bluuebunny/crossref_metadata_2025 huggingface dataset:
1894-P: Interruption of Glucagon Signaling Increases Pancreas Mass
Authors: DAI CHUNHUA , BRADLEY AMBER , COATE KATIE C. , POFFENBERGER GREG , SPEARS ERICK , WRIGHT JORDAN J. , SHRESTHA SHRISTI , DEAN DANIELLE , BRISSOVA MARCELA , POWERS ALVIN C.
Published: June 2020

Interruption of glucagon signaling by glucagon receptor gene inactivation or treatment with a glucagon receptor blocking monoclonal antibody (GCGR-Ab) stimulates alpha cell proliferation and expansion. Surprisingly, pancreas weight is also increased in mice with GCG gene inactivation. To investigate mechanisms linking glucagon signaling and pancreas size, we treated C57BL/6J mice with GCGR-Ab or a control IgG. Eight weeks of treatment (N=4-15 mice/treatment) increased absolute pancreas weight (0.42±0.013 vs. 0.32±0.008; p<0.0001), pancreas weight normalized to body weight (1.39±0.03% vs. 1.11±0.02%; p<0.0001), and serum levels of 15 amino acids (AA), including glutamine (1.7-4.67 fold, p<0.0001). GCGR-Ab treatment promoted acinar cell proliferation (Ki67+, 0.65±0.14% vs. 0.20±0.03%; p=0.0058), increased acinar cell size (peri-islet region: 438.4±12.77 vs. 341.7±22.05μm2; p=0.0045; peripheral region: 431.1±9.34 vs. 334.2±25μm2, p=0.0055; central region: 437.0±10.45 vs. 338.7±13.6 μm2, p=0.0006), and increased pancreas protein content (248.3±9.84 vs. 194±8.67μg/mg tissue; p=0.0003). By electron microscopy, GCGR-Ab treatment increased acinar cell zymogen granule number (129±9 vs. 49±6; p<0.0001; n=28-37 cells/treatment) and led to acinar cell ER dilatation, but did not induce pancreatitis or alter acinar cell apoptosis or pancreatic macrophage number. Serum cholecystokinin and total glucagon-like peptide-1, trophic hormones linked to exocrine growth, were not changed by GCGR-Ab treatment. GCGR-Ab treatment upregulated mRNA and protein levels of the glutamine transporter, Slc38a3, and increased mTOR-related ribosomal protein S6 phosphorylation in acinar cells. Together, these data indicate that interruption of glucagon signaling increases pancreas mass by inducing acinar cell hyperplasia and hypertrophy and activates protein synthesis and mTOR signaling; whether this is mediated by elevated glutamine or AA levels is not known.

Disclosure

C. Dai: None. A. Bradley: None. K.C. Coate: None. G. Poffenberger: None. E. Spears: None. J.J. Wright: None. S. Shrestha: None. D. Dean: None. M. Brissova: None. A.C. Powers: None.

Funding

National Institutes of Health (DK117147)
19-OR: Glycemic Control Differences between Individuals with Accurately and Inaccurately Provider-Perceived Literacy and Numeracy
Authors: LOGENDRAN RASHECA , CRISTELLO ANGELICA , DUBOIS JULIEN , FRIEDMAN BRANDON S. , MAYER-DAVIS ELIZABETH J.
Published: June 2020

Little is known about provider accuracy in assessing health literacy and numeracy of individuals with diabetes and the effect of incorrect assessment on patient outcomes. We conducted a clinic-based study (121 patients, 12 providers) to explore whether there was a discrepancy between patient-actual and provider-perceived literacy and numeracy levels among those (≥18yrs) with type 1 (n=59), type 2 (n=57), and unknown (n=5) diabetes, and to test whether this discrepancy was associated with worse HbA1c. We used multiple linear regression to compare mean HbA1c of patients whose providers overestimated, underestimated, and correctly estimated literacy and numeracy. Literacy was assessed by The Rapid Estimate of Adult Literacy in Medicine-Short Form and numeracy by the Diabetes Numeracy Test. Based on a directed acyclic graph and comparison of precision and bias of multiple models, the final models were adjusted for insurance (public/private), race (white/other), and education (≤high school/≥some undergraduate/≥some postgraduate).

Providers incorrectly identified 33.3% of patients’ literacy and 55.5% of numeracy. Providers overestimated 15.7% of patients’ literacy and 47.1% of numeracy. Providers underestimated 2.5% of literacy and 15.7% of numeracy. Mean Hb1Ac was 8.1%. Patients whose provider incorrectly perceived their literacy and numeracy score had, respectively, an HbA1c that was on average 0.9% (p=0.01) and 0.6% (p=0.05) higher than those whose scores were correctly perceived. Further, patients with overestimated numeracy had a 0.9% higher HbA1c than those whose high numeracy was correctly identified (p=0.001). These findings suggest providers might benefit from accurate knowledge of patients’ numeracy and literacy so that appropriate information can be communicated. Future research is needed to test effects of changing provider communication to minimize overestimation of patient numeracy and literacy levels.

