bluuebunny/crossref_metadata_2025 huggingface dataset:
23-OR: EHR-Based Blood Glucose Alerts Improve Inpatient Glycemic Control at a Large Academic Medical Center
Authors: BAK LEIGH B. , FANDEL THOMAS M. , BOZZO JANIS E. , DEWITT MICHELLE L. , CHEN PING , PANDO RICHARD A. , FERRO LINDA , KAPLAN RORY , HENDRICKSON KARRIE C. , AMPORT STEPHANIE B. , SUSSMAN L. SCOTT , INZUCCHI SILVIO E.
Published: June 2020

Hospital blood glucose (BG) management is a challenge. We implemented an electronic health record (EHR)-based system at our 1541-bed academic medical center (AMC), alerting when a patient (pt) experiences significant hyperglycemia (hyper; 2 BGs ≥300 mg/dL over 48 hours) or hypoglycemia (hypo; <70 mg/dL). These Excursion Event Alerts (EEAs) fired to the clinician entering orders and provided links to insulin order sets and consult requests. The EEAs were launched on 14 non-ICU wards in mid-2019. We compared BG control during the 3 months prior to launch vs. the most recent 3 months. The control group consisted of 12 non-EEA wards. Our 1° outcome was the Quality Hyperglycemia Score-2 (QHS2), previously developed to assess/compare the overall BG quality on individual wards. QHS2 (scale, 0-100) incorporates 5 elements of BG management, crediting overall control as well as the minimization of significant fluctuations. After the intervention, there was a substantial 13.8% improvement in mean QHS2 (+9.36, p=0.029), comprised of more pt-days in target (+4.3%, p=0.024) and a trend for less pt-days with severe hyper (-2%, p=0.09), with no change in hypoglycemia. In contrast, there was no change in QHS2 on control wards. We conclude that a glycemic alert system was associated with improved BG control at our large AMC, suggesting that a simple EHR-based intervention can favorably impact hospital diabetes management.

Disclosure

L.B. Bak: None. T.M. Fandel: None. J.E. Bozzo: None. M.L. DeWitt: None. P. Chen: None. R.A. Pando: None. L. Ferro: None. R. Kaplan: None. K.C. Hendrickson: None. S.B. Amport: None. L. Sussman: None. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics.
230-OR: Personalized Nutrition for Prediabetes by Prediction of Glycemic Responses
Authors: BEN-YACOV ORLY , GODNEVA ANASTASIA , SEGAL ERAN
Published: June 2020

Prediabetes is a leading risk factor for the development of type 2 diabetes mellitus (T2DM) and its metabolic complications. Current practice for prevention of diabetes includes weight loss-targeting dietary and lifestyle modifications but has had limited success. Alternative approaches, such as dietary interventions that directly target blood glucose levels for prevention of T2DM, are not well established and have been much less studied. In particular, postprandial (post-meal) glucose responses (PPGR) are a major determinant of glycemic control, but dietary methods for controlling PPGRs are rare and show limited efficacy. We previously recruited a population-based cohort of 900 people in which we continuously tracked blood glucose and obtained clinical and gut microbiota measurements. Our data of ∼50,000 PPGRs revealed that different people have vastly different responses to the same meal. We devised a machine learning algorithm based on clinical and microbiome features that accurately predicted personalized PPGRs to any food combination. Here, we sought to evaluate the long-term clinical efficacy of a dietary intervention based on our algorithm in prediabetes, and test the hypothesis that a dietary treatment that targets meal PPGR can lead to long-term improvements in glycemic control and other metabolic outcomes, as compared to a standard Mediterranean-style diet. To this end, we conducted a 6-month randomized controlled diet intervention trial (RCT) followed by a 6-month post-intervention follow-up program, and randomly assigned 225 adults with prediabetes to receive a Mediterranean-style (Med) diet or a Personalized Postprandial-targeting (PPT) diet. At 6 months, mean daily time of glucose levels above 140 mg/dl changed by -29% and -65% in the Med diet and PPT diet, respectively (p=3.4x10-10). Mean HbA1c% levels changed by -0.08% and -0.16% in the Med diet and PPT diet, respectively (p=6.9x10-3). The favorable effects of the ’PPT diet’ on glycemic control persisted also at one year follow up.

Disclosure

O. Ben-Yacov: None. A. Godneva: None. E. Segal: Consultant; Self; DayTwo.
238-OR: Once-Weekly Basal Insulin Icodec Offers Comparable Efficacy and Safety vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve Patients with T2D Inadequately Controlled on OADS
Authors: ROSENSTOCK JULIO , KJAERSGAARD MAIKEN I.S. , MOLLER DANIEL , HANSEN MELISSA VOIGT , GOLDENBERG RONALD
Published: June 2020

Insulin icodec* (icodec) is a novel basal insulin analog with a terminal half-life of ∼196 hours in development as the first once-weekly insulin. This 26-week, randomized, double-blind, double-dummy, treat-to-target, phase 2 trial investigated the efficacy and safety of once-weekly icodec vs. once-daily insulin glargine U100 (IGlar U100) in insulin-naïve patients with T2D inadequately controlled (A1C 7.0-9.5%) with metformin ± DPP-4i. Starting doses were 70 U weekly and 10 U daily, respectively, with weekly titration to a pre-breakfast SMBG target of 70-108 mg/dL. Primary endpoint was change in A1C from baseline to week 26. Secondary endpoints included change in FPG from baseline to week 26 and hypoglycemic episodes. Participants (n = 247) were randomized 1:1 to icodec (n = 125) or IGlar U100 (n = 122). Baseline characteristics appeared similar in both groups; mean age was 59.6 years, diabetes duration 9.7 years, BMI 31.3 kg/m2 and FPG 181 mg/dL. Mean baseline A1C was 8.1% (icodec) and 8.0% (IGlar U100). At week 26, estimated mean A1C was 6.69% for icodec and 6.87% for IGlar U100 (estimated mean change from baseline: -1.33% and -1.15%-points, respectively). There was no statistically significant treatment difference for change in A1C from baseline to week 26 (-0.18%, 95% CI, -0.38; 0.02). Estimated mean FPG at week 26 was 123 mg/dL (icodec) and 127 mg/dL (IGlar U100). Observed rates of level 2 (<54 mg/dL) + 3 (severe) hypoglycemia were low (60.55 and 52.36 events per 100 patient years of exposure for icodec and IGlar U100, respectively) and were comparable (p = 0.85). There were no unexpected safety findings.

