bluuebunny/crossref_metadata_2025 huggingface dataset:
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<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<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<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<0.01; CAN: -55%; DAP -48%, P<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<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<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<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.
2004-P: Liraglutide Shows Better Weight Loss and Cardiometabolic Benefits than Lorcaserin and Pioglitazone in a Novel Diet-Induced Obese Rat Model
Authors: BRIAND FRANÇOIS , BROUSSEAU EMMANUEL , SULPICE THIERRY
Published: June 2019

To evaluate drugs targeting obesity/type 2 diabetes on weight loss and cardiometabolic benefits, and mimic human hyperenergetic nutritional behavior, we set-up a new diet-induced obese (DIO) rat model fed a free choice (FC) diet: control chow (CC) or high fat/cholesterol (HFC) diet, and normal water (NW) or 10% fructose water (FW). After an 8-week FC diet period, rats were treated with vehicle, liraglutide 0.4mg/kg s.c. QD (LIRA, a GLP-1 receptor agonist), lorcaserin 18mg/kg p.o. QD (LORCA, a 5-HT2C receptor agonist) and pioglitazone 10mg/kg p.o. QD (PIO, a PPARgamma agonist) for 5 weeks. FC diet induced high intake of HFC and FW, resulting in significantly higher caloric intake and overweight, as compared with rats fed a CC diet alone. LIRA induced a 12% body weight loss (p<0.01 vs. FC), with marked reduction in HFC and FW intake and lower visceral fat mass (p<0.001). LORCA induced lower body weight gain (p<0.001 vs. FC), while PIO showed higher body weight gain (p<0.01). FC diet raised HOMA-IR index by 66% (p<0.05 vs. CC), which was 50% lower with LIRA and PIO (both p<0.05 vs. FC), but unchanged by LORCA. Glucose intolerance induced by FC diet was significantly improved by LIRA, LORCA and PIO. During an insulin tolerance test, glucose area under the curve was 27% higher in FC rats (p<0.001 vs. CC) and was significantly reduced by LIRA and PIO, but not by LORCA. LIRA reduced liver fatty acids, triglycerides and cholesterol by 68, 71 and 51% (all p<0.001). PIO reduced liver triglycerides and LORCA had no effect on liver steatosis. Using echocardiography, we detected a diastolic dysfunction with reduced E/A ratio under FC diet (p<0.01 vs. CC), which was improved by both LIRA and LORCA (both p<0.01 vs. FC). LIRA also raised fractional shortening (p<0.01 vs. FC).

In conclusion, LIRA showed superior cardiometabolic benefits than LORCA and PIO in our DIO rat fed a FC diet. This novel model mimicking human overfeeding will be useful to evaluate drugs targeting obesity/type 2 diabetes.

Disclosure

F. Briand: Employee; Self; Physiogenex. E. Brousseau: Employee; Self; Physiogenex. T. Sulpice: Employee; Self; Physiogenex.
201-LB: The Neuronal Sirt1 Regulate the Metabolic Imbalance in Ischemic Stroke
Authors: LI GE , KIM HYUNG-HWAN
Published: June 2019

Background: Sirt1 is a NAD+ dependent deacetylase that is known as an important metobolic regulator for type 2 diabetes mellitus. To determine the role of Sirt1 in ischemic stroke induced metabolic imbalance, we generated the neuronal specific Sirt1 knock-in (nSirt1 KI) and knock-out (Sirt1 KO) mice and examined its effect and mechanism.

Methods: To determine the role of Sirt1 in ischemic stroke induced impaired metabolic actions including insulin and glucose abnormality, we tested the pharmacological effects of metformin and sirtinol. To determine the genetic role of neuronal Sirt1 in the brain, we generated the nSirt1 KI mice. We used the Ischemia/Reperfusion (I/R: 1h MCAO/23h reperfusion) injury model to induce the abnormal metabolic changes. Infarction volume was measured by TTC staining and we determined neurological deficit score (NDS) at 23h after 1h MCAO. The level of glucose was measured by a drop of tail blood using test-strip before, during (every 10 minutes interval), and after MCAO.