Disclosure

R. Logendran: None. A. Cristello: None. J. DuBois: None. B.S. Friedman: None. E.J. Mayer-Davis: None.
1902-P: Insulin Pulses Do Not Inhibit Glucagon Secretion in Nondiabetic Humans
Authors: LAURENTI MARCELLO C. , MAN CHIARA DALLA , VARGHESE RON T. , RIZZA ROBERT A. , MATVEYENKO ALEKSEY , COBELLI CLAUDIO , VELLA ADRIAN
Published: June 2020

Type 2 diabetes (T2DM) is characterized by defects in insulin secretion and glucagon suppression. It has been assumed that defective glucagon secretion arises due to impaired insulin secretion. Indeed, prior work suggests that pulsatile insulin secretion has an inverse relationship with post-prandial glucagon secretion. However, more recent data suggest that dysregulation of glucagon secretion in prediabetes occurs early, and independently, of changes in insulin secretion. During a series of experiments examining the mechanisms underlying prediabetes, we studied 29 nondiabetic subjects (age = 44 ± 2, BMI 28 ± 1 Kg/m2). Hepatic vein catheterization allowed sampling of insulin and glucagon at 2 minute intervals during fasting and during a hyperglycemic clamp (150mg/dL). Mean insulin concentrations rose from fasting (33 ± 1 vs. 144 ± 2 pmol/L, p<0.01) while glucagon was suppressed (96 ± 1 vs. 62 ± 1 ng/L, p<0.01) during the clamp. A cross-correlation analysis of the two hormones showed, on average, a small in-phase coordination between insulin and glucagon pulses during fasting, which inverted during hyperglycemia (0.2 ± 0.1 vs. -0.4 ± 0.1, p<0.01). Subsequently, Cross-Approximate Entropy (Cross-ApEn), a technique for comparing synchronicity between two time series, was used to evaluate their interaction. This showed a moderate level of synchronicity, unaffected by glucose concentrations, whether calculated using glucagon as the template to assess pattern reproducibility in insulin concentration (0.78 ± 0.03 vs. 0.76 ± 0.03, fasting vs. hyperglycemia), or when using insulin as the template for the glucagon pattern (0.78 ± 0.02 vs. 0.76 ± 0.03, fasting vs. hyperglycemia). The values of Cross-ApEn did not differ between the two scenarios, suggesting the interaction between the two hormones is not driven by either. Overall these data suggest that, on a minute-to-minute basis, direct control and secretion of glucagon is not mediated (or restrained) by insulin.

Disclosure

M.C. Laurenti: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.T. Varghese: None. R.A. Rizza: None. A. Matveyenko: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc.

Funding

National Institutes of Health (DK78646, DK116231)
1904-P: Metabolomic Fingerprints after Metabolic Surgery: The STAMPEDE Trial
Authors: DANTAS WAGNER S. , AXELROD CHRISTOPHER L. , HARI ADITHYA , KASHYAP SANGEETA , SCHAUER PHILIP , KIRWAN JOHN P.
Published: June 2020

Introduction: Metabolic surgery (MS) results in durable resolution of hyperglycemia in ∼50% of patients with type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for more than 90% of all metabolic surgeries, and both have been demonstrated to have greater efficacy when compared to intensive medical and lifestyle therapy (IMT) to improve glycemic control. However, a subset of patients following MS exhibit inadequate weight loss, poor glycemic control, or both. Thus, the purpose of this study was to identify novel biomarkers of biochemical resolution of T2D following IMT and MS.

Methods: Plasma samples from ninety patients (49.9±7.6 years, 57.7% female) randomly assigned to receive either IMT (n=30), RYGB (n=30) or SG (n=30) were retrospectively analyzed and quantified by untargeted metabolomic analysis using UPLC-tandem mass spectrometry at baseline (PRE) and 24 months (POST) of treatment.

Results: We identified 384 metabolites altered by RYGB, SG and IMT treatment. 2-hydroxybutyrate was significantly decreased following all 3 interventions with a greater decrease in SG and RYGB at POST (p≤0.05). Pyruvate was significant lower in the IMT and RYGB group (p≤0.05), but not in SG at POST (vs. PRE). Markers of fatty acid metabolism, including acetylcarnitine and 3-hydroxybutyrate (BHBA), were also decreased following the SG intervention (p≤0.05). Several primary and secondary bile acid metabolites were significantly increased after RYGB compared to SG.

Conclusion: We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to IMT, RYGB, and SG. Notably, the metabolomic profile of both RYGB and SG procedures were distinct, suggesting that the roughly equivalent weight loss is achieved by divergent mechanisms.

Disclosure

W.S. Dantas: None. C.L. Axelrod: None. A. Hari: None. S. Kashyap: Other Relationship; Self; GI Dynamics Inc. P. Schauer: Advisory Panel; Self; GI Dynamics Inc. Consultant; Self; Ethicon US, LLC, Medtronic. Research Support; Self; Ethicon US, LLC, Medtronic. J.P. Kirwan: None.

Funding

Ethicon
1907-P: Using Human Genetics to Test the Disease Consequences of Varying Testosterone Levels in Men and Women
Authors: RUTH KATHERINE S. , DAY FELIX , TYRRELL JESS , MURRAY ANNA , ONG KEN , FRAYLING TIM , PERRY JOHN
Published: June 2020

Circulating testosterone and SHBG levels are associated with type 2 diabetes (T2D). These associations differ between sexes and by total and bioavailable testosterone. For example, in UK Biobank a 1-SD raised bioavailable testosterone is associated with lower risk of T2D in men (OR=0.90 [0.88,0.92]) but higher risk in women (OR=1.24 [1.20,1.29]). Genetic studies provide more robust tests of causality and have indicated that higher circulating SHBG is protective of T2D (OR=0.92 [0.88,0.96], Perry et al 2010), but were limited to few genetic variants. In this study we aimed to: i) expand the set of genetic variants associated with circulating testosterone; ii) separate variants into clusters representing SHBG or direct testosterone effects; and iii) perform Mendelian Randomisation studies to better understand the potential causal effects of SHBG and testosterone on T2D and related traits. We used genome-wide analyses of sex hormones from 425,097 UK Biobank participants. We identified 2,571 genome-wide significant (P<5x10-8) associations (vs. 17 pre-2019). The genetics of testosterone levels were very different between men and women (genetic correlation ∼0). To identify variants with specific testosterone-increasing effects independent of SHBG, we used a hierarchical-clustering strategy. In men, 122 loci were associated with higher testosterone in a dose-response manner with no effect on SHBG, with 241 such signals in women. We found that SHBG and testosterone levels can influence T2D and related traits. A genetically determined 1-SD higher testosterone increased the risk of T2D (OR=1.37 [1.22,1.53]) and polycystic ovary syndrome (OR=1.51 [1.33,1.72]) in women, but reduced T2D risk in men (OR=0.86 [0.76,0.98]). Using clustered variants suggested that diabetes effects were primarily mediated by testosterone in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific analyses of diabetes.