In conclusion, icodec is the first once-weekly insulin with similar glucose-lowering effects and safety profile to once-daily IGlar U100. Icodec could improve treatment acceptance and facilitate T2D management in patients needing basal insulin. *Proposed INN.

Disclosure

J. Rosenstock: None. M.I.S. Kjaersgaard: Employee; Self; Novo Nordisk A/S. D. Moller: Employee; Self; Novo Nordisk A/S. M. Voigt Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. R. Goldenberg: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Johnson & Johnson, Merck & Co., Inc., Novo Nordisk Inc., Sanofi.
24-LB: RIPK1 Activation Induces Necroptosis, Proinflammation, and Profibrosis in Kidney of STZ/HFD-Induced Diabetic Mice
Authors: CHEN QING , LONG YANG , GUO MAN , MA XIU M. , PU YUELI , XU YONG
Published: June 2020

Diabetic kidney disease (DKD) is attributed largely to renal tubular interstitial fibrosis. However, the complex mechanism of renal tubular interstitial fibrosis in DKD pathogenesis remains unclear. Recently, necroptosis has emerged as an important cell death model in many pathological conditions, which is regulated through RIPK1/RIPK3 pathway. In this present study, we aimed to evaluate whether necroptosis is involved in the development of diabetic kidney disease, and to investigate the mechanisms involved. In the current study, the results of immunohistochemistry and Western blot showed that the ratio of p-RIPK1/RIPK1, p-RIPK3/RIPK3, p-MLKL/MLKL were significantly increased in the kidney of STZ/HFD induced diabetic mice. Additionally, the levels of serum MCP-1, and the expression of IL-1 β and TGF - β in kidney were increased in the diabetic mice. Moreover, Necrostatin-1, an inhibitor of RIPK1, can effectively decrease the ratio of p-RIPK1/RIPK1, p-RIPK3/RIPK3, p-MLKL/MLKL, the levels of serum MCP-1, and the expression of TGF-β and IL-1 β in kidney in the diabetic mice. Necrostatin-1 treatment also resulted in delayed progression of renal structural lesions and significantly improved the function of kidney. High glucose stimulation, which induced excessive ROS production, led to necrosis and increased phosphorylation of RIPK1, RIPK3 and MLKL in rat tubular epithelial cell NRK-52E cells. Moreover, NAC treatment, a ROS inhibitor, could partly reverse the effect of glucose on RIPK1, RIPK3, and MLKL.

In conclusion, RIPK1 activation may induce necroptosis, pro-inflammation and pro-fibrosis in kidney of STZ/HFD induced diabetic mice; High glucose induces RIPK1 -dependent necroptosis in NRK-52E cells; excessive ROS production mediate high glucose induced necroptosis.

Disclosure

Q. Chen: None. Y. Long: None. M. Guo: None. X.M. Ma: None. Y. Pu: None. Y. Xu: None.

Funding

Science and Technology Bureau of Luzhou (2016LZXNYD-G02)
241-LB: Positive Regulation of JAK/STAT at Signaling with SOCS3-Derived Cell-Permeable Binding Domain to ObR Induces Anti-obesity Effect
Authors: LEE KUYSOOK , JEON JISOOK , KIM SU JEONG , KANG HYEONTAE , KWAK JEONGHUN , CHOI YOUNGSIL , JO DAEWOONG
Published: June 2020

Aim: Leptin, a hormone which regulates food intake and energy expenditure, is excessively expressed in obese patients. Leptin signaling is regulated by a negative feedback regulator, suppressor of cytokine signaling 3 (SOCS3) that competitively binds to the leptin receptor (ObR) and promotes leptin resistance. We hypothesized that an exogenously delivered SOCS3 binding domain (SH2) would compete with SOCS3 for binding to p-Tyr985ObR, and thereby maintain leptin-initiated JAK/STAT signaling.

Method: Cell-permeable, dominant-interfering ΔSOCS3 protein consists of the SOCS3 SH2 domain, a sequence optimized-advanced macromolecule transduction domain to deliver the protein into cells and tissues to facilitate soluble purification, biologically active proteins. Intracellular delivery of ΔSOCS3 was tested for the ability to enhance leptin signaling and sensitivity in diet-induced obese (DIO) mice.

Result: The cell-permeable ΔSOCS3 was delivered efficiently into cell types and tissues examined including the hypothalamus; thus, the protein appeared to cross the blood-brain barrier. CP-ΔSOCS3 competitively bound p-Tyr985ObR and blocked negative regulation by endogenous SOCS3 as assessed by increased levels of phospho-STAT3. DIO mice treated with CP-ΔSOCS3 showed 12.1% body weight loss in 14 days. In addition, fat volume (53.5%), food intake (29.2%), serum leptin (93.1%) and expression of SOCS3 mRNA were also decreased in CP-ΔSOCS3-treated compared to mice treated with diluent. In addition, treatment group showed a significant increase in STAT3 phosphorylation and pro-opiomelanocortin in the hypothalamus.

