bluuebunny/crossref_metadata_2025_split huggingface dataset:
1845-P: Maternal Overnutrition Causes DNA Alkylation in Fetal Liver, Suppresses FasL, and Upregulates HIF-1 Signaling Pathway in Neonatal Liver in Nonalcoholic Steatohepatitis (NASH)-Based Hepatocellular Carcinoma in Offspring
Authors: TAKIYAMA TAKAO , BESSHO RYOICHI , SAWAMOTO KAZUKI , TAKIYAMA YUMI 
Published: June 2020

Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is associated with hepatocellular carcinoma (HCC). The worldwide prevalence of NAFLD in children suggests an early-life origin. To examine the impact of intrauterine nutrition on the development of NASH/HCC, female C57BL/6J mice were fed with either high-fat diet (HFD) or control diet (CD) during gestation. After weaning, the male offspring were fed with CD, generating two groups of male offspring, HFD and CD. HFD remarkably elevated plasma NEFA and ALT. Consistently, HFD had severe form of NASH, presenting the fibrosis, accompanied with HCC. Synchrotron micro-CT showed the architectural remodeling of the parenchyma in HFD at 14.5 days postcoitum (dpc), one week and 15 weeks of age, not in CD. In the liver of HFD at 14.5dpc, gene ontology term enrichment analysis suggested that up-regulated differentially expressed genes (DEGs) significantly enriched in DNA alkylation, bile secretion, and the down-regulated DEGs mainly enriched in neuronal system, cell maturation. KEGG pathway analysis found down-regulated DEGs significantly enriched in five pathways including Graft-versus-host disease (LogP -24.785) such as FasL, and up-regulated HIF-1 signaling pathway in the liver of HFD at one week of age. On the contrary, 15-week-old HFD had increased cytoplasmic pimonidazole staining, but no nuclear staining of HIF-1α in HCC cells, which suggests breakdown of hypoxic response mechanism, concomitantly with up-regulated miR199a-5p, miR-1949, miR214-3p and miR-3090-5p, which target HIF-1α. This study demonstrates that the early exposure to an overnutrition in utero, subsequent neonatal and adult nutritional alternation cause NASH/HCC in offspring, accompanied by multiple changes in gene expressions. This means a “multi-hit theory.”

Disclosure
T. Takiyama: None. R. Bessho: None. K. Sawamoto: None. Y. Takiyama: Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Roche Diagnostics K.K., Taisho Pharmaceutical Co., Ltd.
1855-P: Early Life Dysbiosis in Offspring of Obese Mice Promotes Hepatic Macrophage Dysfunction
Authors: JONSCHER KAREN R. , JANSSEN RACHEL , KOVATS SUSAN , MCMAHAN RACHEL , FRIEDMAN JACOB E. 
Published: June 2020

Maternal obesity is associated with increased risk for development of metabolic disease in the next generation. Obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) affect over 1 billion people, including 10% of all children. Mechanisms by which early life exposure to poor maternal diet transmits disease risk to offspring in later life are poorly understood but involve early dysregulation of the offspring innate immune system. We fed pregnant dams a “Western-style” diet (WD) to investigate effects of maternal WD on early innate immunity. We found a significant increase in common myeloid progenitors in livers from fetuses at E15 exposed to maternal WD as compared with those exposed to normal chow diet. Despite weaning to a chow diet, adult offspring exposed to maternal WD showed elevated monocyte infiltration to the liver and increased Il1b expression. Glycolytic metabolites, markers of inflammatory metabolic reprogramming, were increased in liver macrophages (Mφ), while bone marrow-derived Mφ (BMDM) had decreased Il10 expression in offspring exposed to maternal WD. Notably, this phenotype was recapitulated in recipients of fecal transfer from 3-wk-old offspring of WD-fed dams. The aryl hydrocarbon receptor (AHR) is a sensor and modulator of the microbiome and immune cell homeostasis. We found decreased expression of the AHR target Cyp1a2 in livers of 3-wk-old offspring of WD-fed dams, concomitant with decreased abundance of circulating indole-3-acetate, a product of gut bacterial metabolism and an AHR ligand. Lastly, phagocytosis, a key Mφ function, was impaired in BMDM from offspring of WD-fed dams and improved by indoles in vitro. These data suggest a role for decreased microbiome-derived indoles in controlling innate immunity at multiple levels.