Disclosure

K.S. Ruth: None. F. Day: None. J. Tyrrell: None. A. Murray: None. K. Ong: None. T. Frayling: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi, Servier. Research Support; Self; GlaxoSmithKline plc. J. Perry: None.

Funding

European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC); UK Wellcome Trust/Royal Society (104150/Z/14/Z); UK Wellcome Trust/Global Challenge Research Fund (SBF004\1079); Medical Research Council UK (MC_UU_12015/1, MC_UU_12015/2)
191-OR: A Web-Based Lifestyle Intervention to Reduce Postpartum Weight Retention in Women with Recent Gestational Diabetes: The Balance after Baby Intervention Trial
Authors: NICKLAS JACINDA M. , SKURNIK GERALDINE , ROCHE ANDREA T. , SCHULTZ CLAIRE , SURESH KRITHIKA , SEELY ELLEN W.
Published: June 2020

Women with gestational diabetes (GDM) have a 30-70% risk for developing type 2 diabetes. Although women with a GDM history can decrease their risk for type 2 diabetes through weight loss and physical activity, few evidence-based programs exist to help decrease their risk in the postpartum period. Women with recent GDM were randomized at ∼6 weeks postpartum to a web-based 12-month lifestyle intervention program or to a control website. We measured weight and administered behavioral questionnaires at 6 weeks, 6 months, and 12 months postpartum. Our study included 181 women (mean 33±5.3 years; 48% White, 22% Asian, 17% African-American, 13% other race, with 35% Hispanic). 31% of women reported household incomes <$35,000 per year. The mean BMI at the baseline study visit was 31 ± 6 kg/m2. Using a mixed effects model, at 12 months, women randomized to the intervention lost 1.4 kg vs. +1.1 kg in the control group (difference between groups -2.6 kg, 95% CI: -6.8 to +1.6, p=0.23). Retention at 12 months was over 85%. In a pre-planned subgroup analysis by ethnicity, non-Hispanic women in the intervention lost significantly more weight than non-Hispanic controls at 12 months (difference between groups of -5.8 kg, 95% CI: -10.9 to -0.6 kg, p=0.03). On the other hand, no significant weight difference between the intervention and control groups was seen at 12 months in Hispanic women (+2.9 kg, 95% CI: -3.2 to 9.1 kg, p=0.35). At 12 months postpartum, the Balance after Baby intervention program was associated with significant postpartum weight loss among non-Hispanic women, but not among Hispanic women. The Balance after Baby intervention program holds promise for decreasing diabetes risk factors in women with recent GDM. Analysis of the behavioral data may help explain the difference in weight outcome by ethnicity, and help guide future optimization of the intervention for Hispanic women.

Disclosure

J.M. Nicklas: None. G. Skurnik: None. A.T. Roche: None. C. Schultz: None. K. Suresh: None. E.W. Seely: None.

Funding

Centers for Disease Control and Prevention (HHSD2002013M53968B); National Institutes of Health (1K23HL133604); Colorado National Center for Advancing Translational Sciences (UL1TR001082, UL1TR001102)
1911-P: The Physiological Role of GLP-1 in Regulating Pancreatic Inflammation in a Sepsis Model
Authors: DAVIS ELLEN M. , HUTCH CHELSEA , KIM KI-SUK , MAERZ BASMA , LEHRKE MICHAEL , SANDOVAL DARLEEN A.
Published: June 2020

Patients who have diabetes mellitus (both type 1 and type 2) have increased susceptibility to sepsis. Among the hormones that are altered by sepsis, there is an increase in the glucoregulatory peptide glucagon-like peptide-1 (GLP-1), and in animal models there is a specific increase in pancreatic-produced GLP-1 vs. glucagon. While the function of GLP-1 during sepsis is unknown, GLP-1 agonists have recently been of interest as an anti-inflammatory agent. We hypothesized that GLP-1 increases are necessary for dampening pancreatic inflammatory responses to sepsis in lean and HFD-fed mice. To model sepsis, we administered 100ng/g lipopolysaccharide (LPS) to C57BL/6 mice who had been fed HFD or chow for 12 weeks. We found that compared to vehicle treatment, LPS significantly increased plasma levels of GLP-1 in both HFD and chow-fed mice, but plasma GLP-1 was significantly higher and plasma glucose was significantly lower in HFD compared to chow-fed mice. To determine whether GLP-1 specifically regulated pancreatic inflammation, 24 hours after LPS we used flow cytometry to isolate pancreatic immune cells from chow-fed mice devoid of GLP-1 (GcgΔNull) and wild type (WT) mice. In chow-fed mice, we found approximately 20% more CD45+ cells in WT LPS treated mice compared to vehicle, and a similar percentage of CD45+ cells in LPS treated GcgΔNull mice compared to WT. In contrast, LPS administration to HFD-fed GcgΔNull mice, resulted in increased F4/80 positive cells compared to WT mice. Taken together, these data suggest that Gcg peptides are necessary to blunt LPS-induced inflammation in the pancreas and that GLP-1 physiologically regulates tissue inflammation. Future studies will determine whether the increased GLP-1 in HFD-fed mice is due to an increased inflammatory state or a decreased effectiveness of GLP-1.