Conclusion: CP-ΔSOCS3 appeared to competitively suppress feedback inhibition of JAK/STAT signaling by endogenous SOCS3 thereby enhancing leptin sensitivity. This establishes the importance of SOCS3 in the biology of leptin signaling and resistance and suggests CP-ΔSOCS3 might be used as a mechanism-specific weight-loss therapy.

Disclosure

K. Lee: None. J. Jeon: None. S. Kim: None. H. Kang: None. J. Kwak: None. Y. Choi: None. D. Jo: None.
242-LB: The Obesity Paradox among Patients Hospitalized for Diabetes and Its Complications: Outcomes of the Nationwide Inpatient Sample
Authors: SHAKA HAFEEZ , PADILLA SORTO MARIA ELENA , GOMEZ TRISHA MARIE A. , EDIGIN EHIZOGIE , XU JING , YAP SARA ELIZABETH T.
Published: June 2020

Background: Obesity has long been considered a risk factor for individual morbidity and mortality for numerous cardiopulmonary diseases. However, multiple studies have shown that patients who are overweight or obese according to BMI have better inpatient outcomes.

Objective: To demonstrate the effect of obesity on outcomes of patients admitted for diabetes with and without complications.

Method: Data were extracted from the Nationwide Inpatient Sample (NIS) Database for 2016 and 2017. The numbers in the database are weighted to optimize national estimates. Hospitalizations involving all adults with a principal diagnosis of type 1 and type 2 DM were included. This group was further categorized based on the presence of obesity, defined as BMI >30, as a secondary diagnosis. The primary outcome was inpatient mortality and secondary outcomes were Length of stay (LOS) and Total hospital Charge (THC). Multivariate regression analysis was used to adjust for possible confounders.

Results: Around 1,031,009 hospitalizations had a principal diagnosis of DM types 1 and 2. This group had a prevalence of 15.67% of obesity as a secondary diagnosis. Inpatient mortality occurred in 6285 cases (0.61%). After accounting for age, sex, disease severity and type of diabetes, the adjusted odds ratio (aOR) for mortality in obese patients was 0.63 (95% CI: 0.526 - 0 .762, p< 0.001) compared to non-obese patients. Obese patients however, had adjusted increase in THC of $560 (95% CI: -347 - 1467, p=0.226) and adjusted increase in LOS of 0.3 days (95% CI: 0.3 - 0.4, p<0.001).

Conclusions: In patients hospitalized with a principal diagnosis of diabetes and its complications, obese patients had a statistically lower mortality rate. Hence, there seems to be growing evidence for the obesity paradox. More research needs to be done to determine the factors responsible for this recurrent phenomenon.

Disclosure

H. Shaka: None. M. Padilla Sorto: None. T.A. Gomez: None. E. Edigin: None. J. Xu: None. S.T. Yap: None.
243-LB: Enzymes for Dicarbonyl Detoxification Are Attenuated with Obesity by Mechanisms of Acetylation
Authors: MIRANDA EDWIN R. , SHADIOW JAMES , LOMBARD DAVID B. , LUDLOW ANDREW T. , HAUS JACOB M.
Published: June 2020

Glyoxalase I (GLOI) is the primary enzyme for detoxifying the reactive dicarbonyl methylglyoxal. Pre-clinical models demonstrate that loss of GLOI promotes the development of diabetes in obesogenic conditions. To determine if GLOI is attenuated with human obesity, we compared GLOI expression in skeletal muscle biopsy samples from 5 obese (OB) and 15 age-matched lean, healthy individuals (LH). GLOI protein was ~50% lower (p<0.05), whereas GLOI mRNA was ~2-fold higher in OB muscle (p<0.001). The NRF2/Keap1 axis, which regulates GLOI transcription, was unperturbed by obesity. Given the NAD+-dependent deacetylase SIRT1 is capable of deacetylating GLOI which may prevent GLOI’s degradation, we measured the expression of SIRT1 as well as NAMPT and HIF1α which regulate NAD+ bioavailability. HIF1α mRNA was increased 3-fold (p=0.002) and NAMPT protein was ~50% lower (p=0.2) in OB muscle suggesting a pseudo-hypoxic environment which may attenuate NAD+ bioavailability. SIRT1 protein was ~50% lower in OB muscle (p=0.09). SIRT1 protein (r = 0.673, p = 0.003) and HIF1α transcripts (r = -0.487, p = 0.041) correlated with GLO1 protein expression. NAMPT inhibition in human primary myotubes increased GLOI acetylation (~50%) and GLO1 protein (~40%) both of which were rescued by treatment with the NAD+ precursor nicotinamide riboside. Silencing of NAMPT or SIRT1 also reduced GLOI protein by 50%. These data suggest that OB muscle may be in a pseudo-hypoxic state that limits NAD+ bioavailability and SIRT1 activity promoting GLO1 acetylation and degradation.

Disclosure

E.R. Miranda: None. J. Shadiow: None. D.B. Lombard: None. A.T. Ludlow: None. J.M. Haus: None.

Funding

National Institutes of Health (R01DK109948)
244-LB: Data-Driven Metabolic Subgrouping of Obesity by Machine Learning (ML)
Authors: LIN ZIWEI , HUI YOU , WU SHANDONG , QU SHEN
Published: June 2020

Aim: Current clinical classification paradigms for obesity are unrefined and demand more precise classification.

Methods: Unsupervised ML is used to cluster patients with obesity on 2 independent cohorts at 1 institution: an outpatient (n=507) and an inpatient (n=229) cohort. The clustering is performed separately on the 2 cohorts, based on 4 physician expert-selected clinical variables (age, AUC of insulin, FSH, urine acid). Statistics of a lean cohort (n=702) are measured as control.

