bluuebunny/crossref_metadata_2025 huggingface dataset:
1428-P: Monocyte Cholesterol Metabolism during Weight Loss and Glycemic Improvement
Authors: DING JINGZHONG , LOHMAN KURT , KRITCHEVSKY STEPHEN B. , PARKS JOHN S. , HOESCHELE INA , NICKLAS BARB J. , DEMONS JAMEHL , LIU YONGMEI
Published: May 2022

Immune cells drive chronic inflammation underlying obesity-related T2DM. We previously reported a cholesterol metabolism pathway as the top coordinated transcriptional module in human monocytes associated with both obesity and T2DM (FDR <0.05) . To investigate whether this pathway is a modifiable link between obesity and T2DM, we randomly assigned 112 adults with obesity and prediabetes aged 40-70 years, 71% woman, 29% African American, to a weight loss intervention using Medifast meal replacement (N=63) or a weight stable control group (N=49) for 4 months. The outcome was a composite measure as the average of standard scores of cholesterol metabolism gene transcripts in monocytes. The intervention achieved 10% weight loss. The control group remained weight stable. Compared with the weight stable group, the weight loss group experienced reductions in both the composite measure and HbA1c (Table) . Changes in the composite measure and HbA1c were correlated (r=0.24, p=0.01) . For individual gene transcripts of this pathway, weight loss reversed obesity-associated upregulation in cholesterol synthesis (FDFT1 and SQLE) , fatty acid synthesis (SCD and FADS1) , and cholesterol uptake (LDLR and MYLIP) (p values <0.05) .

In conclusion, weight loss induces beneficial changes in the cholesterol metabolism pathway in monocytes, a potential therapeutic target for obesity-related T2DM.

Disclosure

J.Ding: Research Support; Medifast, Inc. K.Lohman: None. S.B.Kritchevsky: None. J.S.Parks: None. I.Hoeschele: None. B.J.Nicklas: None. J.Demons: None. Y.Liu: None.

Funding

National Institutes of Health (R01DK103531)
1429-P: Metabolically Healthy Obese Is Actually Not Healthy but at Risk for Developing Diabetes Mellitus
Authors: MIZUSHIRI SATORU , DAIMON MAKOTO , KAMBA AYA , MURABAYASHI MASAYA , NISHIYA YUKI , ITO RYOMA , TAMURA AYUMI , ONO SHOMA , MATSUKI KOTA
Published: May 2022

Objectives: Although obese individuals without obesity related metabolic abnormalities are often defined as metabolically healthy, risks for developing such abnormalities have not been evaluated well. Recently, a prospective study showed that metabolically healthy obese subjects were at higher risk of diabetes, stroke and cardiovascular disease than metabolically healthy subjects without obesity in UK. We here analyzed the association between metabolically healthy obesity and a risk for developing diabetes in a Japanese population.

Research Design and Methods: The participants were recruited from Iwaki study, a health promotion study of Japanese people aimed to prevent lifestyle-related disease. Among 1167 participants of Iwaki study held in 2014, 931 individuals attended at least one time in 2015 to 2019. We excluded 7 and 75 individuals without complete data sets and who were diagnosed with diabetes in 2014 respectively, thus 849 subjects were enrolled in this study. Obesity was defined as BMI >25 kg/m2. We used the National Cholesterol Education Program ATP III Guideline to categorize metabolically unhealthy as participants meeting at least two criteria of metabolic abnormalities. Results: In 2014, the number of metabolically healthy subjects without and with obesity were 6 and 1 respectively. Cox proportional hazard model showed metabolically healthy subjects with obesity were at higher risk of diabetes compared with those without obesity (Hazard ratio 3.70, p=0.002) , even if after adjusted by age and sex (Hazard ratio 3.32, p=0.005) .

Conclusions: Our analysis suggest an importance of encouraging people with obesity to reduce body weight even though they are metabolically healthy. We are extending such analyses in association with other lifestyle-related diseases.

