bluuebunny/crossref_metadata_2025 huggingface dataset:
1388-P: Pancreatic Neural Circuitry in Obesity and Diabetes
Authors: HAMPTON ROLLIE F. , ALVARSSON ALEXANDRA , GONZALEZ MARIA JIMENEZ , LI ROSEMARY Y. , DEVARAKONDA KAVYA , STANLEY SARAH
Published: May 2022

Background: Pancreatic islets are richly innervated. Use of 2D immunohistochemistry and extreme models of obesity and diabetes have limited our understanding of pancreatic nerve anatomy. Additionally, our knowledge of the direct roles of pancreatic nerves in regulating pancreatic function is incomplete. Determining how high-fat diet (HFD) impacts pancreatic nerve structure and function will provide novel insights into the mechanisms and pathophysiology of obesity and type 2 Diabetes.

Aim: To create a comprehensive atlas of pancreatic sympathetic and parasympathetic fibers throughout the pancreas and the time course of HFD-induced structural changes and to determine the direct physiological roles of pancreatic efferent nerves on islet hormone secretion. Hypothesis: HFD increases islet sympathetic density and activity, while decreasing islet parasympathetic density and activity, leading to insufficient plasma insulin to maintain normoglycemia.

Methods: C57BL/6 mice were randomized to HFD or low-fat diet (LFD) groups. Weekly metabolic phenotyping was determined. Pancreata were cleared and immunolabeled according to iDISCO+, imaged by lightsheet microscopy, and analyzed using Imaris software. To test the roles of pancreatic parasympathetic nerves on islet hormone release, cre-dependent hM3D (Gq) -mCherry or mCherry viral constructs were injected into the pancreatic duct of ChAT-IRES-cre mice. ChAT-IRES-cre mice were fed LFD or HFD and the effects of neuromodulation were assessed.

Results: HFD significantly impairs glucose tolerance and insulin sensitivity and rapidly remodels islet sympathetic and parasympathetic innervation. Targeted activation of pancreatic parasympathetic efferent nerves significantly improves glucose tolerance after HFD consumption.

Conclusion: HFD rapidly remodels pancreatic innervation which may contribute to insufficient insulin release to maintain normoglycemia. Targeted activation of pancreatic parasympathetic nerves improves glycemic control.

Disclosure

R.F.Hampton: None. A.Alvarsson: None. M.Jimenez gonzalez: None. R.Y.Li: None. K.Devarakonda: None. S.Stanley: None.

Funding

NIH F31 Predoctoral Fellowship (1F31DK129016-01A1)
1389-P: Asprosin-Neutralizing Antibodies as a Treatment for Binge Eating
Authors: HARMS JERNEY , FENG BING , VIDRINE JACOB , XU PINGWEN , HE YANLIN
Published: May 2022

The central nervous system (CNS) circuits that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. Here, we provide evidence to support the vital role of asprosin, a novel fasting-induced glucogenic and orexigenic hormone, in the development of binge eating. We found that heterozygous deletion of fibrillin 1, the gene encoding asprosin protein, led to a 50% decrease in asprosin production and reduced binge-like eating behavior in mice. Consistently, systemic treatment of asprosin promoted, while an asprosin-neutralizing antibody inhibited, binge-like eating behavior. These behavioral changes were associated with increased or decreased activity of gamma-aminobutyric acid (GABA) producing neurons in the zona incerta (ZI) brain region, respectively. Mechanistically, we further demonstrate that asprosin stimulates ZI GABA neurons by decreasing small-conductance, calcium-activated potassium (SK) currents. Conversely, the asprosin-neutralizing antibody inhibits ZI GABA neurons by increasing SK currents. Our results support a model that asprosin decreases SK currents to stimulate ZI GABA neurons, further promoting binge-like eating behavior and causing obesity in mice. Our findings also provided preclinical evidence that asprosin-neutralizing antibodies could be used to treat binge eating.

Keywords: Asprosin, neutralizing antibody, binge eating, obesity, GABA neurons

Disclosure

P. Xu: None. Y. He: None.

Funding

National Institutes of Health (P30 DK072476)
139-LB: Evaluating the Impact of Quality Initiatives on Improving Insulin Pen and Needles Prescription on Hospital Discharge in Patients with Type 2 Diabetes Mellitus
Authors: MOAZZAMI BOBAK , HWANG PATRICIA , ASHRAF SHANZA , PROOYEN AMANDA VAN , SHABBIR HASAN F. , KLIMENKO MARIA , BRECHTELSBAUER ERIKA , MOLITCH-HOU ETHAN , HINDS MAUREEN A. , WALD MARY , JAGANNATHAN RAM , GALINDO RODOLFO J.
Published: May 2022

Background: Prescribing insulin pens without needles during hospital discharge was common in our hospital system. We assessed the impact of quality initiatives and prescribing guidance on the prevalence of patients discharged on insulin pens with and without an associated prescription for pen needles.

Methods: We retrospectively collected data from Emory-healthcare hospitals, from January 2015-May 2018 (pre-intervention period) , then up to October 2021 (post-intervention period) . Adults (>18 years) with at least one prescription for insulin pens were included. As part of an updated discharge plan, an automated EMR alert was linked to orders for insulin pens without needles, aiming to reduce prescription errors at discharge. We compared the proportion of patients discharged on insulin pens with/without an associated pen needles prescription during the pre and post-intervention periods. We used interrupted time-series analysis (ITS) to examine the intervention impact on 30- and 90-day hospital readmissions.

