bluuebunny/crossref_metadata_2025_split huggingface dataset:
196-LB: Prenatal and Lifestyle Contributions to Child Insulin Sensitivity
Authors: ALVES JASMIN , CHOW TING , ZINK JENNIFER , LUO SHAN , MARTINEZ MAYRA P. , ROMERO ANA , XIANG ANNY , PAGE KATHLEEN A. 
Published: June 2019

Background: Early life exposures play an important role in metabolic health throughout life. We examined how prenatal exposures to maternal obesity or gestational diabetes mellitus (GDM) and low levels of physical activity and increased food intake may contribute to reductions in insulin sensitivity in childhood.
Methods: Participants were 7-10 year old children who were born at Kaiser Permanente Southern California. Maternal pre-pregnancy BMI and GDM status were extracted from electronic medical records. Child weight and height were measured, and oral glucose tolerance tests were performed. Insulin sensitivity was estimated using the Matsuda insulin sensitivity index (ISI). Diet was assessed using 24-hour dietary recalls and daily energy intake (EI) was calculated. Physical activity was assessed using a 3-day physical activity recall and average min/day of moderate to vigorous physical activity (MVPA) was calculated. Linear regression was used to assess ISI associations with the exposures.
Results: 92 children (52 girls; 40 boys; 55 GDM-exposed; 37 unexposed) participated. Maternal pre-pregnancy BMI ranged from 19.0-50.4 kg/m2. Mean±SD child age was 8.3±0.9 years, BMI z-score: 0.60±1.1, ISI: 10.6±5.9, EI: 1790.7±444.2 kcal, and MVPA: 118.7±93.8 min/day. Children who spent more time in MVPA had better insulin sensitivity (β=0.82; P=.02). Adjusting for maternal pre-pregnancy BMI, GDM exposure, child age, sex, and EI, did not affect this relationship (β=0.87; P&lt;.01), nor did further adjusting for BMI z-score (β=0.78; P=.01). Prenatal exposure to GDM and child ISI (β=0.19, P=.28) and maternal pre-pregnancy BMI were not significantly associated with child ISI (β=-0.01, P=0.40), nor was child’s EI associated with ISI (β=0.001; P=.59).
Conclusions: Time spent in MVPA was the strongest predictor of child insulin sensitivity. Our findings suggest that engaging in MVPA during childhood is beneficial for insulin sensitivity and may help ameliorate future risk for metabolic disease.

Disclosure
J. Alves: None. T. Chow: None. J. Zink: None. S. Luo: None. M.P. Martinez: None. A. Romero: None. A. Xiang: None. K.A. Page: None.

Funding
American Diabetes Association (1-14-ACE-36 to K.A.P.); National Institutes of Health (1F31MH115640-01A1)
1962-P: Comparison of the Effects of Three SGLT2 Inhibitors on Metabolic Parameters and Insulin Sensitivity in a Nondiabetic Rat Model of Metabolic Syndrome
Authors: TRNOVSKA JAROSLAVA , HÜTTL MARTINA , MARKOVÁ IRENA , OLIYARNYK OLENA , MALINSKA HANA , MIKLANKOVA DENISA , KRATOCHVILOVA HELENA , SVOBODA PETR , CINKAJZLOVA ANNA , LANKOVA IVANA , MRAZ MILOS , HALUZIK MARTIN 
Published: June 2019

Studies directly comparing metabolic efficacy of various sodium glucose cotransporter-2 inhibitors (SGLT2i) are scarce. To this end, we compared the effect of SGLT2i: Empagliflozin (EMP), Canagliflozin (CAN) and Dapagliflozin (DAP) on biometric, metabolic and hormonal parameters and insulin sensitivity in hereditary hypertriglyceridemic rats (hHTG) - a non-obese model of metabolic syndrome characterized by dyslipidemia, insulin resistance and increased blood pressure. Male rats, 4 months old, were fed standard diet (C) or standard diet enriched by EMP (10mg/kg b.w./day), CAN (100mg/kg b.w./day) or DAP (10mg/kg b.w./day) for 6 weeks. All SGLT2i induced glycosuria which was 8-fold higher in CAN and DAP as compared to EMP group (Mean±SD: EMP:53±6; CAN:416±4; DAP:376±32 mmol/l; P&lt;0.001). CAN decreased body weight relative to C while EMP and DAP had no significant effect. Visceral fat weight decreased in CAN and DAP compared to C (P&lt;0.01). Relative weight of kidneys (g/100g b.w.) was increased in all SGLT2i groups compared to C with a less pronounced effect of EMP relative to CAN and DAP (P&lt;0.01). CAN decreased both fasting and postprandial glycemia relative to other groups. Postprandial triglyceride levels were decreased by all SGLT2i compared to C (EMP: -32%; P&lt;0.01; CAN: -55%; DAP -48%, P&lt;0.001). 14C-palmitic acid oxidation decreased in the myocardium of CAN and DAP compared to C, whereas no significant effect of EMP was noted. CAN and EMP administration reduced liver glycogen content compared to C (P&lt;0.05). Leptin levels decreased in CAN (-79%) and DAP (-56%) compared to C. GLP-1 levels increased in CAN compared to other groups while C-peptide was lower in CAN vs. C group.
In conclusion, our results suggest higher efficacy of CAN compared to DAP and EMP in improving insulin sensitivity and decreasing glucose levels in a non-obese model of metabolic syndrome. The differences could be related to higher SGLT1 inhibition activity of CAN.

