bluuebunny/crossref_metadata_2025 huggingface dataset:
1090-P: Diabetes in Japanese COVID-19 Patients as the Primary Factor of Accelerated Progression to Severe State
Authors: KANEKO SHIZUKA , KITA HIDEO , MOTOHASHI KAZUYA , TOKUMOTO SHINSUKE , YOKO UEBA , EGUCHI HIDEKI , TSUNEMATSU ICHIRO
Published: June 2021

During the COVID-19 pandemic, Japanese victims number less than in other countries, perhaps due to gene specifics, aspects of Japanese lifestyle and coagulation system characteristics typically less potent in Japanese than in Caucasians. The Osaka prefectural government stratified patients into mild, moderate and severe, distributing them amongst various alternative accommodation to relieve overburdened hospitals. Hospitalized patients were managed based on national government guidelines. Focusing on moderate patients, i.e., whose oxygen saturation levels were favorable even if presenting characteristics in computed tomography, we conducted a retrospective analysis in type 2 diabetes (T2D) patients compared with a control. Of a study total of 102 patients (male 51%, aged 62.2±16.0, BMI 27.6±5.2), 49% were T2D patients (aged 71.2±13.8, A1c 6.8±1.3%, BMI 24.5±5.2). Twenty-five patients (24.5%) moved to the severe classification. Eighteen patients (17.6%) (aged 74.8±8.6, A1c 6.9±1.0%, BMI 24.3±2.5), of whom 88.9% had T2D (aged 76.1±10.2, A1c 6.7±1.1%, BMI 23.8±10.2), were ventilated and transferred to another hospital for advanced treatment. Seven patients (6.9%), of whom 71.4% had T2D, died (aged 85±3.4) after ventilation was declined by the families due to advanced age and dementia. One scleroderma patient on home oxygen therapy for intestinal pneumonia died of sudden respiratory failure. Twenty-five diabetes patients (24.5%) improved. No significant correlation exists between hypertension, body mass index, lung disease, renal failure and receiving insulin therapy. In our study, 88% of moderate patients moving to the severe classification had T2D. In Japanese, diabetes may constitute a much larger risk factor than those factors identified in other countries in the evolution of COVID-19 patients from the moderate to severe classifications. A more comprehensive study is needed. BMI: body mass index, A1c: hemoglobin A1c.

Disclosure

S. Kaneko: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Novo Nordisk Pharma Ltd., Research Support; Self; Eli Lilly Japan K. K., Novo Nordisk Pharma Ltd., Speaker’s Bureau; Self; AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sumitomo Dainippon Pharma Co., Ltd. H. Kita: None. K. Motohashi: None. S. Tokumoto: None. U. Yoko: None. H. Eguchi: None. I. Tsunematsu: None.
1096-P: Analysis of Medication Use in Type 2 Diabetes Mellitus in Korea Using a Common Data Model Based on the Claim Data of the Health Insurance Review and Assessment Service
Authors: LEE KYUNG AE , JIN HEUNG YONG , KIM YU JI , PARK TAE SUN
Published: June 2021

Observational Health Data Sciences and Informatics is an international collaboration created an international data network of researchers (Observational Medical Outcomes Partnership Common Data Model, OMOP-CDM). This retrospective, observational study was aim to analyze treatment patterns of type 2 diabetes mellitus (T2DM) using HIRA national patient sample (NPS) from 2012 to 2017 transformed into OMOP-CDM. ATLAS ver. 2.7.6, an OHDSI’s open-source software is publicly available, was used for analysis. HIRA-NPS contain about 1.4 million patients. The proportion of adult patients treated for T2DM increased from 78,581 (5.5%) in 2012 to 101,710 (7.0%) in 2017. Ages 50-69 were the most common (47.7% in 2017), and T2DM was most noticeably increased from 28.7% to 44.9% among those aged 70 and over for 5 years. Metformin was the most prescribed drug (82.8%) followed by sulfornylurea (SU) (62.4%), DPP-4 inhibitor (29.5%) in 2012. In 2017, metformin was still the most prescribed (87.0%), and DPP-4 inhibitor prescription increased rapidly up to 62.7%, while the SU prescription rate decreased to 46.5%. Prescription of the most recently approved SGLT2 inhibitors also continued to increase, reaching 7.2% in 2017. The rate of insulin prescription decreased from 20.2% to 17.5%. Over time, mono and dual therapy decreased while triple and quadruple combinations steadily increased. Dual combination was the most common with metformin and DPP-4 inhibitor, triple combination was the most with metformin, SU, and DPP-4 inhibitor in 2017. Drug prescriptions for hypertension remained unchanged from 71.2% in 2012 to 70.0% in 2017, while prescriptions for dyslipidemia increased from 50.7% in 2012 to 68.4% in 2017. Antiplatelet drugs prescriptions decreased slightly from 47.3% to 42.6%. T2DM is constantly increasing, and medication utilization patterns have changed significantly over the past 5 years with a shift towards newer drugs.

Disclosure

K. Lee: None. H. Jin: None. Y. Kim: None. T. Park: None.
1100-P: A Four-Humanitarian Agency Survey of Diabetes Care in 83 Humanitarian Settings
Authors: KEHLENBRINK SYLVIA , MAHBOOB OMAR , AL-ZUBI SARA A. , BOULLE PHILIPPA , PERONE SIGIRIYA AEBISCHER , KIAPI LILIAN , ALANI AHMAD H. , HERING HEIKO , WOODMAN MICHAEL , KAYDEN STEPHANIE , DONELAN KAREN , PORNEALA BIANCA , MEIGS JAMES B.
Published: June 2021

Background: We are currently facing unprecedented humanitarian crises. With diabetes at record-high levels and projected increases in humanitarian crises globally, data on the burden and management of DM in humanitarian crises is needed to stop unnecessary disability and death.