Results: The classification reveals 4 metabolic different obese clusters on each cohort (Fig 1). Jaccard similarity is 0.865 between the 2 cohorts’ clusters. MHO shows a moderate basal metabolic rate (BMR) with relative healthy hormone levels and glucometabolism. LMO shows the lowest BMR and hormone, oldest age, and most severe glucometabolism. Both HMO-T1 and HMO-T2 show the highest BMR and hormone, lowest glucose, highest incidents of hyperuricemia and female hyperandrogenemia. Moreover, higher urine acid and testosterone in female are observed in HMO-T1, while extremely high insulin secretion and low incidents of diabetes are seen in HMO-T2.

Conclusion: Clinical characteristics-separable subgroups of obesity can be autonomously identified by ML, where the sub-grouping is generalizable across 2 independent cohorts. This may provide interpretation of pathogenesis and enable more precise therapy decision-making for patients with obesity.

Disclosure

Z. Lin: None. Y. Hui: None. S. Wu: Other Relationship; Spouse/Partner; LifeVantage. S. Qu: None.

Funding

National Key R&D Program of China (2018YFC1314100); National Natural Science Foundation of China for Youth (81500687); Fundamental Research Funds for the Central Universities of Tongji University (22120190210)
244-OR: Single Nuclei Chromatin and Transcriptome Profiling across Human and Rat Skeletal Muscle Identifies Regulatory Elements, Genes, and Cell Types Associated with Diabetes GWAS Signals
Authors: PARKER STEPHEN ,   FUSION TISSUE SAMPLING GROUP
Published: June 2020

Skeletal muscle is the largest organ, by weight (>40%), in the human body; insulin resistance in this and other peripheral tissues is a hallmark of type 2 diabetes (T2D). Recent genome wide association study (GWAS) results show significant enrichment for fasting insulin single nucleotide polymorphisms (SNPs) in skeletal muscle tissue chromatin-defined regulatory regions. The next steps towards mechanistic translation are identification of causal variants, the target genes these variants regulate, and the specific cell populations in which they function. To accomplish this, we optimized and performed single-nuclei resolution chromatin (snATAC-seq) and transcriptome (snRNA-seq) profiling across human and rat frozen skeletal muscle, collectively measuring ’omic profiles on 38,386 nuclei. We used integrative non-negative matrix factorization for data fusion across ’omics modalities and species, revealing seven distinct clusters that range in abundance from 58% to 2.1% of all nuclei. The clusters are consistent across independent human and rat samples and across ’omic modalities. We find heterogeneity in fasting insulin GWAS enrichment across snATAC peaks for the muscle cell types (2/7 significantly enriched), one of which is mesenchymal stem cells (∼4% of nuclei). We use genetically fine-mapped SNPs from the largest T2D GWAS and find the highest posterior probability 99% credible set SNP (rs702634) out of three at the ARL15 locus resides in a muscle mesenchymal stem cell-specific snATAC peak. We are nearly finished snRNA+snATAC profiling across 400 additional samples, which will enable muscle cell-specific e/chromQTL analyses and GWAS colocalization reports for the ADA meeting. This work represents a unique resource for the genetic signature of skeletal muscle biology at unprecedented epigenomic, transcriptomic, and cellular scales.

Disclosure

S. Parker: None.

Funding

American Diabetes Association (1-14-INI-07 to S.P.); National Institutes of Health (R01DK117960)
245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction
Authors: ALI MOHAMED M. , HASSAN CHANDRA , MASRUR MARIO , BIANCO FRANCESCO , PHILLIPS SHANE A. , MAHMOUD ABEER M.
Published: June 2020

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity-associated hypoxia in disturbing the methylation of genes involved in inflammation and vascular dysfunction and propose a mediating role of the hypoxia-inducible factor, HIF1α and the DNA hydroxymethylase, TET1.

Methods: We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non-obese (NOB) adults having elective surgeries (n=36; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to increasing pressure gradients. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and promoter methylation/gene expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNɣ were measured in the AT biopsy. Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound.

Results: Flow-induced dilation (FID) was 40-50% higher in NOB than OB adults across all pressure gradients (p<0.05). NO production was higher, and ROS generation was lower in the OB arterioles compared to NOB. HIF1α and TET1 proteins were 2 to 4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID and NO and brachial artery FMD (r=0.82, 0.64, 0.91, respectively; p<0.001) and positively with arteriolar ROS production (r=-0.71, p<0.01). Global hydroxymethylation was observed in OB compared to NOB as well as DNA promoter hypomethylation and increased gene expression of the targeted adipocytokines.

Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines in the hypoxic AT. A downstream target for this pathway could reside in endothelial cells of nearby arterioles and remote arteries resulting in vascular dysfunction.

Disclosure

M.M. Ali: None. C. Hassan: None. M. Masrur: None. F. Bianco: Consultant; Self; Intuitive, Medtronic. S.A. Phillips: None. A.M. Mahmoud: None.

Funding

National Institutes of Health (4R00HL140049, 031K99, HL14004901)
246-LB: Smad3 Deficiency Promotes Beta-Cell Proliferation by Augmenting Glucose-Stimulated UPR
Authors: WANG HONGLIAN , HE HUIJUN , HUANG XR , WANG LI , MA RONALD C. , LAN HY
Published: June 2020

Understanding the mechanism governing β cell proliferation is essential for the in vitro expansion of β cells and the replacement therapy for patients with diabetes. We recently found that deletion of Smad3, a downstream effector of TGF-β signaling, promoted β cell proliferation, while the underlying mechanisms remain elusive. It’s reported that high glucose stimulates β cell proliferation through unfold protein response (UPR). In this study, we tested the hypothesis that whether deficiency of Smad3 promotes β cell proliferation by regulating UPR. As a result, we found that knockout of Smad3 promoted β cell proliferation in diabetic db/db mice, but not in healthy db/m mice. Interestingly, islets from db/db mice of Smad3 knockout presented increased UPR compared with db/m mice of Smad3 knockout. In cultured islet cells, deletion of Smad3 increased β cell proliferation under high glucose (20mM) conditions, which was associated with up-regulated and non-decompensated UPR. Further studies showed that inhibition of UPR with an inhibitor 4-PBA abolished the pro-proliferative effect of Smad3 deficiency in β cells.

