bluuebunny/crossref_metadata_2025 huggingface dataset:
184-LB: Incidence of Herpes Zoster in Patients with Type 2 Diabetes and Consequences for Treatment
Authors: POIRRIER JEAN-ETIENNE , NAGAR SAURABH , MEYERS JULIANA , GLASSER LISA , JABBOUR SERGE
Published: June 2020

Herpes zoster (HZ), or shingles, is a common neurocutaneous disease caused by reactivation of latent varicella-zoster-virus that often includes vesicular rash and neuropathic pain, the latter which may last for months or years. Several studies suggest that type-2 diabetes mellitus (T2DM) may represent an important risk factor for the development of HZ. This retrospective claims database analysis assessed the incidence of HZ in patients with T2DM in the U.S. and measured the impact of HZ on T2DM treatment.

Marketscan family of databases from 2013-2018 (Commercial, Medicare) or 2013-2017 (Medicaid) for adults aged 18 years and older was utilized. Crude rate incidence and incidence rate ratio (IRR) adjusted for age, gender, and payer type were calculated. Diabetes Complications Severity Index (DCSI), Charlson Comorbidity Index (CCI) scores and observed treatment usage (e.g., number of prescriptions, number of covered days) were determined before and after an HZ episode.

The overall crude rate incidence of HZ in patients with T2DM was 1.01% or 0.010 per person per year; in comparison, the overall crude rate incidence of HZ among patients without T2DM was 0.5%. The adjusted IRR was 1.68 (95% confidence interval: 1.67-1.70). Patients with T2DM and HZ had a mean age of 62 years, and 86% were commercially insured. An episode of HZ did not change either the DCSI or the CCI score. Regardless of HZ status, the most common T2DM complications were hypertension (78.9% in patients with T2DM only, 81.2% with T2DM and HZ), chronic pulmonary disease (20.1% and 24.3% respectively) and depression (14.1% and 16.3% respectively). Finally, an episode of HZ did not impact T2DM treatment usage.

In conclusion, patients with T2DM had 1.68 times the risk of having an HZ episode compared to patients without T2DM. An episode of HZ among patients with T2DM does not appear to specifically impact T2DM complications/severity or its treatment.

Acknowledgements: Business and Decision Life Sciences platform for publication coordination.

Disclosure

J. Poirrier: None. S. Nagar: Consultant; Self; GlaxoSmithKline plc. J. Meyers: Research Support; Self; GlaxoSmithKline plc. L. Glasser: Employee; Self; GlaxoSmithKline plc. S. Jabbour: None.

Funding

GlaxoSmithKline Biologicals SA (HO-19-19748)
1840-P: GPR40 Deficiency Is Associated with Steatosis, Hepatic Inflammation, and CD36 Upregulation in C57BL/6 Mice
Authors: LU ZHONGYANG , LI YANCHUN , LOPES-VIRELLA MARIA F. , HUANG YAN
Published: June 2020

GPR40 is a G-protein coupled receptor for medium and long-chain fatty acids. Since GPR40 is highly expressed in pancreatic islets and GPR40 activation increases glucose-stimulated insulin secretion from pancreatic beta cells, GPR40 is considered as a potential target for treatment of type 2 diabetes mellitus (T2DM). However, although nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM and GPR40 is also expressed in hepatocytes and macrophages, the role of GPR40 in high-fat diet (HFD)-induced NAFLD in animal models remains unknown. In this study, we fed wild type or GPR40 knockout (KO) C57BL/6 mice low-fat diet (LFD) or HFD for 20 weeks and then analyzed the effect of GPR40 KO on HFD-induced NAFLD. Metabolic assays showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT) as expected, but GPR40 KO did not further change these parameters in HFD-fed mice. Interestingly, in LFD-fed mice, GPR40 KO increased bodyweight, insulin, insulin resistance, cholesterol and ALT. Histological analysis and Oil Red O staining showed that HFD induced steatosis while GPR40 KO only slightly reduced HFD-induced steatosis. Surprisingly, GPR40 KO in LFD-fed mice induced steatosis. Furthermore, study showed that while HFD increased immunostaining of F4/80, a biomarker for macrophages, GPR40 KO also increased F4/80 immunostaining in LFD-fed mice. Finally, we found that while HFD increased mRNA expression of CD36, a scavenger receptor that also imports long-chain fatty acids into cells, by 5-fold in liver, GPR40 KO increased it by 9-fold in LFD-fed mice. Taken together, this study showed that GPR40 deficiency was associated with insulin resistance, dyslipidemia, steatosis and hepatic inflammation in LFD-fed mice. This study also showed that GPR40-deficiency led to a robust upregulation of CD36 expression in liver, which is likely involved in GPR40 deficiency-associated steatosis and hepatic inflammation.