Disclosure
J. Trnovska: None. M. Hüttl: None. I. Marková: None. O. Oliyarnyk: None. H. Malinska: None. D. Miklankova: None. H. Kratochvilova: None. P. Svoboda: None. A. Cinkajzlova: None. I. Lankova: None. M. Mraz: None. M. Haluzik: None.

Funding
MH CZ - DRO; Institute for Clinical and Experimental Medicine (IN00023001)
1970-P: Epinephrine and Insulin Stimulates White Adipocyte Secretion of Diverse Adiponectin Forms
Authors: MUSOVIC SALIHA , KOMAI ALI M. , NORDBECK ELIN BANKE , NOOR UMUL-KHAIR A. , ASTERHOLM INGRID WERNSTEDT , OLOFSSON CHARLOTTA S. 
Published: June 2019

The white adipocyte hormone adiponectin is released in different molecular forms and a reduction of high-molecular weight (HMW) adiponectin has specifically been associated with the development of metabolic disease. We have recently shown that adiponectin is released via cAMP/epinephrine-stimulated exocytosis, involving activation of beta 3 adrenergic receptors (beta3ARs). However, a number of studies have, seemingly incompatible with the catecholamine-triggered release, reported that insulin (lowers cAMP) increases adiponectin secretion. Here we have pinpointed the differences between insulin- and catecholamine-stimulated short-term adiponectin secretion. Using a combination of biophysical and biochemical techniques applied to mouse and human adipocytes as well as whole animal studies, we show that catecholamines specifically stimulate the rapid exocytosis of high-molecular weight (HMW) adiponectin. In contrast, insulin induces secretion of smaller adiponectin forms only, with slower time kinetics. The catecholamine-stimulated secretion of HMW adiponectin is blunted in adipocytes isolated from obese and diabetic mice (8 weeks high-fat diet) and this secretory defect is paralleled by a ∼50% reduction of serum HMW adiponectin. The insulin-induced release of smaller adiponectin forms is also abrogated i adipocytes from obese/diabetic mice. However, the total serum adiponectin level remains unaltered, likely due to enhanced basal (unstimulated) release of smaller adiponectin forms. Our findings suggest that insulin and catecholamines have entirely different roles in the regulation of adiponectin secretion and demonstrate a previously unknown role of beta3ARs for human white adipocyte physiology. We propose that the reduced levels of HMW adiponectin observed in diabetic individuals, and that have been linked to the development of metabolic disease, is a result of a secretory disturbance largely depending on disrupted adrenergic signaling.

Disclosure
S. Musovic: None. A.M. Komai: None. E. Banke Nordbeck: None. U.A. Noor: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None.

Funding
Swedish Diabetes Foundation; Knut and Alice Wallenberg Foundation; Swedish Medical Research Council
1978-P: Possible Regulation between Estrogen and Gas6 Gene in Adipogenesis
Authors: LEE CHIEN-HSING 
Published: June 2019