Result: Among 7654 patients discharged with insulin pens (median age 56 years, IQR 45-66) , 50.4% were Females, 65.5% were African-Americans, and mean HbA1c was 10.9±2.9%. After the intervention, the proportion of patients without an associated prescription for pen needles decreased compared to the pre-intervention (mean decrease 31.3%, 95% CI: 31.2%, 31.3%) . Inpatient diabetes education consult was more common among those with an associated pen needles prescription during the pre- (61.4% vs. 33.7%) and post-intervention period (64.7% vs. 33%) , compared to those without it, p<0.001. After the intervention, there was a significant improvement in 90-days hospital readmission rates (-0.99% per quarter; P<0.005) , whereas the change in slope was not significant for 30-day hospital readmission rates.

Conclusion: Our initiative significantly decreased the prevalence of missing pen needles prescriptions by ∼30%, and was associated with less 90-days hospital readmission rates.

Disclosure

B. Moazzami: None. M. Wald: None. R. Jagannathan: None. R. J. Galindo: Advisory Panel; Sanofi, WW International, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. P. Hwang: None. S. Ashraf: None. A. Van prooyen: None. H. F. Shabbir: None. M. Klimenko: None. E. Brechtelsbauer: None. E. Molitch-hou: None. M. A. Hinds: None.
1396-P: Critical Cellular Functions That Mediate the Early Stages of Adipogenesis Are Directly Influenced by 14-3-3zeta and Its Interactome
Authors: RIAL SABRI A. , ALKHOURY AMAL , LAVOIE GENEVIEVE , ROUX PHILIPPE , DURCAN THOMAS M. , MARTINEZ-SANCHEZ AIDA , LIM GARETH E.
Published: May 2022

Aim: We previously discovered that 14-3-3-zeta (14-3-3ζ) was essential for adipocyte differentiation. Although 14-3-3ζ scaffold is not a transcription factor (TF) , it undergoes nuclear translocation during adipogenesis. Considering its diverse interactome, we hypothesized that 14-3-3ζ anchors, nucleates and regulates essential transcriptional complexes required for adipogenesis.

Methods: 3T3-L1 pre-adipocytes were modified by CRISPR-Cas9 to express a TAP (Flag-HA) -tagged 14-3-3ζ protein. At 48 first hours of adipogenesis, nuclear TAP-14-3-3-ζ complexes were purified to identify and annotate the 14-3-3ζ interactome by MS and Gene Ontology. Highly enriched proteins functions were assessed for their roles in adipogenesis using pharmacological inhibitors or siRNA. In parallel, chromatin accessibility was assessed by ATAC-Seq from control or 14-3-3ζ-depleted 3T3-L1 cells during early adipogenesis.

Results: We found that the 14-3-3ζ nuclear interactome during the early stages of adipogenesis was significantly enriched with 133 proteins, including CEBP-β, an early adipogenic TF. According to GO analysis, proteins within the 14-3-3ζ interactome were primarily associated (FDR ≤ 0.01) with histone H2B ubiquitination, DNA unwinding for replication, DNA hypermethylation and ribosome assembly. Pharmacological inhibition or depletion by siRNA of these proteins significantly dampened adipocyte differentiation. Principal component analysis of ATAC-seq results revealed that samples from 14-3-3ζ-depleted cells differed from controls in term of whole chromatin accessibility, and DESeq2 identified nearly 3400 (p<0.05) differentially accessible regions of open chromatin following 14-3-3ζ depletion.

Conclusion: These results reveal that via critical protein interactions, 14-3-3ζ has essential roles in chromatin accessibility, DNA replication, and mRNA translation, which are crucial events for the early adipogenesis.

Disclosure

S.A.Rial: None. A.Alkhoury: None. G.Lavoie: None. P.Roux: None. T.M.Durcan: None. A.Martinez-sanchez: None. G.E.Lim: None.

Funding

Natural Sciences and Engineering Research Council of Canada (NSERC) ; Canada Research Chairs (CRC) ; Fonds de recherche du Québec-Nature and Technologies (FRQNT)
14-OR: Harmine and Exenatide Combination Increases Human ß-Cell Survival
Authors: ROSSELOT CAROLINA , LI YANSUI , GUEVARA DANIELA , BELIARD KARA A. , KANG RANDY , WANG PENG , THAKKAR KEYA , LU GEMING , DEVITA ROBERT J. , STEWART ANDREW F. , GARCIA-OCANA ADOLFO
Published: May 2022

GLP1R agonists such as Exendin-4 (E) together with DYRK1A inhibitors such as Harmine (H) significantly increase human β-cell replication in vitro and in vivo. Importantly, 3-month treatment with H+E combination markedly increases human beta cell mass (∼7-fold) in islets transplanted in immunosuppressed mice, beyond the increase induced by proliferation. Therefore, we addressed whether H+E also enhances β-cell survival and that contributes to the increased human β-cell mass expansion in vivo. Treatment with H+E significantly decreased β-cell apoptosis in dispersed primary human islet cells treated in vitro with either thapsigargin (ER stress) , cytokines (inflammation) and H2O2 (ROS) , while the drugs alone or vehicle (V) did not induce such effect. Importantly, H+E treatment for 7 days significantly reduced β-cell apoptosis in human islet grafts transplanted in immunosuppressed mice assessed by insulin and TUNEL staining. Human β-cell mass analysis of these grafts by iDISCO+ revealed a significant ∼50% increase in H+E-treated mice compared with mice treated with drugs alone or V. Human α-cell mass was unchanged. To address the signaling pathways modulated by H+E after 7-day treatment, we performed RNA-seq analysis of these human islet grafts. We identified 29 differentially expressed human genes (> 2-fold, p<0.05) in H+E-treated human islet grafts. GSEA analysis revealed cell adhesion, survival, vascularization and secretion as the main pathways induced by H+E. Among the upregulated genes, VGF (VGF Nerve Growth Factor Inducible) is known to regulate insulin secretion and β-cell survival. We found that H+E treatment of human islets in vitro increases 2-to-3-fold VGF mRNA and secretion. We are now determining VGF involvement in H+E-induced human β-cell survival.