Disclosure

E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Other Relationship; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S.
1921-P: Nonalcoholic Steatohepatitis in Mice with Hepatocyte-Specific Deletion of Mitochondrial Fission Factor
Authors: TAKEICHI YUKINA , MIYAZAWA TAKASHI , SAKAMOTO SHOHEI , SAKAMOTO RYUICHI , NOMURA MASATOSHI , OGAWA YOSHIHIRO
Published: June 2020

Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred as mitochondrial dynamics (MtD), to adapt to nutritional demand. Evidence suggested that impaired MtD leads to metabolic abnormalities such as nonalcoholic steatohepatitis (NASH)-like phenotypes, which are characterized by hepatic steatosis, inflammation and fibrosis. However, how MtD is involved in the development of NASH is poorly understood. In this study, we found mitochondrial fission factor (Mff), a critical mediator of mitochondrial fission, is upregulated in the liver from mice fed high-fat diet (HFD). To explore the role of Mff in the development of NASH, we generated liver-specific deletion of Mff (MffLiKO) mice. Histological analysis revealed that mitochondria are enlarged in the liver from MffLiKO mice fed normal chow diet (NCD), which is followed by hepatocyte apoptosis, slightly increased infiltration of inflammatory macrophages, and fibrosis. However, no lipid accumulation was observed in the liver from MffLiKO mice fed NCD. That is, only the impairment of Mff-regulated mitochondrial fission did not develop NASH-like phenotypes. On the other hand, the liver of MffLiKO mice fed HFD developed NASH-like phenotype with severer steatosis. Expression of mRNAs related to endoplasmic reticulum (ER) stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic triglyceride secretion was downregulated, with reduced hepatic triglyceride secretion in MffLiKO mice in vivo and in primary cultures of Mff-deficient hepatocytes in vitro. Interestingly, thapsigargin-induced ER stress suppressed triglyceride secretion in primary cultured hepatocytes in vitro. This study demonstrates that MffLiKO develop NASH-like-phenotypes in response to HFD and suggests that impaired MtD induces ER stress and thus reduces hepatic triglyceride secretion, which may play a role in the pathogenesis of NASH.

Disclosure

Y. Takeichi: None. T. Miyazawa: None. S. Sakamoto: None. R. Sakamoto: None. M. Nomura: None. Y. Ogawa: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker’s Bureau; Self; Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation.
1925-P: Beneficial Effects of a Novel Long-Acting Glucagon Analog, HM15136, on Obesity and Obesity-Related Metabolic Disorders in Animal Models
Authors: LEE JONG SUK , LEE SEON MYEONG , CHOI JAEHYUK , PARK EUNJIN , LEE JONGSOO , LEE SANG DON , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG
Published: June 2020

Obesity is a major risk factor for a number of metabolic disorders such as hyperlipidemia, glucose intolerance, and T2DM. Recent researches indicated a stimulatory effect of glucagon (GCG) on energy expenditure and appetite inhibition, suggesting the utilization of GCG as a pharmacological therapy for obesity and related metabolic disorders. In line with this, we previously observed that chronic treatment of HM15136, a novel long-acting glucagon analog, conferred efficient body weight loss (BWL) in DIO mice. Here, we further investigated the potential benefits of HM15136 in obesity-related metabolic disorders. In DIO mice, time-course change in fat mass, liver triglyceride (TG), and fasting blood glucose (FBG) was determined. Chronic treatment of HM15136 was associated with progressive BWL (-37.5% vs. vehicle (Veh) at day17) and fat mass reduction with little effect on lean mass, confirming its potent anti-obesity effect. Interestingly, despite marginal BWL at initial drug treatment period, significant reduction in blood TG (-56.5% vs. Veh at day2) and subsequent liver TG (-41.5% vs. Veh at day7) was achieved, and maintained thereafter. Moreover, the TG lowering both in blood and liver was followed by sustainable FBG lowering, suggesting that rapid depletion of lipid, the main sources for gluconeogenesis, might contribute to FBG control by HM15136. To evaluate the potential effect on post-prandial glucose control, oral glucose tolerance test (oGTT) was performed, and reduced BG level during oGTT was observed as BWL occurred. Time-dependent reduction in HOMA-IR evidenced the insulin sensitivity improvement. To our knowledge, this is the first study demonstrating the potential benefits of chronic GCG engagement in the management of BW, blood lipid, and even BG. Based on these results, HM15136 may be a novel option for the management of obesity and related metabolic disorders. Human study is ongoing for the clinical relevance of these findings.

Disclosure

J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Spouse/Partner; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1928-P: ß-Casein–Derived Peptides Prevents Obesity by Activating Adipose Tissue Thermogenesis
Authors: ZHONG HONG , ZHANG XIAOXIAO , ZHANG ZHUO , CHI XIA , JI CHENBO , CUI XIANWEI
Published: June 2020

Caloric intake that exceeds caloric expenditure is the main driver of obesity. Brown fat is characterized by the abundant mitochondria and could dissipate energy as heat, thus giving a feasible way to combat obesity. With the advent of GLP-1 receptor agonist in medical practice for diabetes treatment, peptide drug has been an important element in the pharmaceutical landscape. Discovery of bioactive peptide is hence increasingly appreciated. Presently, we identified an endogenous peptide, TPDHM1, from β-casein in milk. We further demonstrated its function in activating adipose tissue thermogenesis and the potential molecular mechanism involved. Our results confirmed that TPDHM1 could promote brown and white adipocytes energy metabolism both in vitro and in vivo. Chronic administration of TPDHM1 attenuated the high-fat diet induced obesity. Additionally, the insulin resistance and hyperglycemia of diabetic db/db mice were improved following TPDHM1 treatment. Mechanistically, both RNA-seq and protein microarray results revealed that the thermogenic effect of TPDHM1 is possibly mediated by p38-mitogen-activated protein kinase (p38-MAPK) signaling pathway. Inhibition of the p38-MAPK by SB203580 abolished the UCP-1 expression induced by TPDHM1. Taken together, our data suggest that TPDHM1 can potentially alleviate obesity and diabetes by stimulating energy metabolism via p38-MAPK pathways.