Methods: We surveyed data on diabetes care provision in humanitarian medical services in 2018 across 4 humanitarian agencies (Doctors Without Borders, International Committee of the Red Cross, International Rescue Committee, United Nations High Commissioner for Refugees) with 83 randomly selected sites across 27 countries in 5 global regions. Of 83 sites, 65 (78%) reported collecting DM care data and were used for cross-sectional analysis of rates and proportions.

Results: Of 65 sites, most were in the Eastern Mediterranean (n=29, 45%) and Africa (35%), with 20% elsewhere; 34% were refugee camps, 34% rural non-camp sites, 21% urban non-camp sites, 11% internally displaced persons (IDP) camps. Populations were mostly a mix of refugees, IDPs and the general population (n=46/65, 71%), with refugees only at 23% and IDPs only at 6% of sites. Of 65 sites, 58 were affected by conflict (89%), 5% epidemics, 1% natural disasters and 5% multiple crisis types. Most sites (n=49) were in protracted crises (75%), with 23% in recovery stages and 2% in acute crisis. Of 65 sites, 46 (71%) reported providing clinical DM management. However, only 66% had insulin available, 71% had capillary glucose testing, 55% urine dipstick glucose, 19% hemoglobin A1c testing, 22% home glucose monitoring, 35% community outreach, 58% patient education, 32% training of staff and 52% continuity of care systems.

Conclusions: DM services were mostly provided in protracted humanitarian settings. Services were widespread but often rudimentary and delivered to the general population as well as refugees and IDPs. Improving DM care for crisis-affected populations is urgently needed.

Disclosure

S. Kehlenbrink: None. S. Kayden: None. K. Donelan: None. B. Porneala: None. J. B. Meigs: Consultant; Self; Quest Diagnostics. O. Mahboob: None. S. A. Al-zubi: None. P. Boulle: None. S. Aebischer perone: None. L. Kiapi: None. A. H. Alani: None. H. Hering: None. M. Woodman: None.
1107-P: Trends of First-Line Antidiabetic Treatment among 2007-2017 Medicare Beneficiaries Newly Diagnosed with Type 2 Diabetes (T2D) and Their Determinants
Authors: LI YUJIA , HERNANDEZ INMACULADA , GABRIEL NICO , KANE-GILL SANDRA L. , ESSIEN UTIBE , TOLEDO FREDERICO , GUO JINGCHUAN
Published: June 2021

Background: Guidelines recommend initiating metformin at the time of T2D diagnosis in the absence of contraindications for asymptomatic patients. However, the evidence is scarce regarding real-world patterns and factors associated with antidiabetic treatment initiation in patients with newly diagnosed T2D.

Methods: We used a 5% random sample of Medicare beneficiaries newly diagnosed with T2D in 2007-2017 and followed them for one year. The outcome was time to initiation of an antidiabetic agent within the first year of diagnosis. We examined trends in the proportion of outcome and the therapeutic class initiated by year. We constructed Cox Proportional Hazard models to identify factors associated with treatment initiation.

Results: Of 231,408 patients newly diagnosed with T2D, the mean age was 71.7, and 62.2% were female. Only 13.7% initiated an antidiabetic agent within the first year of diagnosis. Although the proportion of initiation within one year of T2D diagnosis was relatively constant over time (12.7% in 2007 to 15.4% in 2017), the mean time to initiation decreased from 74.1 days in 2007 to 21.7 days in 2017 (p<0.05). Of those who initiated treatment, 54.2% and 21.5% initiated metformin and sulfonylurea in 2007, while 84.4% and 6.0% initiated metformin and sulfonylurea in 2017, respectively. In the adjusted model, age (HR 0.92, 95%CI 0.91-0.93 for 10-year increase), female sex (HR 0.89, 95%CI 0.87-0.91), number of comorbidities (HR 0.86, 95%CI 0.86-0.87 for one additional) and residence in urban areas (HR 0.78, 95%CI 0.76-0.80) were associated with decreased hazards of antidiabetic initiation.

Conclusion: We found unexpectedly low rates of initiation of first-line treatment among Medicare beneficiaries with newly diagnosed T2D. The changes in the proportion of different drug classes reflect the change in guideline recommendations. Further investigation is needed to understand the causes underlying the low initiation.

Disclosure

Y. Li: None. I. Hernandez: Consultant; Self; Bristol-Myers Squibb Company, Pfizer Inc. N. Gabriel: None. S. L. Kane-gill: None. U. Essien: None. F. Toledo: Consultant; Self; AstraZeneca. J. Guo: None.
1111-P: Integrating Longitudinal Clinical and Baseline Multiomics Data for Predicting C-Peptide Progression in Newly Diagnosed Type 1 Diabetes
Authors: BRORSSON CAROLINE , ARMENTEROS JOSE JUAN ALMAGRO , MAZZONI GIANLUCA , KAUR SIMRANJEET , SCHULTE ANKE M. , MATHIEU CHANTAL , BRUNAK SØREN ,   ON BEHALF OF THE INNODIA CONSORTIUM
Published: June 2021

Background: Development of disease-modifying therapy for type 1 diabetes (T1D) is hampered by the limited understanding of pathogenesis, heterogeneity, lack of disease biomarkers and stratifiers. Using the INNODIA consortium pan-European infrastructure to collect prospective clinical data from newly diagnosed subjects combined with multi-omics data, we mined integrated datasets using deep learning to identify novel relationships that could transform the disease monitoring landscape.