In conclusion, Smad3 deficiency increases β cell proliferation by augmenting UPR. Therefore, targeting Smad3 may be an effective therapy for diabetes.

Disclosure

H. Wang: None. H. He: None. X. Huang: None. L. Wang: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. H. Lan: None.

Funding

Research Grants Council of Hong Kong (C7018-16G, R4012-18); Health and Medical Research Fund of Hong Kong (14152321, 05161326, 06173986)
257-OR: Profiling Transcriptional Maturation of Human Pluripotent Stem Cell–Derived Islets after Transplantation
Authors: AUGSORNWORAWAT PUNN , MAXWELL KRISTINA G. , MILLMAN JEFFREY R.
Published: June 2020

Differentiation of human pluripotent stem cells to islet organoids (SC-islets) containing functional β cells is a promising source of replacement cells for diabetes cellular therapy. While there has been significant successes in recent years generating these cells in vitro, stem cell-derived β (SC-β) cells are still functionally and transcriptionally immature when compared to donor primary β cells. Here, we identify and characterize the transcriptional changes that occur after transplantation of SC-islets derived from human embryonic stem (hESC) and induced pluripotent stem cell (hiPSC) lines. This was accomplished by developing methodologies to generate SC-β cells capable of undergoing dynamic glucose-stimulated insulin secretion in vitro along with the successful retrieval of high purity and viable transplanted cells. Using single-cell RNA sequencing of SC-islets before and after transplantation into diabetic mice, we identified 5,867 genes that were differentially expressed in SC-β cells. Genes and gene sets associated with β cell maturation were much more highly expressed after SC-β cell transplantation, including INS, MAFA, G6PC2, and UCN3 now matching primary β cells. SC-β cells had substantially reduced expression of the non-β cell hormone genes GCG and SST along with other off-target or immaturity genes, including ALDH1A1 and CRYBA2. Overall, the transcriptome of transplanted SC-β cells matured to closely resemble that of primary β cells from 3 donors. Single-cell analysis revealed that not only SC-β cells but also SC-α cells underwent drastic transcriptional changes to more closely resemble primary α cells. Similar results were observed with hESC- and hiPSC-derived islet organoids. This study provides an extensive indexing of transcriptional maturation of SC-islets through transplantation and serves as an important resource to understanding maturation of differentiated cell types to enable improved protocols for generating replacement cells.

Disclosure

P. Augsornworawat: None. K.G. Maxwell: None. J.R. Millman: Employee; Spouse/Partner; Acera Surgical, Inc. Other Relationship; Self; Harvard University, Washington University.

Funding

National Institutes of Health (R01DK114233, T32DK108742); JDRF (5-CDA-2017-391-A-N); Washington University in St. Louis
259-OR: Epigenetic Coregulation of Beta-Cell Function and Survival in Postnatal Life
Authors: DHAWAN SANGEETA , GURLO TATYANA , WANG JEAN K.
Published: June 2020

Both type 1 and type 2 diabetes are caused by inadequate functional beta-cells. Loss of beta-cells in diabetes is preceded by progressive beta-cell failure due to impaired beta-cell function and adaptive capacity, driven by cellular stress. While plenty of evidence suggests that beta-cell function and mass are co-regulated to dictate adaptive capacity, the molecular mechanisms that direct such co-regulation and are disrupted by cellular stress remain unclear. In the present study, we show that the CCCTC binding factor, CTCF is a novel epigenetic regulator of beta-cell functional maturity and mass. CTCF is a zinc finger protein that regulates 3D chromatin architecture and epigenetic stability towards transcriptional regulation, and plays an important role in cell differentiation, self-renewal, and survival. In addition, the levels of CTCF are sensitive to cellular-stress. Our data show that the beta-cell specific CTCF knockout mice (CTCF-BKO) become diabetic by 4-5 months of age, due to a progressive loss of beta-cell maturity and viability that mirrors evolving T2D. The CTCF-BKO mice have impaired glucose stimulated insulin secretion (GSIS), with metabolic, epigenetic, and gene expression profiles that resemble functionally immature neonatal beta-cells, around 1-2 months of age. This is followed by progressive loss of beta-cell mass due to p53 dependent apoptosis. In addition, mice with haplo-insufficiency of CTCF in their beta-cells display impaired GSIS and a deficit in the adaptive beta-cell expansion in response to high-fat diet challenge. Finally, we show that the CTCF program is disrupted in islets of diabetic mice. Taken together, these studies provide a novel insight into the epigenetic regulation of functional beta-cell mass and adaptive capacity in postnatal life.

Disclosure

S. Dhawan: None. T. Gurlo: None. J.K. Wang: None.
264-OR: Characterizing the Distinct Glycemic Patterns Of Postbariatric Hypoglycemia (PBH)
Authors: LEE DANIEL , DREYFUSS JONATHAN , MULLA CHRISTOPHER M. ,   MARY-ELIZABETH PATTI
Published: June 2020

While bariatric surgery can promote remission of type 2 diabetes (T2D), it can also result in severe hypoglycemia, termed post-bariatric hypoglycemia (PBH). Hypoglycemia is most often recognized after meals, but also can occur after activity or during mid-nocturnal hours and can yield unawareness and disabling neuroglycopenia.