Disclosure

H. Zhong: None. X. Zhang: None. Z. Zhang: None. X. Chi: None. C. Ji: None. X. Cui: None.

Funding

National Natural Science Foundation of China (81770837, 81770866, 81900783)
193-LB: Diabetes Mellitus Does Not Impact Negatively on Outcomes of Hospitalizations Primarily for Systemic Lupus Erythematosus (SLE): An Analysis of the National Inpatient Sample Database
Authors: EDIGIN EHIZOGIE , SHAKA HAFEEZ , XU JING , YAP SARA ELIZABETH T. , PADILLA SORTO MARIA ELENA
Published: June 2020

Background: Diabetes mellitus (DM) is a multisystemic disorder, known to be associated with worse outcomes of multiple conditions.

Objectives: This study aims to determine if diabetes has an impact on outcomes of hospitalizations primarily for SLE.

Methods: Data were extracted from the Nationwide Inpatient Sample (NIS) 2016 and 2017 database. The NIS was searched for SLE as the principal diagnosis for hospitalizations in 2016 and 2017, with and without DM as a secondary diagnosis, using ICD-10 codes. Adult Patients from the above groups were included. The primary outcome was inpatient mortality, while secondary outcomes were length of stay (LOS) and Total hospital charge. Multivariate logistic and linear regression analysis were used to adjust for possible confounders for the primary and secondary outcomes respectively.

Results: 20630 hospitalizations were for adult patients, who had principal diagnosis of SLE. 18560 (90.0%) of these hospitalizations had no secondary diagnosis of DM and 2070 (10.0%) had a secondary diagnosis of DM. A total of 255 inpatient mortality (1.23%) occurred in SLE hospitalizations, 35 (1.19%) of which occurred in patients with DM. The adjusted odds ratio (AOR) of inpatient mortality for SLE with DM compared to without DM was 0.554 (95% CI: 0.233 - 1.315, P=0.180). Hospitalizations with SLE and DM had a decreased adjusted mean LOS of 2.1 days (95% CI -3.0 - {-1.1}, P=0.000) compared to without DM. The adjusted mean total hospital charge for SLE and DM hospitalizations was also decreased by $24875 compared to without DM (95% CI -36154 - {-13596}, P=0.000).

Conclusions: There was no statistically significant difference in inpatient mortality of hospitalizations for SLE with DM compared to SLE without DM. Interestingly, SLE with DM hospitalizations has a shorter LOS and lower total hospital charge compared to without DM.

Disclosure

E. Edigin: None. H. Shaka: None. J. Xu: None. S.T. Yap: None. M. Padilla Sorto: None.
1937-P: ALK-7: A Validated Target for the Treatment of Obesity
Authors: BU YUN , ZHAO MIN , FREDERICKS MAUREEN , CANNELL MARISHKA , DAGON YOSSI , EMDIN CONNOR A. , OKUNISHI KATSUHIDE , WANG HAO , SAKO DIANNE , CASTONGUAY ROSELYNE , SURAGANI RAJASEKHAR N.V. , KATHIRESAN SEKAR , GRINBERG ASYA , KNOPF JOHN , PEARSALL ROBERT S. , KUMAR RAVINDRA , IZUMI TETSURO
Published: June 2020

Genetic variation in the ACVR1C gene has been reported to be associated with decreased waist-to-hip ratio and risk of type 2 diabetes in humans. However, the effect of this naturally occurring variation on ALK7 function is unclear. Here we show that the human ACVR1C variant I195T, which displays the greatest effect on waist-to-hip ratio adjusted for body mass index, fails to signal in response to ALK7 ligands in a cell-based assay. This is consistent with observations in mice that impaired ALK7 signaling increases lipolysis and decreases adiposity. As further validation of ALK7 as an obesity target, we present data showing in the naturally occurring polygenic obese TSOD mouse a specific high affinity neutralizing monoclonal anti-ALK7 antibody (ALK7 mAb) dramatically decreases leptin levels, adipose macrophages and adiposity. The specificity of the ALK7 mAb is demonstrated by its lack of effect in genetically deficient ALK7 mice. These data along with the knowledge that normal Balb/c mice harbor a homozygous ALK7 nonsense mutation suggests that targeting ALK7 in humans should decrease obesity, susceptibility to diabetes and have minimal on-target negative consequences.

Disclosure

Y. Bu: None. M. Zhao: None. M. Fredericks: None. M. Cannell: None. Y. Dagon: None. C.A. Emdin: None. K. Okunishi: None. H. Wang: None. D. Sako: None. R. Castonguay: Employee; Self; Acceleron Pharma. R.N.V. Suragani: None. S. Kathiresan: Advisory Panel; Self; Regeneron Genetics Center. Consultant; Self; Color Genomics, Corvia Medical, Inc., Medgenome, Pfizer Inc. Stock/Shareholder; Self; Catabasis Pharmaceuticals, Maze Therapeutics, San THerapeutics, Verve Therapeutics. A. Grinberg: None. J. Knopf: Stock/Shareholder; Self; Acceleron Phama. R.S. Pearsall: Employee; Self; Acceleron Pharma, Inc. Stock/Shareholder; Self; Acceleron Pharma, Inc. R. Kumar: Employee; Self; Acceleron Pharma. T. Izumi: Research Support; Self; Acceleron Pharma.
194-LB: T1D Exchange Registry: Current Data Insights and Future Impact
Authors: LAFERRIERE KELSIE , LIU JINGWEN , HUGHES ALLYSON , WOLF WENDY
Published: June 2020