In conclusion, we have uncovered a novel prosurvival function of H+E in human β-cells with the potential implication of VGF in these effects. These studies can lead to the discovery of future β-cell protection and regeneration therapies for diabetes.

Disclosure

C.Rosselot: None. A.F.Stewart: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. Y.Li: None. D.Guevara: None. K.A.Beliard: None. R.Kang: None. P.Wang: None. K.Thakkar: None. G.Lu: None. R.J.Devita: None.

Funding

DYRK Inhibitors for Human Beta Cell Expansion RDK105015
1404-P: High Cardiorespiratory Fitness Exerts Metabolic Protection in Obese Rats Regardless of Caloric Restriction or Short-Term Exercise
Authors: THONUSIN CHANISA , PANTIYA PATCHARAPONG , CHATTIPAKORN SIRIPORN C. , CHATTIPAKORN NIPON
Published: May 2022

Caloric restriction (CR) and exercise (EX) attenuate metabolic impairment in obesity. High cardiorespiratory fitness (CRF) also protects against metabolic syndrome. However, the interplay between CRF, obesity, CR, and EX on metabolic health remains unclear. Male rats were fed with either a normal diet (ND; n=6) or a high-fat diet (HFD; n=30) for 12 weeks. Baseline CRF was measured. Then, ND-fed rats received a ND for 16 more weeks. HFD-fed rats were divided into 5 groups (n=6/group) to receive either a HFD for 16 weeks (OB) , 40% CR for 6 weeks followed by an ad lib ND for weeks (CR-S) , 40% CR for 16 weeks (CR-L) , a HFD + an EX for 6 weeks followed by a ND without EX for weeks (EX-S) , or a HFD + an EX for 16 weeks (EX-L) . Then, anthropometry and blood metabolic parameters were evaluated. We found that CR and EX decreased insulin resistance and dyslipidemia in obesity. High baseline CRF was correlated with favorable anthropometry and metabolic profiles at follow-up in the ND, OB, CR-S, CR-L, and EX-S rats. However, these correlations were not shown in the EX-L rats (Figure) . Our findings suggested that high CRF also protects against metabolic impairment in obesity, regardless of CR or short-term EX. Hence, an enhancement of CRF may provide the better effective therapy for obesity. Otherwise, low-CRF people may get the greatest benefit on a protection against metabolic syndrome by long-term EX.

Disclosure

P. Pantiya: None. S.C. Chattipakorn: None. N. Chattipakorn: None.
1425-P: Effect of Ghrelin on Glucose Tolerance after Sleeve Gastrectomy
Authors: HEDBÄCK NORA , DICHMAN MARIE-LOUISE , DIRKSEN CARSTEN , BOJSEN-MOLLER KIRSTINE N. , JØRGENSEN NILS B. , HINDSØ MORTEN G. , KRISTIANSEN VIGGO B. , HOLST JENS J. , SVANE MARIA S. , MADSBAD STEN
Published: May 2022

Introduction: Ghrelin is an appetite-stimulating peptide hormone secreted from the gastric mucosa in the fasting state that decreases in response to food intake. After sleeve gastrectomy (SG) , plasma levels of ghrelin decrease dramatically, whether this may influence glucose tolerance is unknown. We therefore investigated the effects of physiological ghrelin infusions on glucose tolerance in individuals with obesity before and after SG.

Methods: Nine morbidly obese individuals with normal glucose tolerance, scheduled for SG, were enrolled. Four-hour standard mixed-meal tests with concomitant patient-blinded infusions of either acyl-ghrelin (1 pmol/kg/min) or placebo (saline) were performed in randomized order before and 3 months after surgery. All values are mean ± SEM.

Results: Before SG, fasting plasma glucose was unaffected by ghrelin infusion, whereas both peak (7.93 ± 0.3 mmol/L versus 6.98 ± 0.2, p<0.001) and total area under the curve (tAUC) of plasma glucose concentrations (1874 ± 61 mmol/L*min versus 1702 ± 42, p=0.03) increased significantly during ghrelin infusion versus placebo. After SG, fasting plasma glucose was again unaffected by ghrelin infusion, whereas peak of plasma glucose increased (8.65 ± 0.5 mmol/L versus 7.92 ± 0.3 mmol/L, p=0.04) and tAUC of plasma glucose tended to increase (1817 ± 73 mmol/L*min versus 1636 ± 44 mmol/l*min, p=0.054) during ghrelin infusions versus placebo. The increase in tAUC during ghrelin infusion versus placebo was 10% before surgery and 11% after SG (p=0.98) .

Conclusion: Ghrelin infusions increased postprandial plasma glucose concentrations in obese individuals both before and following SG, suggesting a role of ghrelin in the regulation of postprandial glucose metabolism. This response appears to be maintained following SG and the low levels of ghrelin after SG may thus contribute to the improved glucose control after the operation.

Disclosure

N.Hedbäck: None. S.Madsbad: None. M.Dichman: None. C.Dirksen: None. K.N.Bojsen-moller: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S. M.G.Hindsø: Research Support; Novo Nordisk Foundation. V.B.Kristiansen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M.S.Svane: None.