Disclosure

S.Mizushiri: None. M.Daimon: None. A.Kamba: None. M.Murabayashi: None. Y.Nishiya: None. R.Ito: None. A.Tamura: None. S.Ono: None. K.Matsuki: None.
1433-P: Comparative Weight Loss with GLP-1 Receptor Agonists vs. Bariatric Surgery in Obesity: A Systematic Review and Pair-Wise Meta-analysis
Authors: SARMA SHOHINEE , PALCU PATRICIA
Published: May 2022

Background: One in three adults suffers from obesity.1 Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with 15-20% weight loss, a range previously only achieved with bariatric surgery.2,3,4 This systematic review and meta-analysis compares weight loss between GLP-1 receptor agonists and bariatric surgery.

Methods: MEDLINE, Medline-in-Process, Medline EPUBS Ahead of Print, EMBASE Classic + EMBASE (OvidSP) ; and Cochrane (Wiley) databases were searched from inception to April 21, 2021. We included randomized controlled trials (RCTs) and observational studies. Two independent reviewers extracted data, reported risk of bias, and graded certainty of evidence. Risk of bias was reported using Risk of Bias 2 (RoB 2) tool for RCTs and Risk of Bias in Non-randomized Studies- of Interventions (ROBINS-I) tool for observational studies. Data were pooled separately for RCTs and observational studies using random effects models. Change in weight, body mass index (BMI) , and glycated hemoglobin (HbA1C) were summarized.

Results: Seven included studies encompassed 11patients. Among RCTs, mean difference in weight between bariatric surgery and GLP-1 receptor agonist was −22.68 (95% CI: −31.41, −13.96) , mean difference in BMI was −8.18 (95% CI: −11.59, −4.77) , and mean difference in HbA1C was −1.28 (95% CI: −1.94, −0.61) . Among observational studies, mean difference in weight was −16.56 (95% CI: −36.53, 3.42) and mean change in BMI was −10.60 (95% CI:−17.22, −3.98) . These effects all favoured bariatric surgery.

Conclusion: In adults with obesity, bariatric surgery still confers highest reductions in weight and BMI compared to GLP-1 receptor agonists, but similar effects in glycemic control.

Word count: 248

Disclosure

P. Palcu: None.

Funding

Clinician Investigator Program, University of Toronto
144-OR: Adipose Modeling of FGF21 Signaling Mutations in a Severe Insulin Resistance Syndrome
Authors: PHAN NHUNG , ORNITZ DAVID M. , STONE STEPHEN I.
Published: May 2022

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome characterized by tall stature, acanthosis nigricans, obesity, and acromegalic features. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels. Our group previously described a patient with IMPA who carries digenic mutations in fibroblast growth factor receptor 1 (FGFR1) and beta-klotho (KLB) , which form the receptor complex for FGF21. FGF21 is a hepatokine that plays a critical role in adipose insulin sensitivity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Both the uncorrected (mutant) and corrected (wild-type) lines were able to undergo successful differentiation to adipocytes. Western immunoblotting demonstrated that the uncorrected cells demonstrated decreased levels of FGFR1, pERK1/2, and p38-MAPK in response to insulin and/or FGF21. Additionally, the mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY (mean droplet size 62.6 μm2 uncorrected; 40.8 μm2 corrected; p= 0.00016) . To complement the iPSC work, a transgenic knock-in mouse line was created using CRISPR gene editing. Explants of gonadal white adipose tissue isolated from these mice demonstrated significantly decreased lipolysis (Max NEFA in mutant 0.mEq/L; wild-type 0.13 mEq/L; p=0.003) . Additionally, qRT PCR was performed in brown adipose tissue demonstrating decreased Ucp1 expression (mutant mice 37.2% of WT; p=4.0x10-5) . These results suggest that the FGFR1 and KLB mutations lead to decreased FGF21 signaling. Mutant adipose tissues are dysfunctional with impaired lipolysis and Ucp1 expression. Therefore these models are useful for determining the role of the FGF21 signaling in human insulin resistance syndromes.