Background: The physiological withdrawal of estrogen during menopause brings about changes in fat metabolism. Previous cell-based studies showed estrogen had direct effects on adipocytes. Gas6 is the ligand for the Tyro-3, Axl and Mer (TAM) receptors, and Gas6/TAM signaling stimulates cellular responses. Recent studies indicate that Gas6 gene was involved in adipocyte development, and human Gas6 levels were associated with obesity. Our clinical data showed Gas6 levels were positively correlated with estradiol (E2) levels in the postmenopausal women. However, the regulation mechanism between E2 and Gas6 gene in adipocyte functions is still unknown. In this study, we try to investigate the possible role of Gas6 gene that involved in estrogen effect on adipocyte development.
Materials and Methods: Human and mouse adipocyte cell lines, SGBS and 3T3-L1, were used as in vitro cell model and ovariectomy rat was used as the postmenopausal animal model.
Results: Our data showed increased estrogen receptor α (ERα) and Gas6 expression after E2 treatment in both SGBS and 3T3-L1 cell lines. Meanwhile, E2 treatment can decrease adipogenesis-related genes expression. Furthermore, we used estrogen antagonism in adipocyte that blocked the ERα and then reduced Gas6 expression and reversed the expression of adipogenesis-related genes. The luciferase assay confirmed that Gas6 gene expression was activated after E2 treatment through the genomic pathway. In addition, estrogen may also regulate Gas6 expression through non-genomic AMPK pathway. Finally, our animal model data showed significantly decreased Gas6 expression in adipose tissue from ovariectomy rats compared to the sham operation group. Interesting, the Gas6 expression in adipose tissue was increased in ovariectomy rats after E2 supplement.
Conclusion: Our study first elucidates the E2 effect on adipogenesis-related genes expression and adipocyte function and may partially through genomic and non-genomic pathways to activate Gas6 gene expression.

Disclosure
C. Lee: None.
1990-P: STAT1 Knockdown in CD11c+ Cells Prevents Adipose Tissue Inflammation and Metabolic Dysfunction in Mice on High-Fat Diet
Authors: ANTONY ANTU KALATHOOKUNNEL , PERRARD XIAOYUAN , LIAN ZEQIN , PERRARD JERRY , BALLANTYNE CHRISTIE M. , WU HUAIZHU 
Published: June 2019

Background: Classically activated M1-like CD11c+ macrophages/dendritic cells (MDCs) are increased in obese adipose tissue (AT) and may contribute to AT inflammation and the development of insulin resistance in obesity. STAT1 is a key transcription factor for MDC polarization into M1-like phenotypes. Here, we examined the role of STAT1 in obesity-induced AT MDC polarization and inflammation and insulin resistance in mice.
Methods: Mice with specific knockout (KO) of STAT1 in CD11c+ MDCs were generated by crossbreeding STAT1fl/fl and CD11c-Cre mice. CD11c/STAT1 KO and littermate controls were fed high-fat diet (HFD, 16 weeks) to induce obesity and evaluated for immune cells and browning/beige adipogenesis in perigonadal (pAT) and inguinal (iAT) AT and metabolic functions.
Results: Compared to control mice, KO mice on HFD had similar body weight. Analyses of AT immune cells revealed that compared to controls, KO mice had a decrease in M1-like proinflammatory polarization but an increase in M2-like polarization of macrophages and reduced CD8+ T cell number in pAT, and significant increases in the proportion of IL-5+ Th2 cells and eosinophils (CD170+) in pAT and iAT (p&lt;0.05). Furthermore, compared to control mice, KO mice showed significantly increased iAT expression of browning markers (Ucp-1, Cidea, and prdm16) and had increased oxygen consumption rate but lower respiratory exchange ratio, indicating higher energy expenditure and increased fat utilization as energy source. Moreover, KO mice, as compared to controls, had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance examined by insulin and glucose tolerance test (p&lt;0.05).
Conclusion: STAT1 plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

Disclosure
A. Kalathookunnel Antony: None. X. Perrard: None. Z. Lian: None. J. Perrard: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. H. Wu: None.

Funding
American Diabetes Association (1-17-IBS-082 to H.W.)
1992-P: Early and Chronic Exposure to Penicillin Increases Obesity and Insulin Resistance in High-Fat Diet-Fed Mice
Authors: NOH HYE LIM , SUK SUJIN , FRIEDLINE RANDALL H. , HU XIAODI , TRAN DUY A. , TAUER LAUREN A. , CHOI JUNGEUN , KO MIN-JI , KIM BRANDON , SURAPANENI TANUJ , BLASER MARTIN J. , KIM JASON K. 
Published: June 2019

Increasing prevalence of antibiotic use may have health consequences given their effects on gut microbiome. Male and female C57BL/6J mice were exposed to a low-dose penicillin (7 mg/L) during the first 4 weeks of life via maternal drinking water (PCN; n=6-10) or continuously (PCN-C; n=4-5), and a high-fat diet (HFD) was started at 6 weeks of age. Whole body fat mass began to increase in male PCN and PCN-C groups after 5 weeks of HFD (Figure 1). This was largely due to 20% decrease in physical activity in PCN mice. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp after 20 weeks of HFD, and glucose infusion rate (GIR) and glucose turnover (GT) were significantly reduced in PCN-C group. The PCN group showed increased hepatic insulin resistance compared to Control (n=12; Figure 2). In female mice, PCN effects were more pronounced with increased fat mass after 1 week of HFD (Figure 3). This was due to 30% decrease in physical activity in female PCN mice compared to Control (n=5). After 20 weeks of HFD, female Control mice remained insulin sensitive, but female PCN-C mice developed insulin resistance with 20% decreases in GIR and GT (Figure 4).
In conclusion, these results show that early life or chronic exposure to penicillin negatively affects energy balance and glucose metabolism in mice with larger effects in female mice. Our findings indicate an important role of antibiotic exposure in obesity and insulin resistance.