Funding

European Research Council (Grant 695069-BYPASSWITHOUTSURGERY) Novo Nordisk Foundation
143-LB: Hepatic Insulin Resistance Index (HIR-I) in Youth—Does Race/Ethnicity Matter?
Authors: CHO WONHEE , BACHA FIDA , TFAYLI HALA M. , LEE SOJUNG , MICHALISZYN SARA , KIM JOON YOUNG , ARSLANIAN SILVA A.
Published: May 2022

Surrogate indices for insulin resistance of various insulin-responsive tissues are critical in epidemiological studies of youth at risk for developing type 2 diabetes (T2D) . Having established surrogate indices for peripheral insulin sensitivity (JCEM 2011; 96:2136) , we aimed to develop HIR-I in youth spanning from normal-weight (NW) to obese and from normal glucose tolerance to impaired glucose tolerance to T2D, and assessed potential race-related differences. A total of 287 youth (146 black, 141 white) had [6,6-2H2]glucose tracer-measured HIR (hepatic glucose production x fasting insulin [FI]) , lipids and DXA body composition. To develop HIR-I, multiple stepwise linear regression was performed with variables showing r >0.2 with tracer-measured HIR (Diabetologia, 2011;54:540) in each race (Table) . In black youth, HIR-I was generated from (fasting glucose [FG], FI, fat mass and VLDL) while in whites from (FG, FI and BMI) (Figure) . HIR-I correlated with tracer-measured HIR in blacks (r=0.915) and whites (r=0.923, both p<0.001) (Figure) . In both black and white youth, HIR-I was lowest in NW and highest in T2D (Figure) .

In conclusion, different physical and laboratory biomarkers contribute to race-specific formulas of HIR-I with strong correlations with tracer-measured HIR in both. Race-specific HIR-I and its change across the gamut of glycemia may shed light in epidemiological studies of the development of youth T2D.

Disclosure

W. Cho: None. F. Bacha: Other Relationship; AstraZeneca, Takeda Pharmaceutical Company Limited, Research Support; National Institute of Diabetes and Digestive and Kidney Diseases, U. S. Department of Agriculture. H. M. Tfayli: Advisory Panel; Novo Nordisk, Research Support; Novartis Pharmaceuticals Corporation, Sanofi. S. Lee: None. S. Michaliszyn: None. J. Kim: n/a. S. A. Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk.

Funding

American Diabetes Association (7-08-JF-27) , National Institute of Child Health and Human Development grants (K24-HD01357, R01-HD27503) , National Center for Advancing Translational Sciences Clinical and Translational Science Award (UL1TR000005) , National Center for Research Resources grant (UL1RR024153) , National Institute of Diabetes and Digestive and Kidney Diseases (R21DK083654-01A1)
1431-P: Development of a New Index Based on Preoperative Serum Lipocalin 2 to Predict Post-LSG Weight Reduction
Authors: LI NANNAN , XU BEI , ZENG JIANGPING , LEI SHIHUI , GU LEI , FENG LIJIN , ZHU BING , HUANG YUEYE , WANG LU , SU LILI , QU SHEN , CHENG XIAOYUN , BU LE
Published: May 2022

Background: Bariatric surgery is the most effective therapy for obesity, but targeted weight reduction is not always achieved. Serum lipocalin-2 (LCN2) is closely associated with obesity, but its impact on weight loss after surgery is unknown. We aimed to access the reliability of LCN2 levels and other parameters as effective predictors of excellent weight loss (≥75% excess weight loss [EWL]) 1 year after bariatric surgery.

Methods: This retrospective study evaluated 450 patients (aged 18-65 years) with obesity at 3 months and 1 year after laparoscopic sleeve gastrectomy (LSG) surgery. Seventy-four patients who underwent LSG surgery and met the inclusion and exclusion criteria were included in this study. Serum LCN2, thyroid function, and metabolic and anthropometric parameters were assessed. Weight reduction was expressed as %EWL and percent total weight loss (%TWL) at 3 months and 1 year post surgery. Multivariable logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate predictors of ≥75%EWL.

Results: In our cohort, %EWL and %TWL were both strongly associated with preoperative serum LCN2 levels. The binary logistic regression analysis showed that preoperative LCN2, waist circumference, and glycated hemoglobin were independent predictors of excellent weight loss.

Conclusions: Based on these results, we determined a new P index with better predictive value for excellent weight reduction (≥75%EWL) 1 year after LSG surgery.

Disclosure

N.Li: None. L.Su: None. S.Qu: n/a. X.Cheng: n/a. L.Bu: None. B.Xu: None. J.Zeng: None. S.Lei: None. L.Gu: None. L.Feng: None. B.Zhu: None. Y.Huang: n/a. L.Wang: None.

Funding

The Tranditional Medicine Project of Shanghai Municipal Health Commission (grant number 2020JP013) ; Shanghai Natural Science Foundation (grant number 21ZR1449400) ; Shanghai Pujiang Talent Plan (grant number 18PJD038)
1432-P: ALT Elevation Suggestive of NAFLD in Overweight and Obese Youth on Second-Generation Antipsychotics
Authors: CRIMMINS NANCY A. , MOUZAKI MARIALENA , DELBELLO MELISSA P. , CORRELL CHRISTOPH , WELGE JEFFREY
Published: May 2022

Second-generation antipsychotics (SGAs) increase risk for insulin resistance and metabolic syndrome. Less is known about the risk of nonalcoholic fatty liver disease (NAFLD) in youth treated with SGAs. MOBILITY is a large, multi-center, pragmatic study designed to assess the effect of metformin added to lifestyle instruction compared to lifestyle instruction alone on weight gain and metabolic parameters in youth with overweight and obesity (ages 8-19) and bipolar-spectrum disorders receiving SGAs. We examined baseline ALT as a marker for NAFLD in 840 youth in the study (78% with obesity; 46% female; 68% white; 17% black; 11% Hispanic) . Overall, 44% of subjects had mild ALT elevation (ALT>22 females; ALT>25 males) , and 10% had significantly elevated ALT≥ 45 (2× ULN) . Male sex (p<0.001) , obesity (p=0.007) , and white race (p=0.009) were significantly associated with ALT elevation. Hispanic ethnicity and age were not significantly associated with ALT elevation. There was no difference in duration of exposure to SGAs (< 1 year vs. > 1 year of exposure) . There was a trend towards an association between prediabetes and significant ALT elevation (2× ULN; p=0.06) ; however, glucose was not associated with ALT elevation overall. Although we had no imaging or biopsy data in these patients, our study demonstrates that a clinically relevant percentage of youth with overweight and obesity treated with SGAs have elevated ALT suggestive of NAFLD; in fact, the prevalence of elevated ALT is higher than expected with obesity alone. Given that NAFLD is the most common liver disease now in youth and can progress to cirrhosis and liver failure, our findings suggest that pediatric psychiatrists who treat these patients must screen for NAFLD with ALT and refer patients for further evaluation and management as needed.