In a previous T1D Exchange led initiative, the T1D Exchange Clinic Registry encompassed 25,000 participants from 81 clinic sites across the U.S. who drove type 1 diabetes (T1D) research and produced real-world data on T1D. Upon the Clinic Registry’s closing, T1D Exchange launched the online T1D Exchange Registry in June of 2019 to lower barriers to research, increase participation, and strive to develop a more diverse population. The Registry is currently recruiting adults with T1D and parents/guardians of children who have T1D, living in the U.S. The Registry is a streamlined platform where participants enroll by completing screening questions, signing consent, and answering an initial questionnaire. Participants then complete an annual questionnaire to track health, disease management, and changes in outcomes over time. As of March 2020, there are over 5,300 participants enrolled in the Registry, with over 56% having completed their initial questionnaire. Currently, 10.9% of participants are between the ages of 1-17 years, 70.2% are between 18-55 years, and 18.9% are 56 years or above. This cohort represents a wide range of years since diagnosis, with 23.4% diagnosed within the past 5 years and 24.8% diagnosed more than 30 years ago. The majority identify as Caucasian (94.1%) and female (70.2%), with geographic representation from every U.S. state and territory. Among the pediatric cohort (<18 years), 24% reported A1C below 7.0%, whereas 36.1% of adults between 18-55 years reported A1C below 7.0%; 77.8% of adults 56 years or above reported A1C lower than 7.5%. The Registry cohort appears to be more technology-skilled than other T1D cohorts reported in the U.S., with 77.0% of participants currently using a CGM, and 67.2% using an insulin pump. Future projects for the Registry include analyzing longitudinal data, linking device data, sharing clinical trial opportunities, and providing additional research opportunities to participants.

Disclosure

K. LaFerriere: None. J. Liu: None. A. Hughes: None. W. Wolf: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D074)
194-OR: Impaired Awareness of Hypoglycemia and Maternal/Neonatal Outcomes in the CONCEPTT Trial
Authors: BAHRAMI JASMINE , TOMLINSON GEORGE , MURPHY HELEN R. , FEIG DENICE
Published: June 2020

Background: Patients with diabetes and impaired awareness of hypoglycemia (IAH) are at increased risk of severe hypoglycemia (SH). IAH is increased during pregnancy. To date, maternal and neonatal outcomes of pregnant women with hypoglycemia unawareness or SH has not been well described.

Aim: To examine maternal and neonatal outcomes in women with IAH compared to women with normal awareness of hypoglycemia (NAH).

Methods: We included 214 pregnant women with type 1 diabetes who participated in the CONCEPTT trial. Participants completed Hypoglycemia Fear Surveys (HFS-II) at baseline and study completion. Post-hoc analysis of data was conducted using logical regression analysis to estimate the odds of occurrence of events by IAH versus NAH. The role of continuous glucose monitoring (CGM) use on outcomes was also examined.

Results: Overall, 30% of participants reported IAH (n=64). Women with IAH had more episodes of SH during pregnancy (mean 0.44 vs. 0.08, p<0.001). Women with IAH scored significantly higher on the HFS-II worry scale (25.9 vs. 20.1, p 0.0036), indicating more fear of hypoglycemia at baseline. They also spent more time below range (<63 mg/dl) at 12 weeks gestation. Higher overall HFS-II scores were associated with a higher risk of maternal SH episodes (RR 1.78, 95% CI 1.39-2.27) and a lower incidence of neonatal hypoglycemia (OR 0.597, 95% CI 0.385-0.893). There were no other differences in obstetric/neonatal outcomes between women with IAH and NAH. Higher HFS-II scores were associated with more diabetes-related complications, such as nephropathy (OR 1.907, 95% CI 1.06-3.4), independent of duration of diabetes. Finally, CGM did not affect incidence of SH (RR 0.54, 95% CI 0.12 - 2.16).

Conclusion: In pregnant women with type 1 diabetes, IAH is associated with more maternal SH episodes and more fear of hypoglycemia. Fear of hypoglycemia was associated with reduced neonatal hypoglycemia as well as more maternal diabetes-related complications.

Disclosure

J. Bahrami: None. G. Tomlinson: None. H.R. Murphy: Advisory Panel; Self; Medtronic. D. Feig: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic.

Funding

JDRF; Canadian Clinical Trial Network
1941-P: Aging Disturbs the Inflammatory Balance in Adipose Tissue
Authors: LIAN ZEQIN , PERRARD XIAOYUAN , BALLANTYNE CHRISTIE M. , WU HUAIZHU
Published: June 2020

Background: Aging (middle age) is usually associated with obesity and progressive low-grade inflammation in adipose tissue. However, how immune components in adipose tissue respond to aging is still not fully uncovered. Here, we sought to examine immune cells and inflammation in adipose tissue in aging mice.

Methods: Bodyweight and insulin sensitivity were measured in 12-month-old (aging) and 3-month-old (young) C57BL/6J mice on a low-fat normal diet. UCP1 expression was examined in white adipose tissue after stimulation. The immune-cell composition and phenotypes in adipose tissue were analyzed by flow cytometry. The suppressive functions of adipose tissue-resident T regulatory cells (aTregs) for conventional T cell proliferation were evaluated by CFSE-labeling proliferation assay in vitro.

Results: Compared to young mice, aging mice exhibited adipose tissue expansion and insulin resistance. UCP1 was reduced in adipose tissue, indicating impaired adipose tissue browning, in aging mice compared to young mice. The frequency of resident T cells and macrophages was increased in adipose tissue of aging mice compared to those of young mice. Moreover, the Th1 subset of T cells and the M1 subset of macrophages dominated in their parent population in adipose tissue of aging mice. In contrast to diet-induced obesity that reduced aTregs, the frequency of aTregs was increased in old mice compared to young mice. However, the anti-inflammatory cytokines IL10 and inflammation-inhibitory marker CTLA4 were reduced on aTregs in aging mice than young mice. The proliferative assay showed that the suppressive capacity of Treg cell on conventional T cell proliferation was impaired in aging mice.