Method: Samples collected <6 weeks from diagnosis from 100 islet autoantibody positive participants were prioritised for omics analysis and the data integrated with clinical parameters and C-peptide (CP) from mixed meal tolerance tests (at 3, 6 and 12 months). SNP array data, plasma metabolomics, lipidomics and miRNAs, serum proteomics, whole blood RNA-sequencing and multiFACS immunomics from PBMCs were collected. We applied a variational autoencoder (VAE) to simultaneously integrate the data and learn CP progression over 12 months. The latent (lower dimensional) representation of the VAE integrated data was clustered to identify clinically meaningful subgroups.

Results: Clustering identified five age-independent subgroups with significantly different progression patterns (p<0.05). Cluster 1 and 3 associated with lower fasted and stimulated CP. Cluster 2 and 5 associated with higher fasted CP, while cluster 4 most strongly associated with higher stimulated CP. Cluster 1 had the lowest stimulated CP at baseline, cluster 5 the lowest fasted CP and cluster 4 the highest fasted and stimulated CP at baseline. Investigation of the most predictive signals from the omics data is ongoing.

Discussion: The preliminary results suggest that the VAE can learn meaningful progression patterns from integrated clinical and multi-omics data, which holds great promise to uncover important data structures not readily discovered when analyzing single data types.

Disclosure

C. Brorsson: Employee; Spouse/Partner; Novo Nordisk A/S. J. Almagro armenteros: None. G. Mazzoni: Employee; Self; Novo Nordisk A/S. S. Kaur: None. A. M. Schulte: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S, Stock/Shareholder; Self; Hoba Therapeutics Aps, Novo Nordisk A/S. On behalf of the innodia consortium: n/a.

Funding

INNODIA (115797)
1129-P: The Genetic Architecture of Cardiovascular Disease in Individuals with Type 2 Diabetes
Authors: RICHARD ERIN L. , CAO STEVEN , SHADYAB ALADDIN , SALEM RANY
Published: June 2021

Background: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease including coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD). However, the genetic underpinnings of cardiovascular disease in those with T2DM is not well understood.

Methods: Using 15 studies from dbGaP and the UK Biobank, we conducted the largest to date genome-wide association studies (GWAS) for CHD, stroke and PVD in up to 61,880 individuals with T2DM including 47,140 of European, 8,891 of African, 2,622 of Hispanic, 2,120 of South Asian and 1,107 of East Asian ancestry. GWAS were combined via ancestry-specific and transethnic meta-analyses with fixed-effects. Additional transethnic analysis with MR-MEGA was conducted to account for heterogeneity in allelic effects correlated with ancestry.

Results: We replicated previously reported CHD associated loci at genome-wide significance (GW, p≤5×10-8) including 9p21, LPA, and PSRC1. Combining our results with those of prior CHD GWAS in T2DM revealed additional GW significant signals in known CHD loci: PHACTR1, ADAMTS7, HHIPL1, and LPL. European ancestry specific analysis confirmed prior GW significant associations between LPA and PHACTR1 loci and PVD. MR-MEGA analysis of PVD identified novel GW significant loci in CNST and AVPI1. We found a significant genetic correlation of 0.74 (SE= .27) between CHD and PVD. Transethnic analysis of stroke GWAS yielded no GW significant loci. However, African ancestry specific analysis yielded two novel GW signals in the NKAIN2 and BRF1 loci. A significant association between interleukin-6 signaling and stroke was identified using pathway analysis.

Conclusions: Ancestry-specific and transethnic analysis of cardiovascular disease in T2DM confirmed prior CHD GWAS findings and revealed novel associations with PVD and stroke that warrant further investigation.

Disclosure

E. L. Richard: None. S. Cao: None. A. Shadyab: None. R. Salem: None.

Funding

National Institutes of Health
1138-P: Diabetes Induced by Immunotherapy
Authors: VY DUCHDA
Published: June 2021

Introduction: Immunotherapy in the field of oncology consists of administering substances that stimulate the immune system involved in its recognition and destruction of the tumor, on the other hand it gives side effects including diabetes.

Observation: After 29 injections of Pembrolizumab to treat his pulmonary adenocarcinoma, a 62-years old man was hospitalized with inaugural diabetic ketoacidosis with plasma glucose 5.47g and pH 7.07 in blood gas. The dosage of the C peptide is low, the antibodies specific for autoimmune diabetes were negatives at the time of diagnosis. HLA DR3/DQ2 study reveals a predisposition to autoimmune type 1 diabetes. Basal-bolus insulin therapy was started with a correct balance of diabetes.

Discussion: Diabetes induced by anti-PD1 immunotherapy is more common in patients older than 50 years and shown between one month and nineteen months after starting treatment. The reason for hospitalization is always diabetic ketoacidosis with very high plasma blood glucose levels and deep insulinopenia. The HLA studying of patients shown a predisposition to autoimmune diabetes.

Conclusion: The management of diabetes induced by immunotherapy requires consultation between the endocrinologist and the oncologist. Patient education with the initial assessment diabetes are essential before and during treatment with immunotherapy. An initial assessment (the fasting blood glucose, HbA1c) routinely before starting anti-PD1 therapy and determination of fasting blood glucose before each course of treatment, once a month during the first three months then every three months or urgently if clinical signs are present suggestive of diabetes. In addition, insulin therapy should start immediately in case of diagnosis is made.