Disclosure

Z. Lu: None. Y. Li: None. M.F. Lopes-Virella: None. Y. Huang: None.

Funding

National Institutes of Health (DE027070); U.S. Department of Veterans Affairs (BX000854)
1844-P: Agpat5 Promotes Obesity-Associated Hyperinsulinemia
Authors: CLAIR SAMANTHA L. ST. , BELISLE SABRINA L. , BRUGGEMAN SYDNEY , LEYVA JAIMES FERNANDA B. , BURGESS BOBBI A. , LI ZHONGGANG , PARKS BRIAN
Published: June 2020

Hyperinsulinemia in association with obesity is a key contributor to type 2 diabetes. Using a mouse genetic reference population, we identified Agpat5, 1-acylglycerol-3-phosphate O-acyltransferase 5, as a gene associated with plasma insulin levels after high fat feeding. Using a genetic interaction analysis, we also uncovered a relationship between Agpat5 and Foxo1, Forkhead Box O1. Agpat5 is an acyltransferase that produces diverse phospholipids by esterifying lysophospholipids. Foxo1 is an insulin responsive transcription factor. To biologically validate the role of Agpat5 in obesity associated hyperinsulinemia, we treated obese high fat fed mice with an antisense oligonucleotide (ASO) that targets Agpat5 to inhibit its gene expression. We show that Agpat5 ASO treated obese mice have significantly lower fed and fasting plasma insulin, as well as improved glucose tolerance and reduced Foxo1 protein. Analysis of insulin secretion and clearance indicates that Agpat5 ASO treated mice clear insulin more efficiently, as assessed by c-peptide to insulin ratio. To understand the tissue-specific roles of Agpat5 in obesity, we generated liver- and adipose- specific knockout mice. We show that hepatic Agpat5 promotes hepatic insulin resistance and hyperinsulinemia through a mechanism involving hepatic Foxo1. Furthermore, we show that adipose Agpat5 promotes hyperinsulinemia and adiposity. Our studies suggest that Agpat5 promotes hyperinsulinemia in obesity through regulation of Foxo1 signaling and insulin clearance.

Disclosure

S.L. St. Clair: None. S.L. Belisle: None. S. Bruggeman: None. F.B. Leyva Jaimes: None. B.A. Burgess: None. Z. Li: None. B. Parks: None.
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 >199mg/dl was considered T2D and remission was BL<126 mg/ml and HbA1c<6.5% and 2 hr glucose <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),> 7 and ≤ 10.0 mmol/L (loose control, reference group), > 10.0 mmol/L (poor control). Hypoglycemia was defined as any glycemia< 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.
1887-P: Intermittent Hypoxia Increased the Expressions of Interleukin (IL)-8, Osteonectin, and Myonectin via OCT1 and Nrf2 Binding to the Promoters in Muscle Cells
Authors: TAKASAWA SHIN , SHOBATAKE RYOGO , ITAYA-HIRONAKA ASAKO , MAKINO MAI , SAKURAMOTO-TSUCHIDA SUMIYO , UCHIYAMA TOMOKO , OTA HIROYO , YAMAUCHI AKIYO
Published: June 2020