Results: Metformin reduced infarction volume and sirtinol worsened the infarction volume via Sirt1 signaling pathway. Heterozygous Sirt1 KO (Sirt1+/-) mice showed decreased relative cerebral blood flow and worsen infarction volume in ischemic areas, whereas nSirt1 KI mice exhibited increased rCBF, improved NDS, regulating abnormal blood glucose, and reduced infarction volume by 42% compare to that of littermate control in I/R injury model (n=7, p<0.05). Based on western blotting analysis of brain tissue lysates in nSirt1 KI mice, the expression of Sirt1 was significantly increased. Glucose regulation by overexpression of Sirt1 and reduced infarction volume in nSirt1 KI mice was reversed by sirtinol.

Conclusion: These findings indicate that the important neuroprotective effect of neuronal cells is mediated by Sirt1 overexpression and suggest that upregulation of neuronal Sirt1 may be an important therapeutic target for ischemic stroke via regulating metabolic imbalance.

Disclosure

G. Li: None. H. Kim: None.

Funding

Jeongseon County
202-LB: Effect of Testosterone Deficiency on Lipid Metabolism and the Severity of Type 2 Diabetes Mellitus Complications in Men
Authors: KHRIPUN IRINA A. , BOVA ELENA V. , VOROBYEV SERGEY V.
Published: June 2019

Testosterone (T) deficiency is more prevalent in men with type 2 diabetes mellitus (T2DM) than in population. However, there are no data on the effect of hypogonadism on the severity of T2DM complications.

Aim: To study the effect of T deficiency on the severity of T2DM complications in men.

Materials and Methods: A retrospective analysis of 487 case histories of men with T2DM was performed (mean age 54.4±5.7 years). The patients were divided into 2 groups: 1-217 men with hypogonadism, according to the EAU criteria 2015; 2-270 patients, not having hypogonadism. The groups were matched by age, duration and treatment of diabetes, HbA1c and fasting glucose levels. Clinical, anamnestic data, laboratory parameters of carbohydrate and lipid metabolism were analyzed. Statistical analysis was performed using the Mann Whitney U-test and a chi-square test.

Results: The prevalence of hypogonadism in men with T2DM was 44.6%. The analysis revealed an increase in systolic (140 [130; 160] vs. 136 [128; 149] mm Hg) and diastolic blood pressure (87 [80; 96] vs. 83 [80; 90] mm Hg) in the 1stgroup compared to the 2nd (p=0.01). Levels of total cholesterol (5.4 [4.6; 6.4] vs. 5.1 [4.5; 6.0] mmol/l, p=0.04), triglycerides (2.0 [1.4; 3.0] vs. 1.7 [1.2; 2.2] mmol/l) and very low density lipoproteins (1.0 [0.7, 1; 6] vs. 0.8 [0.6; 1.0] mmol/l) (p=0.001); low density lipoproteins (3.1 [2.4; 4.1] vs. 2.9 [2.4; 3.6] mmol/l) (p=0.03) were higher in group 1 compared to 2. Diabetic retinopathy (70.5% vs. 32.6%), nephropathy (92.1% vs. 58.9%) and polyneuropathy (82.9% vs. 65.6%) were more prevalent in patients of group 1 (p<0.01). All diabetes complications were more severe in men with hypogonadism, despite comparable duration of T2DM and parameters of carbohydrate metabolism.

Conclusion: The prevalence of hypogonadism in men with T2DM was 44.6%. The presence of T deficiency in men with T2DM contributes to the progression of micro-and macro-vascular complications of diabetes, and also impairs lipid metabolism.

Disclosure

I.A. Khripun: None. E.V. Bova: None. S.V. Vorobyev: None.