Disclosure

D. Vy: None.
114-OR: Overexpression of Alpha-1 Antitrypsin in MSCs Delays Onset of Type 1 Diabetes in the NOD Mice by Increasing Their Antiinflammatory and Protection Functions
Authors: WEI HUA , GOU WENYU , STRANGE CHARLIE , WANG HONGJUN
Published: June 2021

We have shown that overexpression of human alpha-1 antitrypsin (hAAT) in mesenchymal stromal cells (hAAT-MSCs) improves mobility and function of MSCs. In this study we further characterized hAAT MSCs and control MSCs and compared their therapeutic effects in the prevention of type 1 diabetes in the spontaneous non-obese diabetic (NOD) mice. Bone marrow specimens from three individual donors were purchased from StemExpress. Cells were grown to passage 3-4 and infected with hAAT-containing virus for hAAT-overexpression. Single Cell RNAseq was performed by the 10X Genomic System. Proteomic Analysis of exosomes was performed at the MUSC Proteomic Core. MSCs and hAAT-MSCs from one donor were injected into the NOD mice at 8 weeks of age. Mice blood glucose levels were measured twice per week. Cell infiltration into islets was analyzed by H&E staining of pancreatic tissues. Single cell RNAseq analysis showed that hAAT-MSCs and control MSCs have different gene expression signatures, in which hAAT-MSCs showed increased expressions of chemokine (C-X-C motif) ligands (CXCL1, 3, 8), HES5 and others. Exosome proteomic analysis indicates that exosomes from these two types of cells have distinct protein patterns. In hAAT-MSCs cells, platelet degranulation proteins were upregulated and proteins involved in cell-cell adhesion, and cell division were been downregulated. In the NOD mice, a single dose of hAAT-MSCs led to delayed onset of T1D, associated with reduced cell infiltration into the islets. hAAT-MSC therapy showed more profound protection compared to control MSCs. It is likely that overexpression of hAAT enhanced the anti-inflammatory function (via regulating chemokines) promoting the Notch signaling pathway (via regulating HES5) and lead to improved protection in the NOD mice.

Disclosure

H. Wei: None. W. Gou: None. C. Strange: None. H. Wang: None.

Funding

National Institutes of Health (1R01DK105183, DK120394, DK118529); U.S. Department of Veterans Affairs (I01BX004536)
1143-P: ZnT8 Autoantibody Positivity Does Not Predict Pediatric Diabetes Presentation or Subsequent Clinical Course
Authors: DAHL AMANDA R. , JENKINS SARAH , ZBACNIK JADE , FOSTER JESICA , PITTOCK SIOBHAN
Published: June 2021

Introduction: Type 1 diabetes specific autoantibodies are glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence of ZnT8 antibodies(Ab) was predictive of clinical presentation at diagnosis or subsequent disease course.

Methods: Between January 2003 and May 2019, 105 patients aged ≤ 21 years with a clinical diagnosis of T1DM had at least 1 diabetes autoantibody measured. For subjects who had less than 4 autoantibodies analyzed initially, residual serum sample was retrieved, and remaining autoantibodies were analyzed. Retrospective chart review was completed. At diagnosis, we evaluated BMI z-score, HbA1c, and the presence and severity of DKA. Complications recorded post diagnosis included episodes of DKA, diagnosis of autoimmune (AI) disease, and the presence of vascular complications.

Results: Of the 105 patients, 71 were ZnT8(+) (68%). When comparing ZnT8Ab(+) to (-) patients at diagnosis, there was no difference in age (p=0.94), BMI z-score (p=0.83) or presence of DKA (p=0.26). There was no difference in duration of follow up between ZnT8 Ab (+) and (-) groups (p=0.54). Over follow-up, (0.05-15.7 years), there was no difference in rates of DKA episodes (p=0.71). There were no macrovascular complications recorded and no difference in microvascular complications between the 2 groups (p=0.14). There were more AI conditions in the ZnT8Ab(+) group, 77% compared to 23% in ZnT8Ab(-), but this did not reach statistical significance (p=0.12).

Conclusions: Our study, unlike others, suggests that the presence of ZnT8 Ab does not result in a difference in disease course at presentation. This study adds to the literature as it has follow up on patients. Over up to 15 years of follow-up, there is no difference in complications between those with and without ZnT8 Ab’s. This study should be validated with larger numbers and longer follow up.

Disclosure

A. R. Dahl: None. S. Jenkins: None. J. Zbacnik: None. J. Foster: None. S. Pittock: None.
1148-P: Liver Androgen Receptor Knockout Delays the Onset of Diet-Induced Metabolic Dysfunction in Female Mice Compared with Male Mice
Authors: OLIVER TRINITEE R. , OSEI-NTANSAH ADJOA , ANDRISSE STANLEY , LOFTON TAYLOR , FALZARANO CLAIRE
Published: June 2021

Polycystic ovarian syndrome (PCOS) is a hormonal disorder with insulin resistance (IR) and hyperandrogenism (HA) as drivers of the condition. PCOS women have an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Our lab explores NAFLD in PCOS through a mouse model with a liver androgen receptor (AR) knockout (LivARKO). The role of AR in high-fat diet (HFD) induced metabolic disease is not fully understood. We hypothesized that LivARKO would cause dysglycemia in males but protect from dysglycemia in females.

To test the hypothesis, we collected data from mice fed a HFD or a caloric adjusted control diet (CD) over the course of two months. We performed glucose tolerance (GTT), insulin tolerance (ITT), and pyruvate tolerance (PTT) tests.