Disclosure

N.A.Crimmins: None. M.Mouzaki: None. M.P.Delbello: Board Member; Sage Pharmaceuticals, Consultant; Alkermes, Sunovion Pharmaceuticals Inc., Research Support; Alkermes, Johnson & Johnson, Lundbeck, Shire plc., Speaker's Bureau; Sunovion Pharmaceuticals Inc. C.Correll: Consultant; Alkermes, Janssen Pharmaceuticals, Inc., Lundbeck, Medscape, Mylan N.V., Neurocrine Biosciences, Inc., Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd. J.Welge: None.

Funding

Mobility: Improving Patient-Centered Outcomes Among Overweight and Obese Youth with Bipolar Spectrum Disorders Treated with Second-Generation Antipsychotics. [PICORI (Delbello) ].
1438-P: Association between Screen Time, Including That for Smartphones, and Overweight/Obesity among Children in Japan
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , MORIKAWA SAKIKO Y. , TAKEDA YASUNAGA , ISHIGURO HAJIME , YAMADA MAYUKO H. , HORIKAWA CHIKA , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , OGAWA YOHEI , SONE HIROHITO
Published: May 2022

The association between screen time (ST) , including that for smartphones, and overweight/obesity (OW/OB) in children was examined separately for boys and girls, considering the influence of lifestyle factors including diet, physical activity, and sleep time. A cross-sectional study was conducted in 2242 Japanese children (1278 girls) aged 10-14 years. OW/OB was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4h) , smartphone ST (≥3h) and non-smartphone ST (≥2h) were all independently and significantly associated with overweight/obesity compared to <2h total ST, non-use of smartphones, and <1h non-smartphone ST. In girls with total ST ≥5h or <4h or smartphone ST <2h, the association between ST and OW/OB was not affected by physical activity or sleep time. On the other hand, when total ST was 4-5h or smartphone ST was ≥2h, the significant association with OW/OB disappeared when physical activity was ≥60 min/day and sleep time was ≥8.5h. In addition, none of these associations were significant in boys.

In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with OW/OB. To avoid OW/OB, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to <3h, <2h, and <4h, respectively, and to engage in sufficient physical activity and sleep time.

Disclosure

K. Fujihara: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. C. Horikawa: None. Y. Ogawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.
1443-P: Real-Time In Vivo Analysis of Beta-Cell Autophagy in Autoimmune Diabetes
Authors: MELNYK OLHA , MURALIDHARAN CHARANYA , IRIZARRY MICHELLE M. MARTINEZ , CROWDER JUSTIN , LINNEMANN AMELIA K.
Published: May 2022

Type 1 Diabetes (T1D) is an autoimmune disease caused by a combination of genetic and environmental factors. The onset of disease is associated with autoimmune attack against pancreatic beta-cells leading to a reduction of their number. While a role for the beta-cell in these events is widely hypothesized, a complete understanding of disease pathogenesis is still lacking. Our group recently found that beta-cell autophagy is defective in the context of human T1D as well as in the non-obese diabetic (NOD) mouse model of autoimmune diabetes. Importantly, our data suggested that defective autophagy is present prior to the onset of diabetes but stopped short of definitively demonstrating pre-existing defects. Therefore, here we evaluated autophagic flux in the pancreatic beta-cells of live mice using a fluorescent biosensor coupled to intravital microscopy. A custom beta-cell-selective autophagy biosensor (AAV8-INS-mCherry-EGFP-LC3B) was intraperitoneally (IP) injected into 7-week-old mice of three strains: wild type C57Bl/6J, NOD and NOD scid gamma (NSG) mice. Three weeks after biosensor injections, mice were placed under inhaled isoflurane anesthesia, then externalized pancreata were imaged using a LEICA SP8 DIVE two-photon microscope mounted with a 40x/1.1NA water objective. To evaluate autophagic flux, we assessed fluorescent signal over time in response to IP infusion of either saline or chloroquine, an autophagy inhibitor. Autophagic flux was assessed by quantifying the rate of change of the ph-sensitive GFP and the ph-insensitive RFP, as well as signal colocalization. In wild type mice, we observed clear evidence of autophagic flux over time that was altered in the presence of chloroquine. However, in contrast, in pre-diabetic NOD mice, islet autophagic flux did not respond effectively to chloroquine treatment. Collectively, these data support the conclusion that autophagy defects precede hyperglycemia and suggest a potential role for these defects in beta cell demise during T1D pathogenesis.

Disclosure

O.Melnyk: None. C.Muralidharan: None. M.M.Martinez irizarry: None. J.Crowder: None. A.K.Linnemann: Consultant; Janssen Research & Development, LLC.