Funding

Russian Science Foundation (14-25-00052)
202-OR: Comparing Glycemic Control of Youth with T1D in NICH to Referred Youth: Quality Control (Group)
Authors: WAGNER DAVID V. , MAHON JAKE , JENISCH CELESTE , BARRY SAMANTHA A. , LUZOD HANNAH , KRAUS KIMBERLY , HARRIS MICHAEL A.
Published: June 2019

Objective: Youth with T1D who experience avoidable complications often have dangerously high and relatively stable A1c values. Although Novel Interventions in Children’s Healthcare (NICH) has demonstrated success improving A1c in these youth, this is the first study to compare the A1c values of those served by NICH to those of a control group.

Methods: Youth with T1D and avoidable complications were referred to NICH (n=110). A subset had available lab values and chronically high A1c (≥10%; n=67); 36 received NICH, and 31 were denied NICH by insurance (i.e., unserved). No significant demographic differences existed between NICH and unserved youth (M age= 14.1 years; 54% female; 78% non-Hispanic white). Medical record review included 1 year prior to, during, and two years following NICH.

Results: NICH youth had lower A1c values during (11.1%), 1 year post (11.2%), and 2 years post (11.2%) NICH, when compared to pre-treatment A1c (12.0%; p<.05). Unserved youth did not show meaningful changes when comparing pre-A1c (11.5%) to similar time periods (i.e., 10.9%, 12.0%, 12.2%). Compared to unserved youth, NICH youth demonstrated larger A1c reduction one (p<.01) and two years (p<.05) post treatment.

Conclusions: This study was the first to compare the A1c of NICH youth to a comparable control group. NICH youth demonstrated and maintained improved A1c after treatment, while those denied access did not demonstrate similar changes.

Disclosure

D.V. Wagner: None. J. Mahon: None. C. Jenisch: None. S.A. Barry: None. H. Luzod: None. K. Kraus: None. M.A. Harris: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
2023-P: OXM-001, a Novel Oxyntomodulin Analog, Improves Glucose Tolerance and Reduces Body Weight in High-Fat Diet Mice
Authors: KAYED ASHREF , ANDREASSEN KIM V. , KARSDAL MORTEN ASSER , HENRIKSEN KIM
Published: June 2019

The diabesity epidemic is steadily increasing every year. Therefore, we are searching for new treatments. The therapeutic potential of oxyntomodulin (OXM) is very promising. Based on evolutionary OXMs, we have identified a developmental OXM candidate known as OXM-001.

Acute administration of OXM-001 resulted in hypophagia, and a numerical greater bodyweight loss, when compared to MEDI0382 (Dual GLP-1/Glucagon receptor agonist) treatment. MEDI0382-treated High-Fat-Diet (HFD), fed female C57BL/6J mice. We examined the effect of repeated administration of OXM-001 in HFD fed female C57BL/6J mice in a 20-day study. Repeated administration every third day of OXM-001 (10, 30 and 100 nmol/kg) significantly reduced body weight in a dose-depended manner. The mean body weight loss was 3.6% (10 nmol/kg, ns), 11% (30 nmol/kg, p <0.0001) and 13.9% (100 nmol/kg, (p <0.0001) compared to Vehicle-treated controls. OXM-001 administration lowered the cumulative food intake dose-dependably, 9.4% (10 nmol/kg, ns), 23.6% (30 nmol/kg, p <0.05) and 32.3% (100 nmol/kg, p <0.05) when compared to Vehicle-treated controls. We also examined the chronic OXM effect on glucose control at day 20 by performing an OGTT. Treatment with OXM significantly (p<0.0001) lowered BG levels (%) in a dose-depended manner compared to Vehicle-treated controls. OXM-001 treatment reduced visceral adipose tissue and liver weight when compared to Vehicle-treated controls.

In summary, these preliminary data indicate that OXM-001 is superior to the current lead MEDI0382. OXM-001 treatment markedly enhanced glucose control. Furthermore, treatment with OXM-001 indicated a tendency toward visceral adipose tissue reduction and improved liver health.