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells either to 70 cycles/24 h of IH (5 min hypoxia [1% O2]/10 min normoxia [21% O2]), mimicking SAS patients, or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction, and found that IH significantly increased the mRNA levels of interleukin-8 (IL-8), osteonectin (ON), and myonectin (MN). IL-8, ON, and MN in IH-treated RD cell medium were also increased (P<0.0001, P<0.0001, and P=0.0079, respectively). We further analyzed the IH-induced expression mechanisms of IL-8, ON, and MN genes in RD muscle cells. Deletion analyses revealed that -152 to -151 region in IL-8, -105∼-99 region in ON, and -3,741∼-3,738 region in MN promoter(s) were responsible for the activation by IH. The promoters contain consensus transcription factor binding sequences for octamer binding transcription factor 1 (OCT1) in IL-8 and MN, and for nuclear factor erythroid 2-related factor 2 (NRF2) in ON, respectively. The introduction of siRNA for OCT1, and NRF2 abolished the increase of mRNAs for IL-8 and MN, and ON, respectively. As IL-8, ON, and MN are reported to be myokines and associated with glucose intolerance, insulin resistance, and diabetes, the results could well explain a mechanism of glucose intolerance, insulin resistance, and diabetes in SAS patients.

Disclosure

S. Takasawa: None. R. Shobatake: None. A. Itaya-Hironaka: None. M. Makino: None. S. Sakuramoto-Tsuchida: None. T. Uchiyama: None. H. Ota: None. A. Yamauchi: None.
1889-P: Light Exercise and Liraglutide Synergistically Improve Muscle Insulin Action in Diet-Induced Obesity
Authors: LIU JIA , AYLOR KEVIN W. , LIU ZHENQI
Published: June 2020

Insulin recruits muscle microvasculature which contributes to insulin’s metabolic action but is blunted in humans with obesity. Both exercise and glucagon-like peptide 1 (GLP-1) are potent enhancers of muscle microvascular perfusion and their actions are preserved in the insulin resistant states. To examine whether light exercise and GLP-1 receptor agonism modulate insulin’s microvascular and metabolic actions during the development of obesity, adult male rats were fed a high-fat diet (HFD) for 2 weeks with either free access to running wheel (light exercise), liraglutide (200 mcg/kg subcutaneously twice daily), or light exercise + liraglutide. Rats were then fasted overnight and received a euglycemic insulin clamp (3 mU/kg/min) for 120 min. Insulin-mediated muscle microvascular recruitment was measured using contrast-enhanced ultrasound. Rats on HFD alone (control) displayed marked microvascular insulin resistance. Light exercise increased basal plasma nitric oxide levels and fully rescued insulin’s microvascular action. Liraglutide similarly increased basal plasma NO contents but did not reverse microvascular insulin resistance. Both light exercise and liraglutide improved insulin-stimulated whole body glucose disposal in the first 30 min but did not significantly increase the steady-state glucose infusion rates. Combined light exercise and liraglutide treatment not only fully restored microvascular insulin responses but also significantly enhanced insulin-stimulated whole body glucose disposal (>50%, p<0.01). We conclude that light exercise and liraglutide differentially modulate microvascular insulin responses but synergistically enhance metabolic insulin actions during the development of obesity. Our findings provide a novel insight into the exercise and liraglutide interplay and support the early use of exercise and GLP-1 receptor agonism to correct microvascular and metabolic insulin resistance during the development of obesity.

Disclosure

J. Liu: None. K.W. Aylor: None. Z. Liu: None.

Funding

American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)
1890-P: Glycemic Control and Ultrasonic Measures of Muscle Mass in Older Adults with Type 2 Diabetes
Authors: MADDEN KENNETH M. , FELDMAN BORIS , ARISHENKOFF SHANE , SY SARAH , MENEILLY GRAYDON S.
Published: June 2020

Background: Skeletal muscle is the biggest ’glucose sink’ in the body. Sarcopenia (age-related loss of muscle mass) is extremely common in older adults and is one of the factors responsible for the increased prevalence of type 2 diabetes in this population. We examined the association between bedside ultrasonic measures of muscle thickness and measures of glycemic control in older adults with type 2 diabetes.

Methods: 72 older adults (age >= 65) with type 2 diabetes were recruited sequentially from a geriatric medicine clinic (mean age 80.5±0.6 years, 26 women, 46 men). Each subject had glycosylated hemoglobin (HgAIC) lean body mass (LBM, by bioimpedance assay), and ultrasonic measures of muscle quantity (MT, vastus medialis muscle thickness) measured. Our initial models contained age, sex, bmi, and MT as predictor variables, and our outcome variable was HgAIC.

Results: In our final parsimonious models, HgAIC showed a significant positive association with increasing MT(Standardized β=0.237±0.116, R2 = 0.06, p=0.045) and a trend towards a negative correlation with LBM(Standardized β = -0.239±0.126, R2 = 0.07, p=0.063).

