemia-based worries, and reduced diurnal hypoglycemia, indicating improved QoL.

Disclosure
S.Ramanujan: None. N.Turk: None. E.M.Ayhan: None. C.M.Craig: Employee; Eiger BioPharmaceuticals, Stock/Shareholder; Eiger BioPharmaceuticals. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Stock/Shareholder; Eiger Bio.

Funding
American Diabetes Association (1-19-ICTS-073 to T.M.)