At 1-month, HFD female LivARKO mice displayed no difference in glucose tolerance compared to CD LivARKO female mice, suggesting that at one month LivARKO is protecting female mice from HFD-induced metabolic dysfunction. HFD male LivARKO mice displayed impaired glucose tolerance (IGT) compared to CD LivARKO mice. Thus, LivARKO was not protective against HFD-induced glucose metabolic dysfunction in male mice. At 2-months, HFD showed IGT compared to Control diet in male and female LivARKO mice, suggesting that LivARKO slowed the progression to metabolic disease in female mice but did not fully stop it. HFD male and female LivARKO mice did not display significant changes in insulin tolerance at 1-month compared to CD mice. HFD male and female LivARKO mice showed impaired pyruvate tolerance starting at 1-month and continuing at 2-months compared to CD LivARKO mice. The impairment was significantly greater in male mice.

In conclusion, we found that it took LivARKO female mice longer to show dysglycemia from HFD than male LivARKO mice. Thus, in females, LivARKO slowed the progression to metabolic disease, but did not fully stop it. The impaired PTT suggests the effects of HFD may alter hepatic gluconeogenic regulation.

Disclosure

T. R. Oliver: None. A. Osei-ntansah: None. S. Andrisse: None. T. Lofton: None. C. Falzarano: None.

Funding

National Science Foundation (HRD-1931045)
1153-P: Sodium-Glucose Cotransporter-2 Inhibitors Increase Food Intake via a Mechanism That Acts on the Central Nervous System Involving Phosphorylation of Adenosine Monophosphate-Activated Protein Kinase in the Lateral Hypothalamus
Authors: TAKEDA KENJI , ONO HIRAKU , OHNO TOMOHIRO , YOKOTE KOUTARO
Published: June 2021

Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake. We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. Bolus ICV SGLT2 inhibitor induced an increase in food intake. Tofogliflozin had the strongest effect among these drugs. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Intraperitoneal administration of liraglutide, a GLP-1 receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin. ICV tofogliflozin increased phosphorylation of AMPK in the lateral hypothalamus.

In conclusion, SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

Disclosure

K. Takeda: None. H. Ono: None. T. Ohno: None. K. Yokote: None.

Funding

Japan Society for the Promotion of Science (15K09398, 18K08502, 20H00524); Japan Agency for Medical Research and Development (17GM5010002H0001, 18GM5010002H0002, 19GM5010002H0003, 20GM5010002H0004)
1154-P: Mediobasal Hypothalamic PACAP Is Essential for Energy Balance by Stimulating Energy Expenditure
Authors: JOHNSON DAVID Q. , BASU RASHMITA , FLAK JONATHAN
Published: June 2021

Body energy homeostatic mechanisms dynamically balance energy expenditure with energy intake, and the brain plays a critical role in this process. While mediobasal hypothalamic (MBH) signaling is essential for natural elevations in energy expenditure, the downstream anatomical mechanisms are not clear at this point. The MBH contains several important nuclei for energy expenditure control, such as the Ventromedial Hypothalamus (VMN). Because VMN-specific expression of pituitary adenylate cyclase-activating polypeptide (PACAP) decreases with both under-nutrition and loss of leptin action, we tested the hypothesis that MBH PACAP controls energy expenditure. To test this hypothesis, we administered local AAVCre injections into Adcyap1flox (gene that encodes for PACAP) mice. While our approach ensured that peripheral PACAP expression was completely intact, AAV injections did spread into nearby hypothalamic regions, resulting in a MBH loss of function (PACAPMBHKO), rather than a purely VMN knockout. However, all mice exhibited a near complete bilateral ablation of PACAP mRNA in the VMN without interfering with PACAP mRNA in nearby populations that highly express PACAP (e.g., preoptic area (POA) and medial amygdala). In both male and female mice, PACAPMBHKO induced obesity and more than a two-fold increase in adipose mass. VO2, expressed as a function of lean mass, was decreased particularly in the first few hours of the dark cycle, when the mice consume food. Because MBH PACAP cells do not directly project to the spinal cord, PACAP must activate a circuit via a downstream site to stimulate energy expenditure. PAC1r cells primarily overlay with VMN, the primary MBH site containing PACAP, projections in the POA and to a lesser extent in the periaqueductal grey and bed nucleus of the stria terminalis. MBH PACAP, as well as associated signaling targets, are critical components to the control of energy balance by activating energy expenditure.

Disclosure

D. Q. Johnson: None. R. Basu: None. J. Flak: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-15 to J.F.); Indiana University
1167-P: Nonalcoholic Fatty Liver Disease, Metabolic Dysfunction Associated Fatty Liver Disease, and Associations with All-Cause and Cause-Specific Mortality
Authors: HUANG QI , ZOU XIANTONG , ZHOU XIANGHAI , JI LINONG
Published: June 2021

The change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) has raised heated discussion. Our study aims to investigate which has closer association with all-cause and cause-specific mortality in a population-based cohort. We investigated the association between fatty liver disease and mortality in 12,480 adults from National Health and Nutrition Examination Survey III with a medium follow-up time of 22.7 years. Characteristics were compared in participants without NAFLD or MAFLD, with only NAFLD, only MAFLD, or both; survival analysis and subgroup analysis were applied. Participants with NAFLD or MAFLD were highly overlapped (Weighted Cohen’s kappa coefficient 0.78). MAFLD increased the risk for total mortality in a greater magnitude than NAFLD (HR: 2.07 [95% CI 1.86, 2.29] vs. 1.48 [1.35, 1.65]) in crude, but the risks were neglectable when metabolic parameters were adjusted. The risk for cardiovascular, neoplasm and diabetes-related mortality was similar between MAFLD and NAFLD. In reference to participants without NAFLD or MAFLD, patients with only NAFLD showed a reduced risk for total (0.48 [0.34, 0.68]) and neoplasm mortality (0.46 [0.24, 0.89]), while participants with only MAFLD was independently associated with enhanced risk for total (1.74 [1.40, 2.15]), neoplasm (1.94 [1.30, 2.90]) and diabetes-related mortality (3.24 [1.05, 9.97]) after adjustment. The risk of MAFLD for overall mortality was consistence between subgroups except for race-ethnicity.