We used blinded CGM (Dexcom G4) to characterize glycemia, glycemic variability (GV), and severity and length of hypoglycemia in patients with PBH with prior roux-en-Y gastric bypass (PBH, n=40). We compared results to those of individuals with reactive hypoglycemia with no prior GI surgery (Hypo, no-GS, n=20) and to publicly available Dexcom G4 data from 3 additional groups: healthy controls (HC, n=38), prediabetes (Pre-DM, n=14), and T2D (n=5). Metrics were assessed over 24 hours as well as during daytime (6 AM to midnight) and nighttime (midnight to 6 AM) independently.

Mean and median sensor glucose (SG) were similar for PBH and HC (mean: 99.8±18.6 vs. 96.9±10.2 mg/dL; median: 93.0±14.8 vs. 94.5±7.4 mg/dL, p>0.05 for both). By contrast, PBH had higher coefficient of variation (27.3±6.8 vs. 17.9±2.4%, p<0.0001) and a wider range and IQR of SG values (range: 154.5±50.4 vs. 112.0±26.7 mg/dL; IQR: 28.0±7.4 vs. 20.0±4.4, p<0.0001 for both). Nadir SG was lowest in PBH (42.5± 3.7 mg/dL vs. other groups, p<0.0001) with statistical significance vs. HC (49.0±11.9 mg/dL, p=0.0046). PBH had greater percentage of time with SG<70 mg/dL vs. HC (7.7±8.4 vs. 3.2±4.1%, p<0.002); these differences were greater at night (12.6±16.9 vs. 1.0±1.5%, p<0.0001). Also, the frequency of severe hypoglycemic episodes (<54 mg/dL, duration ≥ 15 minutes) per day was higher for PBH group vs. HC (0.5 vs. 0.1, p<0.002).

In summary, patients with PBH experience higher GV and greater severity and frequency of hypoglycemia compared to HC, especially at night. Future studies should explore the potential of CGM technology in assisting PBH patients to recognize early hypoglycemia and prevent severe hypoglycemia.

Disclosure

D. Lee: None. J. Dreyfuss: None. C.M. Mulla: None. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate.

Funding

National Institutes of Health (R01DK121995); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007260)
266-OR: Rebound Hyperglycemia in Real-World Data and Its Mitigation with a CGM-Based Predictive Alert
Authors: ACCIAROLI GIADA , PARKER ANDREW , WELSH JOHN , PUHR SARAH , WALKER TOMAS C. , AKTURK HALIS K.
Published: June 2020

Symptomatic hypoglycemia is an incentive for carbohydrate intake which, in excess, can lead to rebound hyperglycemia (RH) and contribute to high glycemic variability. We examined whether an optional "urgent low soon" (ULS) alert triggered by impending hypoglycemia could mitigate RH in the real world. Sensor glucose values (SGVs) were from the G5 and G6 continuous glucose monitoring (CGM) systems (Dexcom). G5 does not offer the ULS feature; all G6 usage was with the ULS alert enabled. An RH event was defined as any series of SGVs >180 mg/dL preceded within 2 hours by a low SGV (<70 or <55 mg/dL). Event severity was defined as the area under the curve (AUC) for consecutive SGVs >180 mg/dL. Data from a convenience sample of 24,518 anonymized G5 users who transitioned to G6 and uploaded ≥30 days of data from each system in 2018 were analyzed. RH events preceded by an SGV <70 mg/dL and those preceded by an SGV <55 mg/dL were analyzed separately. For both types of RH events, the transition from G5 to G6 and its predictive alert was associated with favorable and statistically significant reductions in the mean (SD) frequency, severity, and duration RH events (Table). The ULS alert in the G6 CGM system, intended to reduce hypoglycemia, mitigates RH events in users who transition from a system without predictive alerts and may contribute to other metrics of improved glycemic control.

Disclosure

G. Acciaroli: Employee; Self; Dexcom, Inc. A. Parker: Employee; Self; Dexcom, Inc. Stock/Shareholder; Self; Dexcom, Inc. J. Welsh: Employee; Self; CSL Behring. S. Puhr: Employee; Self; Dexcom, Inc. T.C. Walker: Employee; Self; Dexcom, Inc. H.K. Akturk: Advisory Panel; Self; Sanofi US. Research Support; Self; Eli Lilly and Company, REMD Biotherapeutics, Senseonics.
270-OR: Nocturnal Hypoglycemia with Insulin Degludec and Glargine U100 in Patients with Type 1 Diabetes Prone to Severe Nocturnal Hypoglycemia (HypoDeg): A CGM Substudy
Authors: BRØSEN JULIE M. , AGESEN RIKKE M. , ALIBEGOVIC AMRA CIRIC , ANDERSEN HENRIK U. , GUSTENHOFF PETER , HANSEN TROELS K. , JENSEN TONNY , JUHL CLAUS B. , LERCHE SUSANNE , NØRGAARD KIRSTEN , PARVING HANS-HENRIK D. , TARNOW LISE , THORSTEINSSON BIRGER , PEDERSEN-BJERGAARD ULRIK
Published: June 2020

Background and Aims: Nocturnal hypoglycemia is a major source of concern of people with type 1 diabetes (T1D) and may result in suboptimal glycemic control due to avoidance behavior. Optimal basal insulin therapy may reduce nocturnal hypoglycemia. Insulin degludec is associated with lower risk of nocturnal hypoglycemia in T1D. However, it has not been studied in people specifically prone to severe nocturnal hypoglycemia. We report frequencies of CGM-recorded nocturnal non-severe hypoglycemia (NSH) from the HypoDeg trial, which compared insulin degludec with insulin glargine in people with T1D and previous severe nocturnal hypoglycemia.