Conclusions: Unexpectedly, increased measures of muscle thickness were associated with worse, instead of improved, glycemic control. This suggests that other factors, such as muscle quality (myosteatosis) need to be considered in the older adult population with type 2 diabetes.

Disclosure

K.M. Madden: None. B. Feldman: None. S. Arishenkoff: None. S. Sy: None. G.S. Meneilly: Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc.

Funding

Allan M. McGavin Foundation
1893-P: The Integrative Role of ER Protein Quality Control Pathways (ERQC) in Prohormone Maturation
Authors: SHI GUOJUN , PAN XUYA , WANG HETING , ARVAN PETER , QI LING
Published: June 2020

Background: Peptide hormones are crucial regulators of metabolism. However, maturation of hormone precursors (prohormones) in the endoplasmic reticulum (ER) in vivo remains largely unexplored.

Aims: This project aims to study the integrative role of the two major protein quality control pathways in the ER, ER-Associated Degradation (ERAD) and autophagy, in regulating prohormone maturation under physiological conditions. Taking vasopressin precursor (proAVP) as a model, this project will provide novel insights on hormone maturation and the physiological function of ERQC pathways.

Methods: We generated AVP neuron specific ERAD and Autophagy deficient mouse models by deleting Sel1L and Atg7, respectively. We also generated Sel1L and Atg7 deficient cell models. We used immunostaining, sucrose sedimentation, and Western blots to dissect the roles of ERAD and autophagy in proAVP folding and maturation.

Results: Mice with Atg7 deficiency in AVP neurons maintain normal water homeostasis, while Sel1L deficient mice develop central diabetes insipidus. Further, Atg7 deficient neurons show reduced proAVP protein and altered subcellular distribution, but its ER export remains functional. Mechanically, unlike Sel1L deficiency, Atg7 deficiency alone shows amber accumulation of misfolded proAVP in vitro; however, further blocking autophagy with ERAD deficiency shows increased portion of misfolded proAVP comparing with ERAD deficiency along. Further, combined deletion of Atg7 and Sel1L in AVP neurons leads to earlier development of Diabetes Insipidus comparing with Sel1L deficiency alone, suggesting a critical role of autophagy in maintaining AVP maturation with compromised ERAD.

Conclusions: Here we demonstrate that autophagy alone is dispensable for the maturation of proAVP in the ER, but is indispensable in the event of compromised ERAD function both in vivo and in vitro. This study points to the differential roles and crosstalk between ERAD and autophagy in neuroendocrine cells.

Disclosure

G. Shi: None. X. Pan: None. H. Wang: None. P. Arvan: None. L. Qi: None.

Funding

National Institutes of Health (R01DK120047); University of Michigan (U064133)
1905-P: Downregulation of HMGCS2 Expression in Small Intestinal Mucosa Biopsies after Roux-en-Y Gastric Bypass Surgery: A Possible Contributor to GLP-1 Hypersecretion?
Authors: LEGART CHRISTIAN , JORSAL TINA , HAGEMANN CHRISTOFFER A. , WORM DORTE , JUHL CLAUS B. , ANDRIES ALIN R. , ZHANG CHEN , VRANG NIELS , RIGBOLT KRISTOFFER , JELSING JACOB , VILSBØLL TINA , KNOP FILIP K.
Published: June 2020

Background and Aims: Roux-en-Y gastric bypass (RYGB) surgery significantly improves glucose metabolism independently of surgery-induced weight loss; partly due to the increased postprandial secretion of the insulinotropic gut hormone glucagon-like peptide 1 (GLP-1). Mouse studies have shown that intestinally derived ketone bodies inhibit GLP-1 secretion from enteroendocrine L cells, and it was recently suggested that RYGB-induced downregulation of intestinal ketogenesis contributes to the increased GLP-1 secretion after RYGB. We investigated the intestinal expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses before and after RYGB.

Materials and Methods: Twenty obese individuals underwent mixed meal tests and anterograde enteroscopy with gut mucosal biopsy retrieval before and 3 months after RYGB. A global gene expression analysis was performed on the mucosal biopsies. Here, we report the expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses.