Disclosure

A. Kayed: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. 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.
2027-P: Dietary Cholesterol and Neuropeptide Agouti Related Peptide Act in Concert to Regulate Locomotor Activity
Authors: HUANG ALYSSA , MAIER MATTHEW T. , XU ALLISON
Published: June 2019

In an ever-changing environment where food availability is highly unpredictable, the ability to maintain energy homeostasis requires proper sensing of dietary macronutrients, and subsequent adaptive adjustments in feeding behavior. Cholesterol is an important macronutrient, but cytotoxic in excess. Thus, cholesterol metabolism is under tight homeostatic regulation. Cholesterol is a major precursor of bile acids. After a meal, bile acids are released into the intestine and stimulate the secretion of fibroblast growth factor 15/19 (FGF-15/19). FGF-15/19 is an enterokine known to specifically suppress Agouti-related protein (AgRP), a neuropeptide of the central melanocortin system (CMS) that increases with fasting and promotes feeding and locomotor activity. Studies show that the CMS plays a modulatory role in hepatic cholesterol metabolism. However, the effects of dietary cholesterol on feeding behavior and energy homeostasis have remained largely unexplored. In this study, we found, surprisingly, that dietary cholesterol modulates expression of AgRP. Specific removal of cholesterol from the diets of wild type mice under ad-lib conditions leads to increased hypothalamic Agrp, but not Npy, mRNA expression. Furthermore, these mice also have low intestinal fGF-15mRNA expression. Cholesterol deficiency also leads to increased locomotor activities, an effect that is AgRP dependent as locomotor activity in AgRP knockout mice is unaffected by alterations in dietary cholesterol content. In wild type mice, fasting induces increased locomotor activity, which is widely thought to be a proxy for food seeking behavior. Notably, we observe dietary cholesterol content has no effect on ad-libfood intake, suggesting food seeking behaviors may be uncoupled from food intake. Taken together, these results suggest a novel paradigm where dietary cholesterol can act as a peripheral nutrient signal that can ultimately affect locomotor activity and possibly food seeking behavior.

Disclosure

A. Huang: None. M.T. Maier: None. A. Xu: None.
203-OR: Characterizing Moment-to-Moment Fluctuations in Stress, Anxiety, and Blood Glucose Levels in Adolescents with Type 1 Diabetes
Authors: BEBBINGTON KEELY , RUDAIZKY DANIEL , SMITH GRANT J. , HUNT ANNA M. , DAVIS ELIZABETH A. , JONES TIMOTHY , LIN ASHLEIGH
Published: June 2019

Objectives: It is now well documented that adolescents with T1D are at greater risk for elevated anxiety than young people without diabetes. In addition, higher levels of state anxiety are associated with higher haemoglobin A1c (HbA1c), less frequent blood glucose monitoring, and more poorly controlled diabetes. Anxiety is also predictive of poor glycaemic control as far as 12 months into the future. To better understand how stress and anxiety may be related to moment-to-moment fluctuations in blood glucose levels, we used a novel method of measuring changes in emotional state in real time, known as experience sampling methodology (ESM), in combination with continuous glucose monitoring (CGM) technology.

Methods: ESM is an ambulatory research method whereby participants respond to questions sent via a smartphone ‘app’ at multiple times throughout the day. In this study, adolescents (n= 53) diagnosed with T1D (aged 12-18 years) responded to questions regarding their current emotional state 10 times a day, over a 10-day period.

Results: Preliminary analysis, using multilevel regression modelling, explored the relationships between anxiety and measures of glycaemic control. The following measures of glycaemic control were examined: concurrent sensor glucose (SGL), mean sensor glucose in the previous 60 minutes, and standard deviation (SD) of sensor glucose in the previous 60 minutes. The results of the model indicated that a quadratic term for concurrent SGL (p < 0.001) and SD of sensor glucose (p = 0.005) were significant independent predictors of anxiety. The relationship between concurrent SGL and anxiety was U-shaped, with the vertex (minimum) of 7.8 mmol/L.