Disclosure

N.Phan: None. D.M.Ornitz: None. S.I.Stone: Speaker's Bureau; Rhythm Pharmaceuticals, Inc.

Funding

NICHD (R21 HD098872) , NIDDK (KDK124574) , NCATS (UL1TR000448) , NIDDK (P30 DK020579) , NIDDK (P30 DK056341) , Burroughs Wellcome Fund Physician-Scientist Institutional Award, and Centene Precision Medicine Initiative
1445-P: Ogt Is Dispensable for Beta-Cell Development but Essential for Postnatal Beta-Cell Identity Maintenance via Pdx1
Authors: WONG ALICIA L. , AKHAPHONG BRIAN , LOCKRIDGE AMBER D. , ALEJANDRO EMILYN
Published: May 2022

T2D is associated with reduced pancreatic β-cell mass, in part, by increased apoptosis and identity loss as insulin-producing cells. Nutrient-sensor protein O-GlcNAc Transferase (Ogt) is a regulator of pancreas development and β-cell function. We hypothesized that Ogt also regulates postnatal β-cell identity maintenance, in part, by modulating the activity and localization of key β-cell transcription factors. We genetically ablated Ogt in endocrine progenitors in mice (Ngn3-cre;OgtKOEndo) . While phenotypically normal at birth, at postnatal (p) day 23, normoglycemic OgtKOEndo displayed aberrant islet architecture, along with a significant increase in Ins/Gcg-expressing bihormonal cells. Reduced levels of Pdx1 expression and increased incidence of cytoplasmic Pdx1 localization were observed in islets of OgtKOEndo mice compared to controls. All OgtKOEndo mice were diabetic by p60, with severe reductions in both α and β-cell mass. Next, we generated a β-cell Ogt-deficient mouse model (RIP-cre;OgtKOIns) . Like OgtKOEndo, OgtKOIns mice had increased incidence of bihormonal cells, with a trending increase in α-cell associated gene transcription. α-cell mass and β-cell mass were also reduced at p30 compared to controls. We hypothesized, mechanistically, that deletion of Ogt perturbed the activity of Pdx1, a transcription factor modified by Ogt and a key regulator of β-cell fate and insulin biogenesis. As expected, OgtKOIns islets display reduced Ins1/2 mRNA, total insulin content, and Pdx1 protein. Over-expression of Pdx1 in the OgtKO;PdxOEIns mice rescued islet insulin content, and O-GlcNAc modification of Pdx1 is positively correlated with insulin secretion. However, no rescue in β-cell mass was observed in OgtKO;PdxOEIns mice. Next, we will determine the role of the O-GlcNAc modification of Pdx1 in β-cell identity in vivo using the OgtKO;PdxOEIns mice and in vitro, using a proximity-directed nanobody technology to increase Pdx1 and Ogt interactions.

Disclosure

A.L.Wong: None. B.Akhaphong: None. A.D.Lockridge: None. E.Alejandro: None.

Funding

National Institutes of Health (DK115720)
1447-P: The Snd1 Coregulator Controls ß-Cell Function
Authors: KANOJIA SUKRATI , DAVIDSON REBECCA K. , SPAETH JASON , CASEY NOLAN
Published: May 2022