Disclosure
K.R. Jonscher: None. R. Janssen: None. S. Kovats: None. R. McMahan: None. J.E. Friedman: None.
186-OR: Safety and Tolerability of the Next Generation Aldose Reductase Inhibitor (ARI) AT-001 Supports Initiation of the Pivotal Trial in Diabetic Cardiomyopathy (DbCM)
Authors: PERFETTI RICCARDO , LAWSON FRANCESCA C. , ROSENSTOCK JULIO , JANUZZI JAMES , SHENDELMAN SHOSHANA , WANG STELLA , GHANNAM AMEEN F. 
Published: June 2020

The role of Aldose Reductase in diabetes complications, including DbCM is well established. Older generation ARIs were unsuccessful due to lack of selectivity, resulting in off-target toxicity, such as renal and hepatic toxicity, and hypersensitivity reactions.
AT-001 is a next generation ARI with improved selectivity and ∼1,000X higher potency. In preclinical studies, AT-001 demonstrated significant reduction of cardiac damage with no off-target inhibition. The safety, tolerability, PK, and PD of AT-001 were assessed in a phase 1/2, three-part, randomized, placebo controlled study (n=120) in adults with type 2 diabetes. AT-001 induced dose-dependent inhibition of sorbitol, the PD biomarker of AR activity. All doses and dosing regimens were well-tolerated. There were no treatment-related serious adverse events (AEs) and no AEs causing discontinuation of study treatment. No clinically relevant changes in liver and kidney function were reported [Table].
The study results support further clinical development to explore potential use of AT-001 as an emerging therapeutic strategy in preventing diabetes complications. A pivotal phase 2/3 study, ARISE-HF (NCT04083339) was initiated to evaluate the safety and efficacy of two doses of AT-001 vs. placebo to improve or prevent the decline of functional capacity in adults with DbCM.

Disclosure
R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. F.C. Lawson: Employee; Self; Applied Therapeutics. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. J. Januzzi: Consultant; Self; Roche Diagnostic USA. Research Support; Self; Janssen Pharmaceuticals, Inc. S. Shendelman: Employee; Self; Applied Therapeutics. Stock/Shareholder; Self; Applied Therapeutics. S. Wang: Employee; Self; Applied Therapeutics. A.F. Ghannam: Employee; Self; Applied Therapeutics Inc. Stock/Shareholder; Self; Sanofi US.

Funding
Applied Therapeutics (NCT04083339)
1860-P: Alanine Transaminase 2 Is Induced in Diabetic Liver and Contributes to Gluconeogenesis from Amino Acids
Authors: MARTINO MICHAEL R. , AGUILAR MANUEL GUTIERREZ , MCCOMMIS KYLE S. , YOSHINO JUN , FINCK BRIAN N. 
Published: June 2020

Gluconeogenesis from amino acids contributes significantly to hepatic glucose production and hyperglycemia in diabetes. Alanine transaminases (ALT) catalyze the bi-directional interconversion of alanine to pyruvate with concomitant interconversion of α-ketoglutarate to glutamate. ALT1 is cytosolic while ALT2 is localized to the mitochondrial matrix. The mRNA expression and protein abundance of ALT1 and 2 was significantly increased in liver of db/db or diet induced obese mice compared to lean controls. The expression of ALT2 was also increased in obese humans compared to lean controls and was downregulated following bariatric surgery. The increase in hepatic ALT2 expression in diabetic mice was caused by endoplasmic reticulum stress and mediated by activating transcription factor 4 (ATF4). Indeed, inhibition of ATF4 reduced ALT2 expression in liver of db/db mice. Consistent with enhanced use of amino acids in gluconeogenesis, db/db and diet-induced obese mice had elevated blood glucose concentrations following IP administration of L-alanine or glutamine. ALT2 silencing in liver had no effect on glucose concentrations in lean mice, but alleviated alanine-induced hyperglycemia in db/db mice; likely by reducing the incorporation of alanine and/or glutamine into newly synthesized glucose. Plasma alanine tended to rise and glutamate significantly increased in db/db mice with ALT2 silencing whereas concentrations of the branched chain amino acids isoleucine, leucine, and valine decreased or tended to decrease.
In summary, our results are consistent with a significant role for ALT2 in hepatic gluconeogenesis from amino acids and in the regulation of blood glucose levels in obesity and diabetes.