Disclosure
H. Noh: None. S. Suk: None. R.H. Friedline: None. X. Hu: None. D.A. Tran: None. L.A. Tauer: None. J. Choi: None. M. Ko: None. B. Kim: None. T. Surapaneni: None. M.J. Blaser: None. J.K. Kim: None.

Funding
National Institutes of Health (5U2C-DK093000)
1995-P: Optimization of DACRA Dosing Frequency—The Balance between Efficacy and Tolerability
Authors: LARSEN ANNA T. , ANDREASSEN KIM V. , SONNE NINA , KARSDAL MORTEN ASSER , HENRIKSEN KIM 
Published: June 2019

Potent dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity. Notably, DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. This indicates that a less frequent dosing could be feasible, although the tolerability is a question mark. In this study, we compared daily dosing to dosing every other day to characterize the tolerability and efficacy of these regimens. High fat fed Sprague Dawley rats were treated 9 weeks by s.c. injections of the DACRA KBP in two different dosing intervals corresponding to a daily dose of 1.5 nmol/kg. KBP was dosed either daily (q.d., 1.5 nmol/kg) or every other day (q.a.d, 3 nmol/kg). After 3 and 8 weeks of treatment oral glucose tolerance tests were performed 24 hours post injection of treatment. Both treatments resulted in an initial reduction in food intake. KBP q.d. resulted in a transient reduction in food intake that normalized within the first 10 days of treatment, while KBP q.a.d resulted in fluctuating food intake throughout the study. The fluctuations reflected the dosing intervals resulting in a marked suppression of food intake following dosing, however food intake normalized on non-dosing days. This difference is reflected in the accumulated food intake, where KBP q.a.d tended to have a lower food intake than KBP q.d. Both treatments resulted in sustained and significant weight loss as well as reductions in the overall adiposity. Interestingly, KBP q.a.d tended to induce a larger weight loss than KBP q.d., albeit with fluctuations reflecting the dosing intervals. In addition, KBP dose dependently improved oral glucose tolerance with significant reduced insulin levels both after 3 and 8 weeks of treatment.
In conclusion, dosing KBP every other day positively affects the efficacy confirming that less frequent dosing with KBP could be feasible.

Disclosure
A.T. Larsen: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. N. Sonne: None. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.
1997-P: Cross Talk between EPO and Estrogen Signaling in Regulation of Fat Mass
Authors: LEE JEEYOUNG , ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2019

Erythropoietin (EPO), the cytokine that regulates erythropoiesis, contributes to metabolic regulation in rodents. The increase in red blood cell production with EPO treatment in mice was accompanied by improved glycemic control, and by attenuated body weight gain via reducing fat mass in male mice. No change in body weight was observed in mice with EPO receptor restricted to erythroid tissue, suggesting that EPO regulation of body weight is a non-erythroid response. EPO stimulated decrease in fat mass was observed in ovariectomized female mice on high fat diet, but not after estradiol supplementation or in ovariectomized female mice on normal chow, providing evidence for estrogen related gender specific EPO action in metabolic regulation beyond erythropoiesis. Here we determine the contribution of estrogen response in EPO metabolic regulation by assessing EPO treatment in estrogen receptor α knockout (ERαKO) mice. Male and female ERαKO mice exhibit decreased glucose tolerance, increased fat mass and, in female ERαKO mice, increased lean mass compared with WT control mice. Overall, EPO stimulated increase in hematocrit in male and female ERαKO mice on high fat diet was accompanied by improvement in glucose tolerance comparable to that observed in WT control mice treated with EPO. EPO treatment in male ERαKO and WT mice show significantly reduced the increase in fat mass while on high fat diet compared with saline treatment. Similarly, EPO treatment in female ERαKO mice on high fat diet show reduced fat mass gain compared to saline treatment. In contrast, EPO treatment did not affect fat mass in female WT mice on high fat diet. We also observed that on normal chow diet, EPO treatment was able to reduce fat mass in female ERαKO mice, but not in female WT mice, confirming the role of estrogen in mediating the sex-differential effect of EPO in regulating fat mass. These results are evidence of cross talk between EPO and estrogen for metabolic homeostasis and regulation of body mass in female mice.