The main function of the pancreatic β-cell is glucose-stimulated insulin secretion (GSIS) which serves to maintain whole body glucose homeostasis. Under type 2 diabetic conditions, a subset of β-cells fail and lose expression of key transcription factors (TFs) required for GSIS. Among these TFs is Pdx1, which requires the recruitment of a distinct set of transcriptional coregulators to modulate its activity. Recently, Pdx1 has been shown, through and IP-Mass Spec approach, to interact with numerous coregulators, including Snd1 (Staphylococcal nuclease and Tudor domain-containing protein) , which has been shown to facilitate protein-protein interactions and transcriptional control through the recruitment of chromatin modifying enzymes. Here, we first confirmed Pdx1 and Snd1 interact in the rodent β-cell lines by Co-IP, and in primary mouse β-cells and human EndoC-βH1 β-cell lines using proximity ligation assay. Next, we utilized CRISPR-Cas9 technology to generate Snd1-deficient mouse β-cell lines (Snd1KO) . Bulk mRNA-sequencing performed on Control and Snd1KO β-cell lines identified numerous differentially expressed genes linked to insulin secretion and cell proliferation. WST-1 cell proliferation assays revealed impaired proliferation in Snd1KO cell lines and high-glucose stimulated insulin secretion was blunted in INS-1 832/13 cells following siRNA-mediated knockdown of Snd1. As Snd1 has been shown to facilitate protein-protein interactions in other tissues, we found Snd1 interacts with numerous nuclear enriched proteins in the β-cell by IP-Mass Spec, including Stat3, Pax6, Ruvbl2 and Trim28. Future efforts are underway to characterize how Snd1 interactions with these proteins impact gene expression in vitro. Moreover, the role of Snd1 in modulating gene expression and β-cell function in vivo is being evaluated in a novel β-cell-specific (Ins1-Cre) Snd1 knockout mouse model.

Disclosure

S.Kanojia: None. R.K.Davidson: None. J.Spaeth: None. N.Casey: None.

Funding

K01DK115633Wells Center/Pediatric startupCDMD Pilot feasibility grant
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<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<0.05, p value by Student’s t test unless specified otherwise) and number (Scr 2/cell vs. siLIPA 14/cell, p<0.05; DMSO 4.5/cell vs. Lali2 16/cell, p<0.05) . Rat and human beta cells treated with Lali2 also showed increased in LD area and/or number of LDs per cell (p<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<0.05) and to KCl (61.3 ±16.1% of Scr, p<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<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 >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<0.001 and p=0.011) and impact (p<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 >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<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 >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<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.
153-LB: Type 1 Diabetes (T1D) Onset and COVID-19—Effect of the Second Wave on Diabetes Ketoacidosis and ICU Admission Rates in Newly Diagnosed Children with T1D in Kuwait
Authors: OTHMAN FOUZEYAH , AL-ABDULRAZZAQ DALIA , ALKANDARI HESSA
Published: May 2022

Introduction: The COVID-19 pandemic had affected access to healthcare services around the globe. On February 24th, 2020, the first wave of the pandemic was announced. The government of Kuwait had implemented public health measures including curfews, nationwide lockdowns, and limited access to healthcare services. The second wave was declared on March 7, 2021; virtual visits, availability of diabetes clinics, and easier access to healthcare facilities may change the frequency of diabetes ketoacidosis (DKA) and the requirement for ICU admission for children with type 1 diabetes (T1D) onset in the second wave.

Aims: To evaluate DKA at presentation and ICU admission among children with T1D onset during the first and second waves using data from Childhood Onset Diabetes electronic Registry (CODeR) .

Methods: Data were extracted from CODeR. Included patients were aged less than 14 years at the time of T1D diagnosis in the period (February 24th - December 31st, 2021) , and in the same period in 2020.

Results: Between February and December 2021, 253 children were identified to have T1D onset, compared with 282 during the same period in 2020. There were no significant differences between HbA1c levels (11.41% vs. 11.56%;p value=0.21) and frequency of DKA in both groups (56.4% vs. 54%, p value=0.51) . Mild/moderate DKA rates didn't differ in both periods (66.1% vs. 60.7%, p value=0.42) , and Severe DKA as well (33.9% vs. 39.3%, p value=0.42) . No significant difference in ICU admission rates was observed in both periods (25.5% vs. 23.9%,p value=0.74) .

Conclusion: The second wave of the COVID-19 pandemic didn't change DKA frequency or the requirement of ICU admission compared to the first wave. Further studies investigating the frequency of DKA, ICU admission, and other factors are needed over longer periods to evaluate how the COVID-19 pandemic affects DKA changes as the pandemic continues.