Funding

National Institutes of Health (R01DK124380) . Startup funds to AKL from the Herman B Wells Center for Pediatric Research at Indiana University School of Medicine
1463-P: Steroidogenic Factor 1 in ß cells Moonlights as a Brake on Glucose Intolerance in Obesity
Authors: GUO YAN , LIU LIEHUA , LI YANBING
Published: May 2022

Pancreatic β cells compensate with intense insulin secretion in obese individuals, failure of which marks a vital step in progression to type 2 diabetes (T2DM) . Steroidogenic factor-1 (SF-1) is a nuclear receptor which also locates in non-steroidogenic tissues and participates in metabolic regulation. Through immunofluorescence conducted on the pancreas of obese mice, we detected SF1 in the β cells which was surprisingly absent in that of diabetic mice. Genetic deletion of SF1 in β cells predisposed mice to glucose intolerance upon high fat diet (HFD) by perturbing glucose-stimulated insulin secretion (GSIS) , while its ectopic expression by adeno-associated virus (AAV) improved GSIS. Furthermore, we illustrated that mitochondrial improvement may be the underlying mechanism via experiments such as oxygen consumption rate (OCR) , calcium detection and bioinformatics.

In conclusion, SF1 played an important role in β-cell adaptation to lipotoxicity in the obese individuals, which supported SF1 as a potential target for T2DM treatment.

Disclosure

Y.Guo: None. L.Liu: None. Y.Li: None.

Funding

This work was supported by National Key Research and Development Program of China (no. 2018YFC1314100) awarded to L.-Y.B.; National Natural Science Foundation of China (no. 81870557) awarded to L.-Y.B.; Key Field Research and Development Program of Guangdong Province, China (no. 2019B020230001) awarded to L.-Y.B.; Natural Science Foundation of Guangdong Province (no. 2016A030313239 and 2014A030313018) awarded to W.-X.S.; Guangdong Basic and Applied Basic Research Foundation (no. 2020A1515010049) awarded to L.H.; and Graduate Innovative Development Program (no. 19ykyjs08) awarded to G.Y
1464-P: Computational Modeling for Design of Next Generation Microphysiological Systems for Evaluation of ß-Cell Health and Function
Authors: VANDERLAAN EMMA , TEPOLE ADRIAN BUGANZA , HARBIN SHERRY L.
Published: May 2022

Dynamic insulin secretion is a key focus of β cell research, with microfluidic devices emerging as a potential means to effectively evaluate this performance parameter in vitro. However, most devices maintain isolated islets in suspension despite evidence that collagen-islet interactions are critical to β cell viability and function. When designing a microphysiological system with encapsulated islets, important considerations include 1) sufficient oxygenation, 2) rapid exchange of glucose and insulin between cells and perfusate, and 3) detectable levels of secreted insulin. Computational models provide a means to simulate different device design parameters prior to fabrication, reducing the time and cost of testing multiple physical devices and microenvironmental conditions. For this study, COMSOL was used to model a microfluidic device containing islets macroencapsulated in a fibrillar collagen scaffold. A range of flow rates, collagen fibril densities, and islet-collagen construct dimensions were tested, with outcome measures including spatiotemporal changes in oxygen, glucose, and insulin. Simulations for all designs tested showed maintenance of islet viability as indicated by less than 1% of the construct area falling below the hypoxia-induced dysfunction threshold. Additionally, decreasing the construct thickness and increasing the medium glucose concentration yielded more rapid delivery of the target glucose stimulus to the islets, since glucose transport is primarily driven by diffusion within the construct. By contrast, transport of secreted insulin was found to be flow-limited and the presence of an encapsulation material altered the shape of the insulin secretion curve. Collectively, these results support the integrated use of computational models, together with experimental validation, as an efficient strategy for the creation of next generation microphysiological systems for evaluation of β cell health and function.

Disclosure

E.Vanderlaan: None. A.Buganza tepole: None. S.L.Harbin: Other Relationship; GeniPhys, Inc.
1467-P: Chemical Profiles of Acinar Tissue and Pancreatic Islets from Healthy and T2D-Affected Pancreata
Authors: RUBAKHIN STANISLAV , ROMANOVA ELENA V. , SWEEDLER JONATHAN V.
Published: May 2022

Both the endocrine and exocrine pancreas demonstrate morphological and chemical changes associated with T2D development. Despite significant progress, chemical profiles of the islets and acinar tissue following disease progression are not well characterized. In this work we investigated isolated populations of pancreatic islets (n=18) and acinar tissues (n=7) collected from healthy and T2D affected pancreata using several mass spectrometry (MS) approaches. Samples are provided by the ADI IsletCore and the Network for Pancreatic Organ Donors with Diabetes (nPOD) . Both peptide and metabolite profiles were determined and compared via chemical profiling with matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance MS. Not surprisingly, the peptide profiles from T2D islets demonstrated lower signal intensities compared to healthy islets (ROC analysis, AUC=0.9) . Somatostatin, pancreatic icosapeptide, and insulin-related signals are most decreased. Preliminary data for acinar tissues indicate lower peptide levels in samples collected from T2D-affected (n=2) vs. healthy (n=5) pancreata. Several unique peptides are detected specifically in acinar tissue obtained from T2D-affected pancreata. Liquid chromatography-MS reveals a complex endogenous peptide complement of acinar tissue. Analysis of extracellular media for both islet types demonstrated similar differences (AUC=0.7) indicating higher levels of observed peptides in preparations from healthy islets, perhaps suggesting that peptides are released from the islets during shipment. Integrity of received islets was verified using dithizone staining prior to measurement. In contrast, almost no peptide markers of acinar tissue are found in corresponding extracellular media. Our results enhance knowledge on biochemical signature of T2D in the pancreas.

Disclosure

S.Rubakhin: None. E.V.Romanova: None. J.V.Sweedler: None.

Funding

American Diabetes Association (1-18-VSN-19)
1468-P: Effect of Kcnq1ot1 on Influencing the Function of Pancreatic ß-Cells Targeting miR-92a-1-5p
Authors: CHEN YALAN , LI YANLI , XU WEN , LIN BEISI , MAI XIAODONG , PENG YUEYUE , CHEN DANRUI , SU YANNA , LI WANGEN
Published: May 2022

Objective: To study the role and mechanism of Kcnq1ot1 by targeting to regulate miR-92a-1-5p to effect insulin secretion in pancreatic β cells.