Conclusions: These novel findings confirm that elevated anxiety is associated with sub-optimal blood glucose levels in the preceding hour. Further analysis of this data will explore this relationship in greater detail, including possible inter-individual variation in this pattern.

Disclosure

K. Bebbington: None. D. Rudaizky: None. G.J. Smith: None. A.M. Hunt: None. E.A. Davis: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care. A. Lin: None.
2035-P: Treatment with a Dual Amylin and Calcitonin Receptor Agonist Improves Metabolic Health in a Rat Model of Elderly Menopausal Women
Authors: KATRI ANNA , KARSDAL MORTEN ASSER , HENRIKSEN KIM
Published: June 2019

Menopause is often characterized by detrimental metabolic changes, such as obesity, impaired glucose tolerance, insulin resistance and bone loss, often requiring treatment. KBP is a Dual Amylin and Calcitonin Receptor Agonist with promising effects on body weight and glucose control in rats. The objective of this study was to investigate the in vivo effect of KBP on the metabolic health in a model driven by unhealthy diet, age and menopause. Female Sprague Dawley rats were fed a high-fat diet (HFD) for 3 months before initiation of the study. At 6 months of age the rats were randomized into 4 groups (n=12) and subjected to ovariectomy surgery and subcutaneous injections of KBP; (1) HFD-Sham, (2) HFD-OVX + 10 µg/kg once/day, (3) HFD-OVX 5 µg/kg twice/day, (4) HFD-OVX + 30 µg/day 17a-ethynylestradiol (EE2). Body weight, food intake, oral glucose tolerance tests (OGTTs), subcutaneous fat and visceral fat and CTX-II were assessed during the 6 month study. HFD-OVX rats showed a significant and continuous increase in body weight throughout the study (10-13% weight increase compared to HFD alone, p<0.01). In HFD-OVX rats, KBP, independent of dosing frequency, caused an immediate decrease in both food intake and body weight within days and while food intake gradually returned to vehicle level over the first eight weeks, the weight loss remained until termination (P < 0.001). KBP increased glucose tolerance of HFD-OVX rats, significantly more than EE2. Furthermore, treatment with KBP reduced the weight of visceral and subcutaneous fat tissues. The cartilage degradation biomarker, CTX-II, was suppressed by both KBP groups. The data presented here clearly indicate a positive effect of KBP on metabolic health, with respect to weight loss, increased glucose tolerance and reduced weight of adipose tissues, as well as joint health, and may therefore represent a possible treatment opportunity for obese menopausal women.

Disclosure

A. Katri: Employee; Self; Nordic Bioscience. 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.
2043-P: The Biphasic Antiobesogenic Effects of Amlexanox
Authors: GOMEZ ANDREW V. , REILLY SHANNON , ODEH MOHAMMAD ABU , WALK ELYSE , SALTIEL ALAN
Published: June 2019

Obesity is associated with a chronic, low-grade inflammation that plays a key role in the development of insulin and catecholamine resistance. Amlexanox (Amx), an inhibitor of the inflammatory kinases TBK1 and IKKε, has been shown to improve insulin sensitivity and promote weight loss in mice. Here, we elucidate the anti-obesogenic effects of Amx. Diet induced obese mice were treated with Amx or vehicle control via oral gavage. Amx treatment caused a transient drop in food intake that normalized after 7 days. After, Amx treated mice continued to lose weight suggesting food-independent drivers of weight loss. Furthermore, Amx treated animals exhibited increased energy expenditure compared to pair-fed vehicle control mice. Increased energy expenditure in Amx treated mice is likely due to beiging of white adipose tissue as UCP1 KO mice exhibit a defect in weight loss after food intake normalizes. These data suggest Amx transiently down-regulates food consumption through an unknown mechanism while continuously promoting energy expenditure through beige fat. We conclude that Amx promotes weight loss through a biphasic mechanism involving an early transient decrease in food intake and long term increased thermogenesis via beiging of white fat. Further research will focus on the molecular mechanism controlling beiging and investigate possible central effects of Amx on food consumption.