Disclosure

F. Othman: None. D. Al-abdulrazzaq: None. H. Alkandari: None.

Funding

Dasman Diabetes Institute (RA MoH 2021-017)
154-LB: Population-Based Optimization of Metabolic Monitoring for Autoantibody-Positive Individuals at Risk for Type 1 Diabetes
Authors: OROURKE COLIN , SPEAKE CATE , YLESCUPIDEZ ALYSSA , BENDER CHRISTINE , LORD SANDRA
Published: May 2022

Diabetic ketoacidosis (DKA) is often the sentinel event to a diagnosis of clinical type 1 diabetes. Research studies involving antibody positive (AAB+) individuals at risk for developing type 1 diabetes have demonstrated that metabolic monitoring every 6 months with oral glucose tolerance testing can dramatically reduce the incidence of DKA at diagnosis. It is unknown whether other schedules can reduce the population level burden of metabolic monitoring in AAB+ individuals while retaining the potential benefit of reducing DKA.

We reasoned that the shorter the time time-period during which clinical type 1 diabetes (T1D) remains undetected, the lower the likelihood of DKA. We aimed to develop models of optimized monitoring visit schedules to limit undiagnosed (UnDx) time for the population. Using OGTT data from 6193 islet AAB+ relatives identified in TrialNet’s Pathway to Prevention study, we developed models and an algorithm to optimize visit schedules to limit population-based UnDx time. The results of modeling were presented using estimated hazard rate as a function of age. An "optimal" visit schedule was determined for each model to achieve a minimum average level of UnDx time for the population. This was applied for risk patterns identified by each model thus producing optimal schedules for pediatric and adult populations with single or multiple antibodies.

Modeling an optimized visit schedule to keep UnDx time ≤ 6 months at a population level, we find that conducting half the number of metabolic monitoring visits usually done in research studies is likely to be effective in significantly impacting the population incidence of DKA at diagnosis of T1D. Our approach has implications for public health screening and monitoring for T1D risk.

Disclosure

C. Orourke: None. C. Speake: Advisory Panel; Vertex Pharmaceuticals Incorporated. A. Ylescupidez: None. C. Bender: None. S. Lord: Other Relationship; Pfizer Inc.

Funding

Helmsley Charitable Trust (2103-05008) ; Helmsley Charitable Trust (2210-05590)
155-LB: Evaluating Community COVID-19 Vaccination Status and Diabetes Visit Frequency during the Pandemic
Authors: OJUKWU SANDO , ADAM ATIF , KAUSHAL TARA , CHEN CHARLOTTE , TINSLEY LIANE J. , VOLKENING LISA K. , LAFFEL LORI M.
Published: May 2022

Aim: The COVID-19 pandemic highlighted potential healthcare misalignment as seen by vaccine rates. We investigated pediatric diabetes visit frequency in patients living in lower vs. higher COVID 19 vaccination areas.

Method: We obtained EHR-extracted visit data for youth with T1D, ≤18 years old, with ≥1 visit in both the pre-pandemic (9/15/18-3/15/20) and pandemic (4/1/20-12/31/21) period. Residential addresses were geocoded and linked with CDC county level COVID vaccination data from 2/2/2022. High vaccine counties were defined as those in which ≥75% of the population ages 12 and older were fully vaccinated. We performed paired t-tests and logistic regression. Models were adjusted for age, gender, pre-pandemic A1c, and diabetes duration.

Results: There were 1,029 youth (49% female, pre-pandemic age 13.7±3.8 yrs, T1D duration 6.7±4.3 yrs) who had clinical encounters in both periods. 541 youth were from high vaccine counties. There was no difference in age, gender, T1D duration, CGM or pump use, or baseline A1c between youth from high vs. low vaccine counties. Overall there was increased visit frequency in the pandemic (5.1±3.0) vs. pre-pandemic (4.7±2.6) (p=0.03) . The mode of visits shifted from in person to virtual during the pandemic (p<0.001) . In adjusted models, there was no association between county-level COVID vaccination coverage and visit frequency (OR 1.03, 95% CI 0.99-1.07) .