Disclosure
J. Lee: None. H. Rogers: None. C.T. Noguchi: None.
2-OR: Metabolic Inflexibility in Patients with Type 2 Diabetes and Heart Failure
Authors: HOŠKOVÁ EVA , KOPECKY JAN , VELEBA JIRI , VELEBOVA KATERINA , MELENOVSKY VOJTECH , PELIKANOVA TEREZIE 
Published: June 2019

Introduction: Patients with type 2 diabetes (DM) are known to have decreased metabolic flexibility when switching between carbohydrate and lipid oxidation. Our aim was to assess the energy substrates utilization in patients with isolated heart failure (HF) and HF with DM.
Methods: A cross-sectional comparative trial with 77 subjects in 4 age matched groups. 21 healthy subjects (HF-DM-), 14 patients with HF alone (HF+DM-), 21 patients with diabetes alone (HF-DM+) and 21 patients with DM or prediabetes and heart failure (HF+DM+). The subjects underwent indirect calorimetry before and during hyperinsulinemic isoglycemic clamp.
Results: Metabolic clearance of glucose (MCG) was significantly lower (p ˂ 0.05) in the groups of patients with DM+ (HF-DM-: 6.08 ± 2.03; HF+DM-: 5.86 ± 2.37; HF-DM+: 4.29 ± 2.2; HF+DM+: 3.9 ± 1.76 ml/kg.min). Compared to healthy subjects all the other groups had significantly smaller increase in respiratory quotient during clamp (p ˂ 0.01 for HF-DM- vs. HF+DM- and HF-DM- vs. HF-DM+; p ˂ 0.05 for HF-DM- vs. HF+DM+). Differences between groups with isolated HF and isolated DM were not significant, see Table.
Conclusions: Our results on a unique group of patients show similarly deteriorated metabolic flexibility of carbohydrate versus lipid oxidation in patients with type 2 diabetes and heart failure supporting the comparable deleterious effect of both diseases on utilization of energy substrates.

Disclosure
E. Hošková: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None.

Funding
Czech Health Research Council (AZV16-27496A)
200-LB: Pregestational Diabetes and Pregnancy Outcomes
Authors: ALI DALAL S.A. , HATUNIC MENSUD 
Published: June 2019

Pre-gestational diabetes, type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are associated with adverse outcomes: miscarriage, stillbirth, macrosomia and increased rates of emergency cesarean sections (EMCS). We reviewed 175 women with pre-gestational diabetes who attended the National Maternity Hospital in Dublin, Ireland between 2015 to 2017. Fifty women (28.6%) had T2DM and 125 women (71.4%) had T1DM. The mean age for T1DM group was (34 ± 4.7years) and T2DM (35.5 ± 3.8 years). Most of our patients were of European descent (85%) others were mostly of Asian and North African origin (15%). Mean duration of diabetes was 5.4 years in T2DM and 15.7 years in T1DM. Structured pre-pregnancy planning attended by 38.3% of our patients. Pre-pregnancy folic acid was used by 45.7% of patients for at least one month prior to booking. Forty women (29%) of T1DM were on Continuous Subcutaneous Insulin Infusion (CSII). Patients with T2DM were treated with Metformin (20%) only, Metformin and multiple dose insulin (MDI) injection combined (44%), MDI (28%) and diet control alone (2%). Mean BMI for T2DM was 32.6 ± 8.1 kg/m2 at booking and for T1DM 26.2 ± 4.5 kg/m2. Diabetic Retinopathy was more frequent in T1DM. The HBA1C in CSII group was 53.5 mmol/mol in the first trimester and improved to 42.9 mmol/mol in the third. T1DM group on MDI had HBA1C of 56.9 mmo/mol at booking and 44.7 mmol/mol in the third trimester. The mean HBA1C in T2DM at booking was 44.5 mmol/mol and 37.5 mmol/mol in the third trimester. Cesarean section (CS) was common in T1DM 48% with mostly EMCS 32%. In T2DM rate of CS was 38%. The most neonatal ICU (NICU) admission was due to hypoglycemia; in the T1DM group was 16.5% and 10% in T2DM group. Total neonatal birth weights above 4.0 Kg in our cohort was 21.7%. Our cohort with pre-gestational diabetes were overweight, older with long standing diabetes. Initial inadequate diabetes control in T1DM was better in patients with CSII with a significant improvement during pregnancy in all patients. With appropriate multidisciplinary treatment we minimized adverse outcomes.

Disclosure
D.S.A. Ali: None. M. Hatunic: None.