Disclosure

A.V. Gomez: None. S. Reilly: None. M. Abu Odeh: None. E. Walk: None. A. Saltiel: None.

Funding

National Institutes of Health
2044-P: Histone Methyltransferase DOT1L Regulates Brown Adipocyte Differentiation and Thermogenesis
Authors: SHUAI LIN , LI JIA , LI JINGYA
Published: June 2019

Brown fat has been extensively studied due to its potential in therapies against obesity. Various epigenetic regulators have been shown to modulate brown fat development and function. Here we show that histone methyltransferase DOT1L is a key regulator of brown adipocyte differentiation and thermogenesis. In vitro, we demonstrate that inhibition by DOT1L inhibitor or knockdown of DOT1L markedly promotes brown adipocyte differentiation of C3H10T1/2 cells. Moreover, depletion of DOT1L enhances differentiation and thermogenesis of primary brown adipocytes which separated from DOT1LFlox/Flox mice by transfection with Cre-expressing lentiviruses ex vivo. Mechanistically, knockdown of DOT1L results in increased expression of brown-selective genes, and the expression of brown preadipocyte maker EBF2 is significantly increased due to knockdown of DOT1L at early stage. Furthermore, ChIP assays suggest that DOT1L-mediated H3K79 methylations are negatively associated with transcription of UCP1 and PRDM16. Finally, we observe that the skin surface temperature in interscapular area of DOT1LMyf5 knockout mice is significantly higher. Notably, energy expenditure and the oxygen consumption rate are also increased in knockout mice. These in vivo data suggest that DOT1L depletion leads to enhanced thermogenic function of brown fat. Collectively, our work indicates that DOT1L plays an important role in regulating brown fat differentiation and thermogenesis, and provides another linkage between epigenetics and brown fat development and function.

Disclosure

L. Shuai: None. J. Li: None. J. Li: None.

Funding

China Postdoctoral Science Foundation
2048-P: The Physiological Effects of VLCD in Overweight Nondiabetics
Authors: ABDUL AZIZ MUHAMMAD HARIZ , PHILLIPS BETHAN E. , RAMZAN IMRAN , CEGIELSKI JESSICA , SMITH KEN , IDRIS ISKANDAR RAUF , ATHERTON PHILIP J.
Published: June 2019

Background: Very Low-Calorie Diets (VLCD) are being increasingly used as a treatment for obesity and diabetes, yet concerns persist regarding reductions in muscle mass (as a crucial locomotory and insulin sensitive organ), while many physiological effects of VLCD are ill-defined. We thus explored the effects of VLCD on body composition, insulin sensitivity and vascular function in the overweight.

Methods: Eight overweight men (47±7y; 103±14kg; BMI 32±4, mean±SD) were placed on a VLCD, of <800kcal/day for 6-weeks via meal replacements. Before/after VLCD, we conducted: OGTT, DXA to quantity fat and lean body mass, ultrasound (U.S.) to determine flow-mediated dilatation (FMD), and echocardiogram (ECHO) for left ventricular function (LVF). Insulin sensitivity was assessed via: i) HOMA-IR ii) area under the curve (AUC) for insulin and glucose iii) QUICKI iv) Matsuda Index.

Results: VLCD reduced body weight (∆ -10.5±3 kg), fat mass (∆ -6.8±2 kg) and lean body mass (∆ -4.1±2 kg); all p<0.001. Significant improvements occurred in insulin sensitivity (HOMA-IR ∆ -0.6 ±0.6; AUC insulin ∆ -2147±2153 miliU/L*minute; QUICKI ∆ +0.05±0.03, and Matsuda Index ∆ 5.4±3.5); all P<0.05). No significant differences were observed in FMD (∆ 0.5±1.7%, P=0.5), LVF (∆ 1.4 ±6.9%, P=0.6), or AUC glucose (∆ -23.3±167.2 mmol/L*minute, P=0.7). No correlation was evident between degree of insulin sensitivity biomarkers and body weight or fat loss (e.g., Pearson -0.1<r<0.1, P>0.8).