Conclusion: The COVID 19 pandemic resulted in a shift in care delivery to telehealth. Telehealth allowed for increased visit frequency. Patients coming from low COVID 19 vaccination counties attended diabetes visits as frequently as those coming from high COVID vaccination counties. County COVID vaccine status did not impact visit frequency of a chronic condition.

Disclosure

S. Ojukwu: None. A. Adam: None. T. Kaushal: None. C. Chen: None. L. J. Tinsley: None. L. K. Volkening: None. L. M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc.

Funding

National Institutes of Health (K12DK094721, P30DK036836)
156-LB: New Gestational Diabetes Mellitus Risk Algorithm
Authors: MENDIZABAL LEIRE , ARREGI MADDI , DEOGRACIA JOHANNA VALERIO , RAMOS LEVI ANA M. , BARABASH ANA , DE LA TORRE NURIA GARCÍA , ARANA EUNATE , URRUTIA INES , GAZTAMBIDE SONIA , CASTANO LUIS , MARTÍNEZ MARÍA DE LOS ANGELES M. , CAMARILLO-ROMERO ENEIDA , ZERÓN HUGO MENDIETA , GARDUNO-GARCIA JESUS , CORCOY ROSA , SIMON LAUREANO , ZULUETA MIRELLA , CALLE ALFONSO L.
Published: May 2022

Background and Objective: GDM is associated with life-long adverse outcomes for mother and baby, and its incidence is increasing. Markers beyond clinical factors are needed to identify women at high risk and catalyze early preventive interventions. Our aim was to develop a risk assessment algorithm that integrates genetic and clinical variables.

Methods: We analyzed a retrospective cohort of 711 women from Hospital Clínico San Carlos (HCSC, Madrid, Spain) , with 425 control pregnancies and 286 GDM cases diagnosed per IADPSG criteria. The HCSC cohort was randomly divided into a training/development dataset (70% of cohort) for algorithm development and a test dataset (30% of cohort) for validation. In addition, we tested the model in a cohort of 157 women (89 controls, 68 cases diagnosed per NDDG criteria from Hospital Cruces (Bilbao, Spain) and in a cohort of 416 women (346 controls, 70 cases per IADPSG criteria from HMPMPS, México) . A total of 114 SNPs were selected for this analysis after exhaustive exploration of the databases published to date of SNPs associated with GDM. The SNPs were selected based on their predictive power and population frequency, with the following criteria: OR>1.2, RAF>0.20, p<1×10-5. Discrimination and calibration of risk scores were assessed using the receiver operating characteristic (ROC) curve in the internal and the external validation groups.

Results: The algorithm provided a risk score for GDM, integrating 10 SNPs, maternal age, and pregestational BMI. In the training dataset the AUC was 0.74, sensitivity of 77% and specificity of 64%. AUCs in the HCSC, UAEM and Cruces validation sets were 0.71, 0.70 and 0.62 respectively.

Conclusions: This new tool for GDM risk assessment suggests that the utilization of genetic markers in combination with clinical characteristics may improve GDM risk evaluation and accelerate adoption of prevention interventions. Our study also highlights the importance of applying consensus criteria for the diagnosis of GDM.

Disclosure

L. Mendizabal: Employee; Patia Biopharma S. A. L. Castano: None. M. M. Martínez: None. E. Camarillo-romero: None. H. Mendieta zerón: None. J. Garduno-garcia: Speaker's Bureau; Boehringer Ingelheim International GmbH. R. Corcoy: None. L. Simon: Board Member; Nelum Corp., Oncomatryx Biopharma SL, Patia Biopharma S. A., Quimatryx, SunRock Biopharma S. L., Other Relationship; Precsion Diabetes, Inc. M. Zulueta: None. A. L. Calle: None. M. Arregi: Employee; Patia Biopharma S. A. J. Valerio deogracia: None. A. M. Ramos levi: None. A. Barabash: None. N. García de la torre: Other Relationship; Ferrer. E. Arana: None. I. Urrutia: None. S. Gaztambide: None.