Methods: The qRT-PCR was used to detect the expression of Kcnq1ot1 in different tissues of C57BL/6J mice, Min6 with PA intervention, islets of T2D model mice and the serum of T2D patients. The biological information website was used to predict that Kcnq1ot1 had complementary binding sites with miR-92a-1-5p, which was verified by the luciferase reporting gene system. The si-Kcnq1ot1, miR-92a-1-5p mimics, miR-92a-1-5p inhibitors and their respective controls were respectively transfected into Min6, and the effect of Ins1, Ins2, Insr, Nkx6.1, Irs1 and Ngn3 were detected by qRT-PCR, the Western blot method was used to detect the expression of insulin and Insr, and the GSIS experiment was used to detect its effect on insulin secretion.

Results: The expression of Kcnq1ot1 in pancreas was significantly higher than that in other tissues. Compared with the control group, the expression of Kcnq1ot1 in T2D patients' serum, Min6 after PA treatment and the islets of T2D model mice were lower. And the expression of Kcnq1ot1 in serum is negatively correlated with FBG or HbA1c. Low expression of Kcnq1ot1 led to remarkable reduction of insulin secretion in Min6 cells. Down-regulation of Kcnq1ot1 or overexpression of miR-92a-1-5p reduced the mRNA expression levels of Ins1, Ins2, Insr, Nkx6.1, Irs1 and Ngn3, and the protein levels of insulin and Insr. We screened miR-92a-1-5p as targets of Kcnq1ot1, and their interaction was validated with dual luciferase reporter gene experiment. After knocking down Kcnq1ot1, the expression of miR-92a-1-5p was found to increase. Further rescue experiments showed that down-regulation of miR-92a-1-5p could reverse the effect of low Kcnq1ot1 expression on the function of pancreatic β-cells.

Conclusion: Kcnq1ot1 may regulate the function of pancreatic β cells by targeting to negatively regulate miR-92a-1-5p.

Disclosure

Y.Chen: None. Y.Li: None. W.Xu: None. B.Lin: None. X.Mai: None. Y.Peng: None. D.Chen: None. Y.Su: None. W.Li: n/a.

Funding

Science & Technology Project of Guangzhou（202102010175）
1470-P: GABA Stimulates or Inhibits Insulin and Somatostatin Secretion in Human Pancreatic Islets Depending on Glucose Concentration
Authors: FERREIRA SANDRA MARA , HAGAN DAVID W. , PHELPS EDWARD
Published: May 2022

GABA is an inhibitory neurotransmitter synthesized and secreted by β-cells that is reported to modulate glucagon, somatostatin (SST) , and insulin secretion. However, the direction of the effect of GABA, whether stimulatory or inhibitory, on insulin secretion is controversial. Our results from human islets show that GABA is inhibitory to insulin secretion under glucose-stimulating conditions. Further, islets from conditional knockout mice lacking the GABA-synthesizing enzymes GAD65 and GAD67 oversecrete insulin during glucose stimulation, consistent with GABA being inhibitory. However, the inhibitory effect of GABA is somewhat paradoxical as ligation of GABA-A receptor Cl channels are expected to depolarize the β-cell that should contribute to stimulating insulin secretion. It is also unclear if GABA signaling in β-cells is strictly autocrine or if the observed inhibition is mediated through an indirect effect of inducing SST secretion which, in turn, inhibits β-cells. Here, we improve understanding of GABA’s effect on insulin secretion by transiently applying 100 μM of GABA to human islets during perifusion with low (3 mM) and high glucose (16.7 mM) . GABA stimulated both insulin and SST in low glucose but inhibited insulin and SST when applied in high glucose. Thus, the modulation of GABA presents both stimulatory and inhibitory effects on β- and δ-cells depending on glucose concentration. In addition, the effect of GABA on β-cells appears to be direct and independent of SST signaling because SST and insulin secretion both change in the same direction with applied GABA. These results suggest the hypothesis that β-cell GABA-A receptors convey stimulatory responses to GABA under low glucose, but that G-protein coupled GABA-B receptors mediate inhibitory GABA signaling under high glucose. This mechanism would provide a consensus model that reconciles decades of seemingly antithetical studies where GABA is either inhibitory or stimulatory.

Disclosure

S.Ferreira: None. D.W.Hagan: None. E.Phelps: Research Support; Immunocore, Ltd.

Funding

National Institutes of Health (R01DK124267)
1472-P: Dual Pancreatic Adrenergic and Dopaminergic Signaling as a Therapeutic Mechanism for Treatment of Dysglycemia by Bromocriptine
Authors: ASLANOGLOU DESPOINA , BERTERA SUZANNE , FRIGGERI LAURA , SOTO MARTA SANCHEZ , LEE JEONGKYUNG , XUE XIANGNING , LOGAN RYAN , LANE ROB , YECHOOR VIJAY , FREE R BENJAMIN , SIBLEY DAVID R. , BOTTINO RITA , FREYBERG ZACHARY
Published: May 2022

Dopaminergic agonism effectively treats dysglycemia, with dopaminergic agonist bromocriptine approved as a type 2 diabetes therapy. Though bromocriptine’s actions have been mainly attributed to stimulation of dopamine D2 receptors (D2R) in the brain, we previously showed that bromocriptine also targets metabolically-relevant peripheral tissues including the endocrine pancreas. Here, we employ bromocriptine as a tool to elucidate roles of dopaminergic and adrenergic signaling in regulation of pancreatic hormone secretion. Using bromocriptine, we demonstrate a new mechanism for metabolic actions in pancreatic α-cells and β-cells via D2R and adrenergic α2A receptor (α2A-AR) signaling. In β-cells, bromocriptine acts jointly on D2R and α2A-AR to reduce glucose-stimulated insulin secretion (GSIS) , while in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. Bromocriptine reduces cAMP in β-cells via concurrent actions on D2R and α2A-AR, further emphasizing shared roles of adrenergic and dopaminergic receptor agonism in GSIS regulation. At the receptor level, α2A-AR activation by bromocriptine leads to receptor recruitment of an ensemble of G proteins driven mainly via G protein signaling with no β-arrestin2 recruitment. In contrast, D2R recruits both G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating signaling unique to each receptor. Docking studies also reveal that bromocriptine binding to α2A-AR is distinct from bromocriptine-bound D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia in diabetes.