Disclosure
M.R. Martino: None. M. Gutierrez Aguilar: None. K.S. McCommis: None. J. Yoshino: None. B.N. Finck: Advisory Panel; Self; Cirius Therapeutics. Stock/Shareholder; Self; Cirius Therapeutics.

Funding
National Institutes of Health (R01DK117657)
1862-P: Remission of Type 2 Diabetes and Metabolic Parameters Changes with a High-Protein Diet
Authors: STENTZ FRANKIE B. , AMMONS ANN 
Published: June 2020

The purpose of this study was to determine if remission of type 2 diabetes(T2D) can be achieved by macronutrients dietary changes without diabetes medications. High Protein (HP)(30% protein, 30% fat, 40% carbohydrates) or High Carbohydrate (HC)(15% protein, 30% fat, 55% carbohydrates) diets were used to study remission of type 2 diabetes(T2D) to Normal Glucose Tolerance(NGT), weight loss, body composition, and metabolic parameters in this randomized controlled clinical trial feeding study for 6 month(mo) in obese T2D adults.
T2D adults age 20-65 years were randomized to a HP or HC diet for 6 mo with all food provided. Caloric need for weight loss was determined by Resting Metabolic Rate(RMR) -500 calories/day. Oral Glucose Tolerance Tests (OGTT) were performed at Baseline (BL) and 6 mo to determine T2D/NGT status. A BL ≥126 mg/dl and HbA1c ≥6.5% and 2 hr glucose &gt;199mg/dl was considered T2D and remission was BL&lt;126 mg/ml and HbA1c&lt;6.5% and 2 hr glucose &lt;140 mg/dl. DXA was done at BL and 6 mo. Food pick up and weight checks were weekly.The T2D subjects on HP diet had 100% remission to NGT while the HC diet subjects had 33% remission. Both diet groups had significant weight loss (HP =15.4±5 lb, HC=19.9±5 lb), improvement in insulin sensitivity determined by HOMA IR [HP(BL 5.3±0.29; 6 mo 2.1±0.13)], [HC(BL 5.2±0.27; 6 mo 4.4±0.26)] and decrease in HbA1c [HP(BL 7.7±.05; 6 mo 5.6±.02)], [HC(BL 7.8±.04; 6 mo 6.6±.06)] and blood pressure improvement S/D [HP (BL 129/85, 6 mo 117/78)], [HC(BL 130/85; 6 mo 117/78)]. HP group had a 2.7%± 0.4% increase in lean body mass and 2.9± 0.4% decrease in fat mass while the HC group had a 1.9%±0.3 and 3.3±0.9 % decrease in lean and fat mass respectively.
Both diets resulted in weight loss, improvement in glucose tolerance and insulin sensitivity but only the HP diet produced 100% remission of T2D to NGT.

Disclosure
F.B. Stentz: None. A. Ammons: None.

Funding
AD Baskin (R073316012)
1869-P: Elevated Maternal BCAAs during Gestation and Lactation Reprograms Offspring’s Glucose Regulation
Authors: TZENG JOYCE , AGUILLARD ASHLEY , LORENZO DAMARIS 
Published: June 2020

Maternal nutrition impacts neonate development and can have long-lasting physiological effects. Newborns from obese and type 2 diabetes (T2D) mothers are at a higher risk of developing metabolic deficits later in life. Women with gestational diabetes (GD) or T2D often have elevated serum branched chain amino acids (BCAAs), one of the most accurate predictors of insulin resistance (IR) in adults. Since BCAAs are actively taken up by the placenta, fetuses are exposed to elevation of BCAAs in their mothers. Additionally, newborns can be exposed to high BCAA levels via breast milk or formula feeding. Interestingly, BCAAs levels are higher in breast milk from obese mothers and some infant formulas have higher BCAA content than average breast milk. However, the direct impact of BCAA overnutrition in utero and early postnatal life on newborn predisposition to obesity and T2D is poorly understood. To investigate the effects of exposure to high BCAA levels during gestation and postnatally, we fed female mice during pregnancy and lactation two different isocaloric diets with equal total protein content, but one of the diets enriched in BCAAs. Their offsprings was weaned onto normal or high fat (HFD) diets and evaluated for changes in body composition and systemic metabolic regulation over a six-month period. We found that maternal BCAA supplementation triggered hyperglycemia and impaired insulin secretion in newborns. Progeny from mothers fed the high BCAA diet exhibited elevated fasting glucose levels, reduced insulin secretion, and striking reductions in glucose tolerance and insulin sensitivity, which were exacerbated by HFD supplementation. These findings suggest that early exposure to BCAA overnutrition has a strong dysregulating effect on systemic glucose metabolism. We will provide insights into the molecular underpinnings at play.