In conclusion, participants with MAFLD or NAFLD were highly concordant. Compared with NAFLD, MAFLD was certified with greater risk in all-cause mortality and similar risk in cause-specific mortality. The new terminology excluded participants with lower mortality risk and included participants with higher risk. Drug development for MAFLD should consider ethnicity difference.

Disclosure

Q. Huang: None. X. Zou: None. X. Zhou: None. L. Ji: None.

Funding

National Key Research and Development Program of China (2016YFC1304901, 2016YFC1305603); National Natural Science Foundation of China (81800515); Beijing Nova Program of Science and Technology (Z191100001119026)
1174-P: Application of NIS4 Technology for Stand-Alone and Sequential Identification of At-Risk NASH or Advanced Fibrosis in Nondiabetic, Prediabetic, and Type 2 Diabetic Patients
Authors: ROSENQUIST CHRISTIAN , HAJJI YACINE , MAGNANENSI JÉRÉMY , STANKOVIC-VALENTIN NICOLAS , HOSMANE SUNEIL , SANYAL ARUN J.
Published: June 2021

Background: Type 2 diabetes (T2D) is an independent risk factor for the development of nonalcoholic steatohepatitis (NASH. However, there is a need for non-invasive tests (NIT) to identify at-risk NASH patients requiring intense lifestyle or clinical intervention.

Aim: The aim of this study was to access clinical performance metrics of NIS4™ either alone or in combination with other NITs in patients characterized as nondiabetic, pre-diabetic and T2D and with either at-risk of NASH (NAS≥4 and F≥2) or advanced fibrosis (F≥3).

Methods: Patients in the RESOLVE-IT DIAG cohort presented with one or more risk factors for NAFLD and had corresponding NIT data: NIS4™ (miR-34a-5p, α2M, YKL-40, HbA1c), Fibrosis-4 (FIB-4), NAFLD activity score (NFS), and FibroScan™ (FS). NIT data were used to simulate different testing strategies to identify patients with at-risk NASH or advanced fibrosis.

Results: The 467 patients were divided into 3 subgroups with 200 (43%) non-T2D, 67 (14%) pre-diabetic and 200 (43%) T2D with a prevalence for at-risk NASH ranging 42-71%, 58-78% and 66-84%, respectively. The corresponding prevalence for advanced fibrosis in the same groups was 18-27%, 34-40%, 42-49%, respectively. Generally, the performance was impacted by variability in sample size and prevalence which mainly affected PPV and NPV. Under these circumstance NIS4™ together with FS or FIB-4 provided a strong overall balanced performance (Acc: 66-82%, Sen: 50-80%, Spe: 58-94%).

Conclusion: In this cohort, the sequential use of NIS4™ together with another blood-based test FIB-4 or an imaging-based FibroScan™ test provided an overall more balanced performance for identification of at-risk NASH or advanced fibrosis for nondiabetic and T2D patients. Therefore, NIS4™ has the potential to be a valuable clinical tool for also identifying diabetic patients at higher risk of negative outcomes.

Disclosure

C. Rosenquist: Employee; Self; GENFIT. Y. Hajji: None. J. Magnanensi: Employee; Self; GENFIT. N. Stankovic-valentin: Employee; Self; GENFIT, Stock/Shareholder; Self; GENFIT. S. Hosmane: Stock/Shareholder; Self; GENFIT, Stock/Shareholder; Spouse/Partner; Vertex Pharmaceuticals Incorporated. A. J. Sanyal: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Akero Therapeutics, Inc., Alnylam Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Genentech, Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Lilly Diabetes, Lipocine Inc., Merck & Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Genetics Center, Siemens Corporation, Other Relationship; Self; AstraZeneca, UpToDate, Stock/Shareholder; Self; GENFIT, HemoShear Therapeutics, LLC, Indalo Therapeutics, Inc., Tiziana Life Sciences plc.
1183-P: Effect of Dairy Consumption and Its Fat Content on Gut Microbiota in Patients with Type 2 Diabetes: A Secondary Analysis of a Randomized Controlled Trial
Authors: TOMAH SHAHEEN , KOSTIC ALEKSANDAR , MITRI JOANNA , WILKINSON JEREMY E. , LI CHENGCHEN , TASABEHJI MHD WAEL , ELDIB AHMED H. , AL-BADRI MARWA , GARDNER HANNAH , HAMDY OSAMA
Published: June 2021