Disclosure

S. Bertera: None. L. Friggeri: None. R. Logan: None. R. Free: None. R. Bottino: Employee; Imagine Pharma.

Funding

Department of Defense (PR141292) , National Institutes of Health (R01DK124219, R01DK097160, RDA046138) , the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation, Intramural Research Program of the National Institute of Neurological Disorders and Stroke (ZIA-NS002263) , Veterans Affairs VA-ORD-BLR&D (I01BX002678) , the Deutsche Forschungsgemeinschaft (SFB1423, project number 421152132) .
152-LB: Decision Tree Modeling Identifies Factors Associated with Increased Time-in-Range (TIR) during Inpen Smart Insulin Pen and Continuous Glucose Monitor (CGM) Use In Youth
Authors: SMITH MADISON , HEUNGYONG IM GLEN , GAETANO ANGELA , THANASEKARAN SNEHA , MACLEOD JANICE , VIGERSKY ROBERT A.
Published: May 2022

Background: Previous InPen decision tree modeling (DTM) in adults indicated that missed meal dosing was a major modifiable factor associated with TIR (70-180mg/dL) . We used DTM to find characteristics/use-behaviors associated with TIR for InPen+CGM users <18 years of age.

Methods: InPen+CGM data from youth (N=883) with T1D starting InPen between 7/20 and 6/21 were used to identify characteristics (prior delivery method, diabetes duration) and use-behaviors (frequency of missed/correction doses, priming/bolus count, meal therapy mode, InPen bolus calculator use, app reminders, time settings, and report generation) associated with TIR. A variance inflation factor >10 was used to reduce multicollinearity for feature importance. Those with insufficient CGM and/or bolus data and lack of consistent insulin therapy settings were excluded.

Results: DTM of users determined 1) diabetes duration, 2) frequency of missed meal doses, 3) bolus count and 4) correction frequency as the top variables associated with TIR (Figure) . Highest average TIR (68.0%) was observed in newly diagnosed (≤1 year) users. Users with >2 years diabetes duration, <5.5 boluses/day, and >35.1% missed dose frequency demonstrated lowest average TIR (35%) .

Conclusions: DTM is a novel application for understanding glycemic outcomes due to modifiable and non-modifiable factors.

Disclosure

M. Smith: Employee; Medtronic. G. Im: Employee; Medtronic. A. Gaetano: None. S. Thanasekaran: None. J. Macleod: Employee; Medtronic. R. A. Vigersky: Employee; Medtronic.
156-OR: Central Neural Processing of Sweet Taste Is Altered following Bariatric Surgery
Authors: ALESSI JONATHAN , SAWIN KEEGAN , CHITTUM GEORGE D. , OSWALT SARAH E. , DZEMIDZIC MARIO , KAREKEN DAVID A. , CONSIDINE ROBERT V.
Published: May 2022

Bariatric surgery causes marked changes in eating behavior, including reduced preference for highly sweet foods. No studies have addressed the brain response to receipt of this primary taste modality following weight loss surgery. Eighteen women (BMI 47.5±7.6 kg/m2, age 43.1±10.2 y) rated perceived intensity and liking of sucrose solutions (0, 0.1, 0.4, 0.86 & 1.M) in a three-block randomized design, and underwent functional magnetic resonance imaging (fMRI) to assess brain responses to 0.40 M and 0.M sucrose sprayed onto the tongue relative to water (14 sucrose and 34 water trials in two 5:52 min long scans) , before and after bariatric surgery-induced weight loss. Eight women underwent Roux-en-Y and had sleeve gastrectomy. The post-surgery visit occurred 4.7 months (range 3-9) following the pre-surgery assessment. BMI was significantly reduced to 38.0±7.8 kg/m2. There was no effect of weight loss on rated sucrose solution intensity. However, post-surgical “preferred sweetness” of the test solutions was significantly lower (0.53±0.12 vs. 0.22±0.M; p<0.008) . Across the whole sample (pre- and post-surgery) , both sucrose concentrations relative to water activated bilateral insula and lateral frontal/orbitofrontal areas (p<0.001, k=5) . However, only 0.4M sucrose elicited the left nucleus accumbens (NAc) response (pFW E=0.005, k=17, family wise error-corrected within a bilateral NAc mask) . Pre-surgery activations included the anterior cingulate cortex (ACC) and bilateral insula as well as NAc (left: p=0.001, k=33; right p=0.009, k=17) . Post-surgery activations were present only in the ACC and bilateral insula. NAc responses were significantly greater pre-surgery relative to post-surgery (pFWE =0.026, k=6) . These data strongly suggest that bariatric surgery significantly affects central neural processing of sweet taste. While salience-assigning ACC and insula responses did not differ, nucleus accumbens region coding reward responded less post-surgically.

Disclosure

J.Alessi: None. K.Sawin: None. G.D.Chittum: None. S.E.Oswalt: None. M.Dzemidzic: None. D.A.Kareken: None. R.V.Considine: Other Relationship; Lilly.

Funding

American Diabetes Association (1-18-ICTS-036)