Results: We observed a significant 7.6-fold downregulation of the gene encoding 3-hydroxy-3- methylglutaryl-CoA synthase 2 (HMGCS2) (the rate-determining enzyme in ketogenesis) in the alimentary limb after RYGB. The proglucagon gene encoding GLP-1 was significantly upregulated after surgery and postprandial plasma GLP-1 responses increased significantly after RYGB.

Conclusions: RYGB-induced downregulation of intestinal HMGCS2 gene expression in obese individuals may indicate reduced intestinal ketogenesis; supporting the notion (originating from animal studies) that reduced ketone body-mediated inhibition of L cells constitute a contributor to postprandial hypersecretion of GLP-1 after RYGB.

Disclosure

C. Legart: None. T. Jorsal: None. C.A. Hagemann: Employee; Self; Gubra. D. Worm: None. C.B. Juhl: None. A.R. Andries: None. C. Zhang: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.
1908-P: Glucagon Receptor Expression Evaluated by Antibody-Dependent and -Independent Approaches
Authors: KJELDSEN SASHA , GALSGAARD KATRINE D. , WINTHER-SOERENSEN MARIE , SERIZAWA REZA , PEDERSEN JENS , ORSKOV CATHRINE , ALBRECHTSEN REIDAR , SORENSEN CHARLOTTE M. , GLUUD LISE , HOLST JENS J. , WEWER ALBRECHTSEN NICOLAI J.
Published: June 2020

Glucagon regulates metabolic functions through the glucagon receptor (GCGR). Agonists as well as antagonists of GCGR are evaluated as treatments of diabetes and obesity. To understand the role of glucagon, knowledge of GCGR localization is important but limited. Twelve commercially available GCGR antibodies were evaluated using HEK293 cells transfected with mouse or human GCGR cDNA transcripts. Eleven of the 12 GCGR antibodies showed staining of GCGR protein from both species, but not in cells transfected with a scrambled vector. Several of the antibodies stained liver sections from both GCGR+/+ and GCGR-/- mice. Staining was absent in fat and muscle tissues but present in the distal tubuli of the kidney. Two antibodies did not react with tissue from GCGR-/- and were further evaluated by western blotting of GCGR transfected cells. Bands corresponding to the predicted size of the GCGR (62kDa) were identified but larger bands were also observed. Liver tissue from healthy subjects and individuals with nonalcoholic steatohepatitis (NASH) was stained using same GCGR antibodies and based on qualitative intensities GCGR staining did not seem to vary between healthy and NASH liver sections. We used autoradiography to confirm the immunohistochemistry findings. In mice injected with 125I-labeled glucagon, grains were found in the liver and in the distal tubuli of the kidney, whereas fat and muscle sections were negative. To investigate the role of renal GCGR’s, we infused glucagon (1µg) in rats with and without blockade of the GLP-1 receptor (GLP-1R) (Exendin 9-39). Glucagon increased diuresis and renal blood flow, but not blood pressure, in a GLP-1R dependent manner. Urea excretion was numerically increased by glucagon (P=0.08).

In conclusion, glucagon receptor localization is challenging due to the lack of suitable commercially available GCGR antibodies. The actions of glucagon on renal parameters may be mediated by the GLP-1R. Glucagon’s role in kidney physiology needs further investigation.

Disclosure

S. Kjeldsen: None. K.D. Galsgaard: None. M. Winther-Soerensen: None. R. Serizawa: None. J. Pedersen: None. C. Orskov: None. R. Albrechtsen: None. C.M. Sorensen: None. L. Gluud: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

Funding

Novo Nordisk Foundation (NNF19OC0055001)
1909-P: The Natriuretic Action of Glucagon-Like Peptide-1 in Humans Is Abolished by the GLP-1 Receptor Antagonist Exendin 9-39
Authors: ASMAR ALI , CRAMON PER K. , ASMAR MEENA , SIMONSEN LENE , MADSBAD STEN , SORENSEN CHARLOTTE M. , HARTMANN BOLETTE , HOLST JENS J. , HOVIND PETER , JENSEN BOYE L. , BÜLOW JENS
Published: June 2020

We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days.

In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519.

Disclosure

A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. P. Hovind: None. B.L. Jensen: None. J. Bülow: None.