Conclusion: Aging in mice is associated with increased aTregs, which have reduced anti-inflammatory functions and may, therefore, contribute to increased Th1 and M1 inflammation in adipose tissue, leading to metabolic disorders in aging mice.

Disclosure

Z. Lian: None. X. Perrard: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corvidia, Denka-Seiken Co., Ltd., Esperion Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amgen, Esperion Therapeutics, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA. H. Wu: None.

Funding

American Diabetes Association (1-17-IBS-082 to H.W.); National Institutes of Health (R01HL098839); American Heart Association (16GRNT30410012)
1944-P: CREBZF Acetylation at Lys126 Couples Glucose to White Adipose Tissue Browning
Authors: CUI AOYUAN , SU WEITONG , XUE YAQIAN , LIU ZHENGSHUAI , MA FENGGUANG , LIU YUXIAO , HU ZHIMIN , HAN YAMEI , CAI GENXIANG , GAO JING , CHIN EUGENE , XU AIMIN , LI YU
Published: June 2020

Glucose uptake is highly induced during cold exposure or feeding in adipocytes, which is utilized as an important energy source for most cells. However, little is known about whether glucose regulates downstream targets that govern thermogenesis and metabolic homeostasis in adipose tissue. Here, we characterize CREB/ATF bZIP transcription factor CREBZF as a novel glucose sensor and regulates thermogenesis via acetylation in adipocytes. Proteomic analysis using LC-MS/MS identifies Lys126 as an evolutionally conserved residue that is acetylated in a glucose-dependent manner. Ectopic expression of CREBZF mutant, in which Lys126 is substituted by alanine, abolishes glucose-stimulated acetylation and protein stabilization of CREBZF. The effects of glucose on protein stabilization of CREBZF are regulated by reversible acetylation that is mediated by transacetylase CBP/p300 and deacetylase HDAC3. Interestingly, endogenous levels of CREBZF are induced by pharmacological inhibition of HDAC3 RGFP966 in SVF-differentiated primary adipocytes. Adipose specific CREBZF knockout (FKO) mice were cold insensitivity and showed enhanced browning and energy metabolism. In the inguinal white adipose tissue (iWAT) of mice in response to cold exposure or β3-adrenergic receptor agonist, the activity of CREBZF is increased, leading to decreased thermogenic gene expression, energy expenditure, and cold tolerance. These findings 1) characterize glucose as a chemical signal to regulate acetylation and stabilization of CREBZF in adipocytes; 2) reveal that Lys126 may play a key role in mediating glucose’s effects on the stimulation of CREBZF activity and inhibition of white adipose tissue browning; 3) uncover an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.

Disclosure

A. Cui: None. W. Su: None. Y. Xue: None. Z. Liu: None. F. Ma: None. Y. Liu: None. Z. Hu: None. Y. Han: None. G. Cai: None. J. Gao: None. E. Chin: None. A. Xu: None. Y. Li: None.

Funding

National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Chinese Academy of Sciences (XDA12030210); Shanghai Science and Technology Commission (19140903300)
1947-P: RE1-Silencing Transcription Factor (REST) Regulates Mitochondrial Activity in White Adipocytes
Authors: FUWA MASAYUKI , KAJITA KAZUO , TAGUCHI KOICHIRO , IKEDA TAKAHIDE , ISHIZUKA TATSUO , MORITA HIROYUKI
Published: June 2020

RE1-silencing transcription factor (REST) is a transcriptional factor which negatively regulates the expression of numerous neuronal genes. In this study, model mice lacking REST in adipocytes were generated to investigate the role of REST in adipocytes. This was achieved by mating Rest2lox/2lox mice with Adipoq-Cre mice, and the resultant Adipoq-Cre/Rest2lox/2lox mice were compared with Adipoq-Cre mice. Adipoq-Cre/Rest2lox/2lox mice exceeding 10 weeks of age showed increased body weight, fat mass, and adipocyte size; however no difference was observed in food intake. Glucose tolerance deteriorated under a high fat diet, but not under normal diets in Adipoq-Cre/Rest2lox/2lox mice. Oxygen consumption decreased in Adipoq-Cre/Rest2lox/2lox mice. The characteristics of gene expression in epididymal fat, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT), isolated from Adipoq-Cre/Rest2lox/2lox mice, were compared by microarray with those from Adipoq-Cre mice. Although expression of numerous neuronal genes increased in Adipoq-Cre/Rest2lox/2lox mice, there were no differences in adipocyte-specific genes. Gene analyses utilizing a cluster one program detected a significant decrease in the mitochondrial translation gene group in WAT, but not BAT. There was no difference in the amount of mitochondrial DNA, whereas the expression of cytochrome C protein was reduced in WAT but not BAT, which was isolated from Adipoq-Cre/Rest2lox/2lox mice. These results indicate that obesity in Adipoq-Cre/Rest2lox/2lox mice is due to a mitochondrial dysfunction in WAT. It is also suggested that REST might regulate the mitochondrial function in WAT.