Studies have demonstrated differences in gut microbial characteristics in diseases compared to healthy states. Knowledge of how diet alters the gut microbiome is limited by the lack of dietary interventional studies reporting on gut microbial characterization. We explored whether dairy foods differing in fat content alter the gut microbiota of patients with type 2 diabetes (T2D). We randomized 111 subjects with T2D into 3 groups: high-fat (HF) and low-fat (LF) dairy groups (≥ 3 servings/d of HF and LF dairy, respectively), and a control group (CON) maintained baseline dairy intake. Subjects were evaluated at baseline, 12 wk, and 24 wk. Next generation sequencing was performed using an Illumina NextSeq (2x150 bp, high output mode) in 32 subjects (16 in HF, 5 in LF, and 11 in CON). At 24 wk, featurewise testing revealed a higher Faecalibacterium prausnitzii abundance (MaAsLin2 coefficient = 0.0746, FDR-adjusted p = 0.0034; MaAsLin2 coefficient = 0.0691, FDR-adjusted p = 0.0195; respectively) and a higher Bifidobacterium pseudocatenulatum abundance (MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.0673; MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.1135; respectively) in LF compared to HF and CON in univariable models. Functional analyses revealed 11 significant associations including a lower abundance of UDP-glucose-derived O-antigen building blocks biosynthesis pathway (MaAsLin2 coefficient = –0.0006, FDR-adjusted p = 0.1584) related to lipopolysaccharides (LPS) production in HF compared to CON in a multivariable model and a lower L-methionine biosynthesis III pathway abundance (MaAsLin2 coefficient = –0.0015, FDR-adjusted p = 0.1975) in LF compared to HF in a univariable model.

In conclusion, consumption of ≥ 3 servings/d of LF and HF dairy changed the gut microbiota of patients with T2D compared to CON. Further analysis will reveal whether a decrease in LPS biosynthesis-related pathway in HF influences inflammation.

Disclosure

S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. J. Mitri: Consultant; Self; L-Nutra. J. E. Wilkinson: None. C. Li: None. M. Tasabehji: None. A. H. Eldib: None. M. Al-badri: None. H. Gardner: None.

Funding

National Dairy Council; National Institute of Diabetes and Digestive and Kidney Diseases
1187-P: Time to Take Your Steroids: Circadian Regulation of Glucocorticoid Effects on Muscle Metabolism
Authors: QUATTROCELLI MATTIA , WINTZINGER MICHELLE , RATHBUN RICHARD M.
Published: June 2021

Glucocorticoid steroids are circadian regulators of energy balance and tissue metabolism. Chronic daily intake of synthetic glucocorticoids commonly promotes insulin resistance and metabolic syndrome. In dystrophic mice, we previously showed that frequency of glucocorticoid intake determines their effects on muscle metabolism. We also found that, compared to daily intake, once-weekly intermittent administration of these drugs reduced obesity and metabolic stress biomarkers in persons with muscular dystrophy. In newer experiments, we sought to understand whether the muscle effects of pulsatile glucocorticoids extend to conditions of metabolic stress. We first investigated the muscle-autonomous effects of a single pulse of glucocorticoids. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the steady-state basal metabolism in isolated wildtype muscle. Considering the intrinsic circadian regulation of glucocorticoids, we compared opposite circadian times of drug exposure in muscles isolated at day-time versus night-time of test mice. We found that within 4 hours from ex vivo exposure, prednisone increased the mitochondrial respiratory capacity rate in muscle tissue but, strikingly, only in muscle from the day-time phase. We then restricted in vivo prednisone regimens (intermittent versus daily) to the day-time of mice with dietary obesity, established with 12 weeks of ad libitum high-fat diet (60% kcal from fat). Opposite to daily regimen, intermittent diurnal prednisone promoted strength and mitochondrial oxidation in muscle of obese mice. Moreover, this correlated with partial counteraction of weight accrual and hyperglycemia, while daily prednisone exacerbated dietary obesity.

In summary, our data indicate that circadian time and dosing frequency can upend our current understanding of glucocorticoids and provide a novel strategy to boost nutrient utilization in persons with metabolic stress.

Disclosure

M. Quattrocelli: None. M. Wintzinger: None. R. M. Rathbun: None.

Funding

National Institutes of Health (K01DK121875); Cincinnati Children's Research Foundation
1199-P: The Oncogene MDM2 Induces M1 Macrophage Polarization and Adipose Tissue Inflammation in Obesity
Authors: CHENG KENNETH KING YIP
Published: June 2021

Obesity is characterized by chronic low-grade inflammation that contributes to the pathogenesis of type 2 diabetes. Adipose tissue macrophages predominantly switch to a pro-inflammatory phenotype known as M1 during obesity. The accumulation of pro-inflammatory M macrophages in obese adipose tissue results in the secretion of a cluster of pro-inflammatory cytokines that instigate adipose tissue inflammation and insulin resistance.

Here we discovered that expression of oncoprotein murine double minute 2 (MDM2) was elevated in obese white adipose tissues. Also, MDM2 protein expression was drastically induced in macrophages activated with lipopolysaccharide (LPS) and interferon-γ (IFNγ). Mice with myeloid cells-specific MDM2 haploinsufficiency (Mye-MDM2 KO mice) were generated and subjected to high-fat-diet (HFD) feeding. After 16 weeks of HFD feeding, obesity-induced glucose intolerance and insulin resistance were alleviated in Mye-MDM2 KO mice with reference to their wild type (WT) controls. Systemic inflammation induced by LPS injection was also reduced in Mye-MDM2 KO mice. In vitro, expression of M1 genes induced by LPS and IFNγ were inhibited in bone marrow-derived macrophages with haplodeficiency of MDM2. Similarly, pharmacological inhibition of MDM2 with the small molecule inhibitor Nutlin-3a attenuates pro-inflammatory cytokines secretion by macrophages. Mechanistically, haplodeletion of MDM2 led to decreased expression of glycolytic genes in BMDM during M1 activation.

Taken together, we demonstrated a novel role of MDM2 in regulating glycolysis and M1 macrophage activation in addition to its role as a negative regulator of p53 tumour suppressor protein, suggesting it as a potential therapeutic target for treating type 2 diabetes.