Disclosure
J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None.

Funding
American Diabetes Association (1-19-JDF-081 to D.L.); National Institute of Diabetes and Digestive and Kidney Diseases (DK072476-15225-UNC01)
1874-P: The Improvement of Type 2 Diabetes by DJB Is related to the Improvement of Intestinal Glucose Sensing and Glucose Transportation
Authors: JIANG BIN , WANG HUAIJIE , WANG WEI-YU , YAN QINGTAO , QU MEI-HUA , GAO ZHIQIN 
Published: June 2020

Duodenojejunal bypass (DJB) is an experimental procedure to study the mechanism of metabolic surgery in type 2 diabetes (T2DM),independent of weight changes. The aim of this study was to evaluate the role of Gastrointestinal (GI) glucose sensing and glucose transportation in DJB regulated glucose metabolism using T2DM rat model. T2DM was induced in Wistar rats with 2 months of high-fat diet and one low-dose streptozocin (STZ) injection. T2DM rats were randomly divided into sham operation group (T2DM-Sham, n=8) and DJB group (T2DM-DJB, n=8). Eight Wistar rats were used as wild type control group(Control, n=8). The results showed that DJB surgery significantly improved blood glucose homeostasis in T2DM rats. The hematoxylin-eosin staining results revealed that DJB operation thickened the wall of small intestine comparing to Sham operation. DJB also increased the length of villus in small intestine. Western Blot and qRT-PCR results showed that DJB significantly increased the expression of sodium-glucose co-transporter-1 (SGLT1) while reducing the expression of glucose transporter-2 (GLUT2) in the alimentary limb of DJB rats. The results also showed the expression of intestinal sweet receptors (T1R2/T1R3), Glucagon-like peptide 1/2 (GLP1/2) and its receptor (GLP1/2R) increased significantly in the alimentary limb after DJB surgery. Here we describe a new observation that DJB surgery lowers blood glucose level via intestinal glucose transport and glucose sensing regulation in the alimentary limb.

Disclosure
B. Jiang: None. H. Wang: None. W. Wang: None. Q. Yan: None. M. Qu: None. Z. Gao: None.

Funding
National Natural Science Foundation of China (81871892); Natural Science Foundation of Shandong Province (ZR2019BH036); Technology Development Plan of Weifang (2018YX027)
188-LB: The Association between Glycemic Control during Hospitalization and Risk of Adverse Events: A Retrospective Cohort Study
Authors: DENG LAN , AIBIBULA WUSIMAN , TALAT ZAHRA , FILION KRISTIAN B. , EINTRACHT SHAUN , DASGUPTA KABERI , TAGALAKIS VICKY , MAJDAN AGNIESZKA , YUN YU ORIANA HOI 
Published: June 2020

Introduction: The glycemic target for patients with diabetes in non-critical care hospitalization has not been well studied. The primary objective of this study is to determine the association between glycemic control during hospitalization and adverse events. The secondary objective is to assess the association between hypoglycemia and adverse events.
Methods: We conducted a retrospective cohort study of patients with diabetes hospitalized on medicine wards from 2015 to 2018 in a tertiary care teaching hospital. Exposure was the average glycemia in the first 4 days of hospitalization, categorized into: ≥ 4.0 and ≤ 7.0 mmol/L (tight control),&gt; 7 and ≤ 10.0 mmol/L (loose control, reference group), &gt; 10.0 mmol/L (poor control). Hypoglycemia was defined as any glycemia&lt; 4 mmol/L. Primary outcome was a composite of adverse events, including infection, thromboembolic events, acute kidney injury, and mortality. Logistic regression models were used to assess the relationship between glycemic control and the primary composite outcome.
Results: A total of 1368 patients were included; 407 adverse events were recorded. Compared to loose glycemic control, tight and poor glycemic control was not associated with increased adverse events (tight control adjusted odds ratio [OR] 0.88, 95% confidence interval [CI] 0.63-1.23; poor control adjusted OR: 0.98, 95% CI 0.75-1.28). Any occurrence of hypoglycemia during hospitalization was associated with increased adverse events (adjusted OR 1.85, 95% CI 1.31-2.60).
Conclusion: Tight and poor glycemic control during hospitalization was not associated with increased adverse events compared to loose glycemic control. The result for poor glycemic control was unexpected and may be due to lack of significant difference between the average glycemia in loose and poor glycemic control groups. Hypoglycemia was associated with increased adverse events, suggesting the importance of hypoglycemia prevention during hospitalization.

