bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&lt;0.01 vs. FC), with marked reduction in HFC and FW intake and lower visceral fat mass (p&lt;0.001). LORCA induced lower body weight gain (p&lt;0.001 vs. FC), while PIO showed higher body weight gain (p&lt;0.01). FC diet raised HOMA-IR index by 66% (p&lt;0.05 vs. CC), which was 50% lower with LIRA and PIO (both p&lt;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&lt;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&lt;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&lt;0.01 vs. CC), which was improved by both LIRA and LORCA (both p&lt;0.01 vs. FC). LIRA also raised fractional shortening (p&lt;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&lt;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&lt;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&lt;.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&lt;.01) and two years (p&lt;.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 &lt;0.0001) and 13.9% (100 nmol/kg, (p &lt;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 &lt;0.05) and 32.3% (100 nmol/kg, p &lt;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&lt;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 &lt; 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&lt;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 &lt; 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 &lt;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&lt;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&lt;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&lt;r&lt;0.1, P&gt;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