Disclosure

K. Cheng: None.

Funding

Hong Kong General Research Fund (17100717)
120-LB: The Metabolic Effects of Initiation Pitavastatin vs. Rosuvastatin: Twelve Months Real-World Data on Hyperlipidemic Patients with and without Diabetes (DM)
Authors: LYGNOS DIMITRIOS , PAPAZAFIROPOULOU ATHANASIA , SOTERIADES SOTERIS , LOXAS NIKOLAOS D. , XENOU MARIA , ZOUPAS IOANNIS , FOUSTERIS EVANGELOS
Published: June 2021

Introduction & Purpose: Statin treatment is an integral part of cardiovascular prevention. Recent studies have highlighted their potential diabetogenic action, mostly in a dose-dependent mode. Pitavastatin has studies showing that this statin may not follow the above rule. The present retrospective study highlights the metabolic effects of initiating pitavastatin vs. rosuvastatin therapy in diabetic and nondiabetic statin-naive patients.

Materials & Methods: A total of 74 hyperlipidemic patients included: 41 with DM, mean age 62.4 years (23 on Pitavastatin + 18 on Rosuvastatin)33 non-DM, mean age 62.2 years (15 on Pitavastatin + 18 on Rosuvastatin)Biochemical data were extracted from the medical records of the participants after consent.

Results: For the group of patients with DM, we found that those on Pitavastatin showed statistically significant difference in increasing HDL and decreasing total cholesterol, LDL, triglycerides and γGT. Those on Rosuvastatin showed decrease in total cholesterol, LDL, triglycerides without HDL increase. For the group of patients without DM, we found that mean fasting blood glucose was 97.2mg/dl before Rosuvastatin initiation and 104.1mg/dL after 1 year. A statistically significant difference was recorded also in reducing total cholesterol and LDL and increasing γGT. Accordingly, blood glucose was 102 before Pitavastatin initiation and 95.6mg/dL after 1 year. A statistically significant difference was recorded in HDL increase and total cholesterol, LDL, triglycerides, γGT and ALT decrease.

Conclusion: In accordance to prospective studies, this retrospective short term “real world” study highlights the rosuvastatin-induced carbohydrate metabolism disorder and the favorable effects of pitavastatin in glucose metabolism and biochemical liver markers, as well as the beneficial effect on lipid profile, regardless the presence of DM.

Disclosure

D. Lygnos: None. A. Papazafiropoulou: None. S. Soteriades: None. N. D. Loxas: None. M. Xenou: None. I. Zoupas: None. E. Fousteris: None.
1210-P: Subcutaneous-Depot Specific Adiposity Change Is Associated with the Ectopic Fat Depot and Tissue Damage in High-Fat High-Sucrose (HFHS) Fed Fabp4 Cre-ERK2 Knockout Mice
Authors: ISHINODA YUKI , IDO YASUO , NOGUCHI MIDORI , YUMITA YUSUKE , KAGAMI KAZUKI , OSAKI AYUMU , SATOH YASUSHI , ENDO SHOGO , KASUGA AKIRA , ADACHI TAKESHI , KUMAGAI HIROO
Published: June 2021

Previous reports suggested that low subcutaneous adiposity increases the risk of cardiovascular events and diabetes. Mechanisms of depot-specific differences are still unknown. During studying tissue-specific roles of ERK2 (MAPK1), we observed Fabp4Cre mediated adipocyte-specific ERK2 knockout mice (AE2KO) with HFHS diet showed diminished the size of adipocytes in an only subcutaneous depot and increased ectopic fat depot and fibrotic steatohepatitis. The male AE2KO was created by crossing the C57BL/6 background Fabp4-Cre with ERK2flox/flox mouse. ERK2flox/flox Cre- mouse was used as a control. ERK2KO was observed only in white adipose tissues. With a normal diet, AE2KO mice showed no phenotype. HFHS diet started at age 6 weeks for 18 weeks. AE2KO exhibited 18% increase in body weight (n=8 each, p<0.05). Whereas HFHS increased adipose weight, the distribution of adipocyte size showed a significant decrease in subcutaneous depot (30 vs. 60 µm in mode, p<0.05 by 2-way ANOVA, n=8 each), but not in gonadal. RNA-sequence analysis (n=4, each) revealed a significant increase in expression of lipolysis gene (Prkaca, Tshr, and Adcy) and of the genes reported to cause a defect in fat storage (L3mbtl3, Pik3r1). Fasting glucose was increased and the Insulin tolerance test showed no change in plasma glucose in AE2KO compared to control (105% vs. 75% at 60 min, p<0.05, n=8 each). Liver weight increased 1.8-fold (n=8, p<0.05). NAS score increased (6.2 vs. 4.4, p<0.05, n=6) with prominent fibrosis. The increased ectopic fat depot was also observed in skeletal muscle and kidney. Oxygen consumption and RER was not changed. ERK2 knockout in human subcutaneous preadipocyte by Crispr Cas9 decreased adipocyte differentiation by 50%, suggesting an involvement of ERK2 in adipogenesis. These results strongly indicated that ERK2 is involved in subcutaneous depot abnormality which causes ectopic fat depot and organ damage by a high caloric diet.

Disclosure

Y. Ishinoda: None. T. Adachi: None. H. Kumagai: None. Y. Ido: None. M. Noguchi: None. Y. Yumita: None. K. Kagami: None. A. Osaki: None. Y. Satoh: None. S. Endo: None. A. Kasuga: None.