Disclosure
L. Deng: None. W. Aibibula: None. Z. Talat: None. K.B. Filion: None. S. Eintracht: None. K. Dasgupta: None. V. Tagalakis: None. A. Majdan: Advisory Panel; Self; Abbott, Insulet Corporation. Consultant; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Lilly Diabetes, Sanofi-Aventis. O. Yu: None.
1884-P: Cardiomyocyte-Specific PKA Inhibition Ameliorates Cardiac Dysfunction Induced by Obesity
Authors: CHEN XIONGWEN 
Published: June 2020

Obesity and type 2 diabetic (T2D) cause cardiac dysfunction, which could be related to chronically activated sympathoadrenergic system (SAS). SAS system activation leads to the activation of PKA in cardiomyocytes. In this study, we aimed to test the hypothesis that chronically activated PKA plays an important role in obese induced cardiac dysfunction.
Methods and Results: 1. Cardiomyocyte specific PKA inhibition (cPKAi) transgenic (TG) mouse model (n=18) and nontransgenic littermate control (NLC, n=20) mice (3-month old) were fed with high fat food (D12451, Research Diet) or normal chow for 6 months.2. In 3-month old male TG mice, intraperitoneal glucose injection did not increase blood glucose as high as in 3-month old NLC mice. The area under the curve of cPKAi TG mice was significantly less than that of control mice. cPKAi transgenic mice had decreased cardiac function after overnight fasting while control mice did not have cardiac function decrement even though both types of mice had the same extend of glucose reduction after overnight fasting. 3. The BW increase was more in TG mice. 4. After HFD feeding, cPKAi TG group had better cardiac function: (1). The maximal systolic pressure (mmHg) of TG (107.8±4.49) was significantly higher than that of NLC (83.0±8.1) mice. (2). The end diastolic pressure (EDP, mmHg) of TG (2.7 ± 2.2) was significantly lower in TG mice (11.5 ± 3.3); (3). Maximum dp/dt was significantly greater in TG than in NLC mice; (4). The relaxation rate of the heart was significantly better in TG than in NLC mice; 5. The HW/BW (mg/g) was significantly less in TG mice (4.6 ± 0.2) than in control mice (5.2 ± 0.2). 6. HFD reduced myocytes contractions, Ca transients, and Ca currents in both groups but the reduction was less in TG myocytes. 7. TG hearts had less inflammatory cell infiltration and fibrosis than control hearts.
Conclusion: cPKAi enhances cardiac glucose uptake and ameliorates cardiac remodeling and preserves cardiac function in HFD-induced obese.

Disclosure
X. Chen: None.

Funding
American Diabetes Association (1-19-IBS-210)
1885-P: Fyn Regulates Sarcopenia by Autophagy
Authors: YAMADA EIJIRO , UEHARA RYOTA , NAKAJIMA YASUYO , HORIGUCHI KAZUHIKO , ISHIDA EMI , MATSUMOTO SHUNICHI , OKADA SHUICHI , BASTIE CLAIRE C. , YAMADA MASANOBU 
Published: June 2020

Sarcopenia is an important factor in reducing Activity of Daily Life. Sarcopenia has also been linked to insulin resistance. It has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. We focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation (Cell metabolism 2010, Cell Rep. 2012). We proceeded with further studies and demonstrating that Fyn-dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6-dependent and Fyn-dependent mechanisms. The binding of STAT3 and Fyn was confirmed by immunoprecipitation in an in vitro system. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not sufficient as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle. In addition, the findings are consistent with autophagy failure, and accumulation of glycogen (PAS staining) was observe. Increase of both IL6 and STAT3 expression/phosphorylation were observed in the muscles of those mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods.

Disclosure
E. Yamada: None. R. Uehara: None. Y. Nakajima: None. K. Horiguchi: None. E. Ishida: None. S. Matsumoto: None. S. Okada: None. C.C. Bastie: None. M. Yamada: None.