Disclosure

M. Fuwa: None. K. Kajita: None. K. Taguchi: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.
1950-P: Fat Mass Affects Metabolic Response to Erythropoietin in Mice
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T.
Published: June 2020

Erythropoietin (EPO) is required for erythrocyte production. However, EPO receptor (EpoR) expression extends beyond erythroid tissue. To assess EPO activity on glucose homeostasis and fat mass accumulation, wild type (WT, C57BL/6) mice, ΔEpoRE mice with EpoR restricted to hematopoietic tissue and ΔEpoRWAT mice with targeted EpoR deletion in fat tissue were fed a high fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at age 3, 4, and 6 months. EPO increased hematocrit in all mice and improved glucose tolerance when fat mass was less than 35% which included all female mice. In male WT mice EPO improved glucose tolerance and reduced fat mass which at 6 months was 40% on HFD and below 35% with HFD/EPO treatment. In female mice, estrogen interferes with EPO fat mass regulation. EPO treatment did not affect fat mass in ΔEpoRE mice, indicating that EPO regulation of fat mass is a non-hematopoietic response. EPO improved glucose tolerance in female and only age 3 month male ΔEpoRE mice when fat mass was less than 35%. In male ΔEpoRWAT mice, EPO minimally reduced fat mass indicating that EPO fat mass regulation in males is largely a direct fat tissue response. EPO treatment improved glucose tolerance in male ΔEpoRWAT mice when fat mass was below 35% but not at 6 months when fat mass exceeded 40%. These data demonstrate that EPO improved glucose tolerance when fat mass was below 35%, that the sex-dimorphic EPO regulation of fat mass is primarily mediated by EpoR in fat, and that EPO activity in glucose metabolism and fat mass is differentially regulated and does not follow EPO stimulated erythropoiesis.

Disclosure

H. Rogers: None. C.T. Noguchi: None.

Funding

National Institutes of Health
1953-P: Influence of High-Fat Diet on Adipokine, Leptin, Betatrophin, and PTX3 in Obese Sprague-Dawley Rats Undergoing Metabolic Surgery
Authors: NABRDALIK KATARZYNA , SAWCZYN TOMASZ , STYGAR DOMINIKA M. , GUMPRECHT JANUSZ
Published: June 2020

Introduction: High-fat diet (HFD) leads to obesity which causes low grade inflammation and changes in adipokines and hepatokines. Metabolic surgery, like ileal transposition (IT) leads to beneficial metabolic effect and lowers inflammatory state. However these positive effects diminish with time and data related to dietary factors modifying these effects are scare.

Aim: To assess influence of HFD on plasma adiponectin, leptin, betatrophin and pentraxin 3 (PTX3) in obese rats undergoing metabolic surgery.

Methods: There were 24 rats fed for 8 weeks with HFD to induce obesity. After 8 weeks half of them underwent IT and half of them SHAM surgery. For 8 weeks after surgery half of the rats in the IT and in the SHAM group were fed with HFD and half of them with control diet (CD). After 8 weeks following surgery adipokines namely adiponectin and leptin as well as hepatokine namely betatrophin and inflammatory protein PTX3 were assessed.

Outcomes: When comparing HFD to CD groups following two surgery procedures rats who underwent IT comparing to SHAM surgery had significantly higher concentration of betatrophin (1751.2 vs 594.5 pg/ml; P=0.0041) when continued to be fed with HFD as well as when the diet was changed to CD (2391.2 vs 922.9 pg/ml; P=0.0047) and significantly higher concentration of adiponectin (72.6 vs 28.7 ng/ml; P=0.007) only among those rats who continued to be fad with HFD. There was higher concentration of betatrophin observed among rats who were postoperatively fed with HFD comparing to rats who were fed with CD in the IT surgery group but the difference was not significant (2301.2 vs 1751.2 pg/ml; P= 0.0552). There was no difference in PTX3 and leptin observed among IT compared to SHAM operated animals in relation to diet.

Conclusion: The study indicates that diet may modify the effects of metabolic surgery on adiponectin and betatrophin which are hormones influencing metabolic state and this may serve as a motivation to investigate this phenomenon in humans.

Disclosure

K. Nabrdalik: None. T. Sawczyn: None. D.M. Stygar: None. J. Gumprecht: Consultant; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier. Speaker’s Bureau; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier.
1959-P: Sel1l-Hrd1 ER-Associated Degradation (ERAD) Controls Mitochondrial Dynamics, ER-Mitochondrial Dynamics, and ER-Mitochondria Contacts in Brown Adipocytes
Authors: TORRES MAURICIO , ZHOU ZHANGSEN , QI LING , WANG SIWEN
Published: June 2020

Heat generation, mediated by mitochondrial respiration in Brown Adipose Tissue (BAT), is important for defense against cold and maintenance of whole-body homeostasis. Recent works have demonstrated the presence of metabolically active BAT in adult humans, raising the prospect that augmenting brown fat abundance and/or function may provide an effective avenue for the treatment of obesity and its associated metabolic disorders. In this work, we show that the Sel1L-Hrd1 ERAD complex is essential for cold-induced thermogenesis in part by managing mitochondrial dynamics and ER-mitochondria contact in brown adipocytes. While largely indistinguishable from their wildtype littermates, adipocyte-specific Sel1L-deficient mice are cold sensitive associated with mitochondrial dysfunction. Using a combination of transmission electron microscopy (TEM), high-resolution three-dimensional (3D) imaging techniques such as Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) and Serial Block-face Scanning Electron Microscopy (SBEM), revealed that mitochondria in Sel1L-deficient brown adipocytes are dramatically enlarged and polymorphic in response to acute cold challenge. Strikingly, mitochondria in Sel1L-deficient brown adipocytes exhibit increased interaction with ER tubules leading to the formation of unique intramitochondrial tubule(s). Lastly, Sel1L affects mitochondrial biology as a part of the Hrd1 ERAD complex, as adipocyte-specific Hrd1-deficient mouse, phenocopy Sel1L-deficient mice in terms of mitochondrial phenotype. Hence, our data provide novel molecular insights and platform for future studies into ER-mitochondrial interaction and position Sel1L-Hrd1 ERAD at the center of organelle crosstalk.

Disclosure

M. Torres: None. Z. Zhou: None. L. Qi: None. S. Wang: None.

Funding

National Institutes of Health (1R35GM130292)