Conclusion: VLCD predictably induced marked weight loss and improved insulin sensitivity during just 6-weeks of VLCD, and this was associated with body fat loss and muscle wasting. Nonetheless, the poor correlation between total weight or body fat loss and improved indices of insulin action points to metabolic reprogramming of insulin sensitive tissues in response to energy restriction, rather than fat loss per se, in driving some of the health benefits of VLCD. Developing means to mitigate muscle atrophy with VLCD is crucial to maximizing therapeutic benefits, especially in aging.

Disclosure

M. Abdul Aziz: None. B.E. Phillips: None. I. Ramzan: None. J. Cegielski: None. K. Smith: None. I.R. Idris: None. P.J. Atherton: None.

Funding

Medical Research Council UK
2051-P: Deep Transcranial Magnetic Stimulation Attenuates Depressive and Anxiety Symptoms Associated with Obesity
Authors: FERRULLI ANNA , MACRÌ CONCETTA , DANGELO VALENTINA , LUZI LIVIO
Published: June 2019

The association between obesity and psychological distress has been widely demonstrated. Systematic reviews have highlighted the bidirectional nature of this relationship. Strategies aimed at improving dopamine function may be beneficial in the treatment of both obesity and the associated psychological symptoms. Deep Transcranial Magnetic Stimulation (dTMS) has been demonstrated capable of inducing satiety and body weight loss in obesity, through modulation of dopaminergic system. Aim of this study was to evaluate possible beneficial effects of a 5-week dTMS treatment on psychological conditions in obesity. A total of 33 obese patients (9 males, 24 females, age 48.1±10.6 years, BMI 36.9±4.7 Kg/m2) were randomized and completed the study: 13 obese subjects underwent a 5-week treatment with high-frequency (HF) dTMS (18 Hz), 10 were treated with low-frequency (LF) dTMS (1 Hz), and 10 were Sham-treated. Depressive symptoms [Zung Self-Rating Depression Scale (SDS), Beck Depression Inventory (BDI)], state [State-Trait Anxiety Inventory (STAI-1)] and trait anxiety (STAI-2), impulsiveness [Barratt Impulsiveness Scale (BIS)] were evaluated at baseline and at the end of 15 dTMS sessions. After 5 weeks, a significant weight loss was found in HF vs. LF and vs. sham (p=0.001). In the same group, a significant decrease in both Zung SDS (37.3±4.2 vs. 26.7±5.4, p=0.049 vs. baseline; p=0.036 vs. Sham) and BDI scores (4.8±4.1 vs. 2.6±2.5, p=0.019 vs. baseline) was found. In HF, state (37.1±7.9 vs. 32.4, p=0.024) and trait anxiety (35.6±10.5 vs. 30.1±7.8, p=0.016), and impulsiveness (55.6±9.3 vs. 51.6±8.4, p=0.021) scores significantly decreased compared to baseline. Weight loss over 5 weeks of dTMS treatment was associated with psychological benefit; the improvement of psychological conditions in obese subjects has been hypothesized to be due to a direct effect of HF dTMS, as well as a weight loss secondary result. The reduction of impulsivity could concur to a greater control of food craving in HF.

Disclosure

A. Ferrulli: None. C. Macrì: None. V. Dangelo: None. L. Luzi: Consultant; Self; McKinsey & Company. Research Support; Self; Allergan, Gelesis, SunStar Inc. Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Menarini Group, Novartis AG, Novo Nordisk Inc., Sunstar Foundation.

Funding

Italian Ministry of Health