Materials and Methods: Seventy-four people completed 4 x 6 days of blinded CGM (Medtronic iPro) during a 2-year randomized cross-over study. CGM traces were reviewed for clinically important hypoglycemic events ≤ 3.0 mmol/L according to current international consensus.

Results: When defining night-time from 23-06:59 a total of 193 episodes of nocturnal NSH were found at the glucose threshold ≤ 3.0 mmol/L. A 53% (95% confidence interval [CI] 35%-64%; p<0.001) relative risk reduction (RRR) in nocturnal NSH during treatment with insulin degludec (0.6 episodes/person-week) was observed as compared to insulin glargine (1.3 episodes/person-week). The reduction in nocturnal NSH was mainly due to a 52% (95%[CI]:32-70%; p<0.001) RRR in nocturnal asymptomatic hypoglycemia with insulin degludec (0.4 episodes/person-week) as compared to insulin glargine (0.9 episodes/person-week). Similar results were found when defining night-time from 00-05:59.

Conclusion: People with T1D prone to nocturnal severe hypoglycemia have lower rates of CGM-recorded nocturnal hypoglycemia with insulin degludec as compared to insulin glargine.

Disclosure

J.M. Brøsen: None. R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S.
28-LB: Improved Time in Glucose Range over One Year Is Associated with Reduced Albuminuria in Sensor-Augmented Insulin Pump–Treated Type 1 Diabetes
Authors: RANJAN AJENTHEN , ROSENLUND SIGNE , HANSEN TINE W. , ROSSING PETER , ANDERSEN STEEN , NØRGAARD KIRSTEN
Published: June 2020

Objective: To investigate the association between treatment induced change in continuous glucose monitored (CGM) time in range (TIR) and microalbuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented pumps (SAP).

Methods: In an open labelled controlled trial, 60 participants with T1D treated with multiple daily injections (MDI) and history of albuminuria were randomised to MDI- or SAP-therapy for 1 year. During the study, the SAP group wore a CGM (Enlite®, Medtronic). The MDI group wore blinded CGMs (Ipro2®, Medtronic) for 6 days at baseline and study end. Anthropometrics, CGM data, blood and urine samples were collected at 0, 1, 3, 6, 9, and 12-month visits. Based on CGM data collected between each visit, the percentage of time spent within 3.9-10.0 mmol/l (%TIR) was calculated. Urine albumin creatinine ratio (UACR) was measured in 3 samples at all visits. Only CGM data for the SAP group were included in the analysis. A linear mixed model with a participant-specific random intercept was used to analyse the effect of %TIR during 1 year after start of SAP on UACR, adjusting for changes in mean arterial pressure (MAP), HbA1c and body mass index.

Results: Twenty-six participants were assigned to the SAP group and had a baseline median (interquartile range) age of 51.5 (45.9; 62.1) years, HbA1c of 66 (58; 77) mmol/mol, UACR of 78.8 (37; 205) mg/g and 51Cr-EDTA-GFR 85.0 (73.0; 96.5) ml/min/1.73m2. From baseline to study end, the mean improvement (95% CI) in %TIR was 11.3 (6.0; 16.6) %, HbA1C was -14.4 (-17.5; -11.2) mmol/mol and UACR was -13 (-33; -22) %; all p<0.001. HbA1c decreased with 4.7 mmol/mol per 10% increase in %TIR (p<0.001). The UACR decreased with 13% per 10% increase in %TIR (p=0.038), with 15% per 10 mmol/mol decrease in HbA1c (p=0.071), and with 31 % per 10 mmHg decrease in MAP (p<0.001).

Conclusion: In this longitudinal study, treatment induced increase in CGM-derived %TIR were significantly associated with decrease in albuminuria in T1D.

Disclosure

A. Ranjan: None. S. Rosenlund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. T.W. Hansen: None. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. S. Andersen: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc.

Funding

Novo Nordisk Foundation (NNF17SA0031406); Medtronic A/S
285-OR: Long-Term HbA1c Trajectories and Mortality and Major Atherosclerotic Cardiovascular Events (MACE) in Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , COSTACOU TINA , ORCHARD TREVOR J.
Published: June 2020

While poor glycemic control is a well-established risk factor for mortality and MACE in T1D, specific patterns of control over time have not been well-studied. Thus, we sought to identify long-term trajectories of HbA1c and examine associated participant characteristics, mortality, and MACE incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a prospective observational cohort with childhood-onset (<17 years) T1D. These data were analyzed as part of a DNA methylation sub-study (currently in progress), where n=422 (baseline mean T1D duration 21 yrs, 53% male) have been followed for outcomes, including 28-year mortality and MACE. Beginning in 1988, HbA1c was measured at baseline, 2, 4, 6, 8, 15, and 22 yrs. HbA1c trajectories were identified using latent class growth modeling. Five HbA1c trajectories were identified (Figure). There were no significant differences in age, T1D duration, age at T1D onset, sex, education, or insulin dose between groups. Both mortality and MACE were significantly increased in IMPROVED (p<0.02) and even more so in HIGH (p<.0001) compared to LOW. MODERATE and WORSENED did not have increased risk of either outcome compared to LOW. These results demonstrate that, despite improvement, past high HbA1c remains associated with increased long-term mortality and MACE risk in this T1D cohort.

Disclosure

R.G. Miller: None. T. Costacou: None. T.J. Orchard: None.

Funding

American Diabetes Association (1-19-JDF-109 to R.G.M.)
29-OR: Comparison of Empagliflozin and Sitagliptin on Ectopic Fat Accumulation and Tissue-Specific Insulin Sensitivity
Authors: HIRUMA SHIGENORI , SHIGIYAMA FUMIKA , HISATAKE SHINJI , MIZUMURA SUNAO , SHIRAGA NOBUYUKI , HORI MASAAKI , IKEDA TAKANORI , HIROSE TAKAHISA , KUMASHIRO NAOKI
Published: June 2020

Background: Ectopic fat accumulation is the major pathogenesis of insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. To date, no prospective study compared the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific insulin sensitivity.

Methods: This is the prospective, randomized, open-label, and blind-endpoint study in 44 Japanese patients with T2DM. Patients (HbA1c: 7.2±0.9%, known duration: 3.9±4.0 years, BMI: 29.1±4.8 kg/m2) were randomized to empagliflozin (Empa) add-on group or sitagliptin (Sita) add-on group, and treated for 12 weeks. The primary endpoint was the change of pericardial fat content estimated by magnetic resonance imaging. The secondary endpoints were the changes in the amount of intrahepatic, intra- and extra-myocellular lipid content estimated by proton magnetic resonance spectroscopy, and tissue-specific insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp tests using stable isotope.

Results: There was no difference in pericardial fat content between the groups. Interestingly, intrahepatic lipid content (IHL) was reduced significantly from baseline in Empa group compared to Sita (-23.0±26.3 vs. -3.9±19.8%, respectively, p<0.05). However, the change in clamped % suppression of endogenous glucose production was comparable between the groups. On the other hand, rate of glucose disappearance was significantly increased in Empa group compared to Sita (+18.5±55.2 vs. -8.6±20.2%, p<0.05), while the amount of intra- and extra-myocellular lipid content remained similar between the groups.

Conclusion: This is the first study that compared Empa and Sita on ectopic fat content and tissue-specific insulin sensitivity. Empa significantly reduced IHL and increased insulin sensitivity in muscle compared to Sita. SGLT2i might be preferable in treatment of T2DM with hepatic steatosis.

Disclosure

S. Hiruma: None. F. Shigiyama: None. S. Hisatake: None. S. Mizumura: None. N. Shiraga: None. M. Hori: None. T. Ikeda: None. T. Hirose: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd. N. Kumashiro: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding

Nippon Boehringer Ingelheim Co., Ltd. (1245-0162)
292-OR: Treg Cells Control Systemic Lipid and Iron Metabolism via the OGT-STAT5 Axis
Authors: SALGADO BARRERO OSCAR C. , RUAN HAI-BIN
Published: June 2020

Adipose tissue-resident regulatory T (Treg) cells have been proposed to exert metabolic roles in controlling inflammation, insulin sensitivity and thermogenesis. However, it is still largely unclear how Treg cells integrate immunological and metabolic signals to maintain systemic energy balance. Here we show that the glucose-sensitive O-linked N-Acetylglucosamine (O-GlcNAc) post-translational modification in Treg cells is activated by T cell receptor signaling. Through modifying the STAT5 protein and IL-2 signaling, protein O-GlcNAcylation supports the lineage stability and effector function of Treg cells, while loss of O-GlcNAc transferase (OGT) in Treg cells leads to systemic inflammation in mice. When fed with high fat diet, heterozygous Foxp3-OGT knockout females gain more fat mass as a result of reduced energy expenditure. On the other hand, constitutively active STAT5-mediated Treg-cell expansion and activation protect mice from diet-induced obesity and glucose intolerance. Mechanistically, Treg cells inhibit fatty acid uptake and regulate iron cycling in the adipose tissue. Taken together, we propose that the OGT-STAT5 axis enables Treg cells to maintain systemic lipid and iron homeostasis.

Disclosure

O.C. Salgado Barrero: None. H. Ruan: None.

Funding

American Diabetes Association (1-18-IBS-167 to H-B.R.); National Institutes of Health (R01AI139420)
293-OR: Mitochondrial Hexokinase Dissociation Correlates with Obesity-Induced Inflammation and Regulates the Fate of Glucose
Authors: NEJAD FARNAZ KEYHANI , DEJESUS ADAM , GEIER JUSTIN A. , ARDEHALI HOSSEIN
Published: June 2020

It has been shown that high fat diet (HFD) induced obesity triggers local immune cell infiltration leading to pro-inflammatory cytokine production and subsequently to a state of chronic low-grade inflammation in adipose and spleen tissues. However, the underlying mechanisms driving this chronic inflammation remains poorly defined. The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis to produce ATP and pyruvate or alternative pathways, such as the pentose-phosphate-pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal domain that permits mitochondrial binding, but its physiologic significance is unclear. We found that adipose and spleen tissues from HFD mice had increased cytosolic HK1, which correlated with an increase in inflammatory cytokine mRNA levels. To elucidate whether HK1 subcellular localization to the mitochondria affects the inflammatory response we generated mice lacking the HK1 mitochondrial binding domain, termed ΔE1HK1. These mice appear normal and show no change in body weight, Mendelian ratios, glucose tolerance or hexokinase activity across different tissues as compared to littermate controls. However, lipopolysaccharide challenge in these mice produced a hyper-inflammatory phenotype in vitro and in vivo. We performed steady-state and flux metabolomics in ΔE1HK1 mouse tissues and found increased glucose derived metabolites above the level of GAPDH, including PPP metabolites. Additionally, we found that GAPDH activity was attenuated in the ΔE1HK1 mice and may explain the elevated PPP flux upstream of GAPDH. Since PPP is vital for proper inflammatory cell activation, we treated cells from these mice with PPP inhibitors and found a reversal of the hyper-inflammatory phenotype observed in ΔE1HK1 mice. Our data suggests that mitochondrial dissociation of HK1 alters glucose utilization, which subsequently increases the pro-inflammatory response.

Disclosure

F. Keyhani Nejad: None. A. DeJesus: None. J.A. Geier: None. H. Ardehali: None.