bluuebunny/crossref_metadata_2025 huggingface dataset:
2002-P: A Long-Acting GLP-1 and Y2-Receptor Dual Agonist Improves Body Weight and Glucose Control in Obese and Diabetic Rodent Models
Authors: OLDHAM STEPHANIE , HOWARD VICTOR G. , WILL SARAH , HORNIGOLD DAVID C. , RHODES CHRISTOPHER J. , MADALLI SHIMONA , SERMADIRAS ISABELLE , NAYLOR JACQUELINE , RIVERA CHRSITAN
Published: June 2019

Bariatric surgery can result in profound weight loss and remission of type 2 diabetes. Following meal consumption post-surgery, patients exhibit an exaggerated increase in the circulating levels of the enteroendocrine L-cell peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). We have developed a long-acting PYY Y2 and GLP-1 receptor agonist (GLP-1-Fc-PYY), which exerted potent effects on improving glucose metabolism and body weight loss in diabetic db/db mice and diet-induced obese (DIO) mice. Administration of GLP-1-Fc-PYY to diabetic db/db mice for 28 days normalized HbA1c levels (4.3%) compared to vehicle controls (9.1%), and exceeded that observed with Fc-GLP-1 monotherapy treatment (7.2%). GLP-1-Fc-PYY administration also preserved circulating insulin levels and increased pancreatic insulin content in db/db mice, which was not observed in mice treated with Fc-GLP-1. Administration of GLP-1-Fc-PYY for 21 days in DIO mice resulted in a 28% (p<0.0001) decrease in body weight, whereas vehicle-treated mice gained 13% and Fc-GLP-1-treated mice only exhibited a 13% reduction in body weight. To further characterize the GLP-1-Fc-PYY molecule, DIO GLP-1R knockout (KO) mice were treated for 13 days, and effects on body weight loss were partially attenuated in GLP-1R KO mice (10% BW loss), compared to wild type mice (32% BW loss). Additionally, when GLP-1R KO DIO mice were challenged with an IP glucose bolus following sub-chronic GLP-1-Fc-PYY treatment, the improvement in glucose excursion was lost compared to wild type mice. DIO Y2R KO mice treated for 11 days with GLP-1-Fc-PYY had attenuated BW loss (9%) compared to wild type mice (32%). These data suggest that GLP-1-Fc-PYY is a balanced dual agonist with in vivo activity at both the GLP-1 and Y2 receptors. GLP-1-Fc-PYY therefore represents a PYY/GLP-1 long-acting dual agonist that produces robust bariatric surgery-like weight loss and antidiabetic efficacy in relevant rodent models.

Disclosure

S. Oldham: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Will: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca, MedImmune. S. Madalli: None. I. Sermadiras: None. J. Naylor: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. C. Rivera: None.
2011-P: Totum-63 Lowers Adipose Tissue Inflammation and Reverses Both Hepatic Steatosis and Insulin Resistance in High-Fat Diet-Induced Obese Mice
Authors: DER ZANDE HENDRIK JOHANNES VAN , ZAWISTOWSKA-DENIZIAK ANNA , OTTO FRANK , CHAVANELLE VIVIEN , PELTIER SEBASTIEN , SIRVENT PASCAL , GUIGAS BRUNO
Published: June 2019

The worldwide prevalence of obesity, metabolic syndrome and type 2 diabetes (T2D) is reaching epidemic proportions that urge the development of new therapeutic strategies. Obesity-associated meta-inflammation contributes to nonalcoholic fatty liver disease (NAFLD) and plays a central role in the development of insulin resistance and T2D. Totum-63 has recently been developed for the management of prediabetes and shown to prevent high-fat diet (HFD)-induced metabolic disorders in mice. In the present study, we investigated whether Totum-63 could also improve metabolic homeostasis in insulin-resistant obese mice. For this purpose, C57Bl6/J male mice were fed a low- (LFD) or HFD for 12 weeks followed by supplementation with or without Totum-63 (2.7% w/w) for 4 additional weeks. Although no metabolic phenotype was observed in LFD-fed mice, Totum-63 decreased body weight in HFD-fed mice, an effect exclusively due to reduced fat mass and associated with a transient reduction in food intake confined to the first days of supplementation. The liver and brown adipose tissue weights were significantly reduced, whereas adipose tissue (AT) mass and adipocyte size distribution were not affected. Totum-63 markedly reduced hepatic macrovesicular steatosis and liver triglyceride content. Furthermore, potent decreases in fasting plasma glucose, insulin and leptin levels, and improvements in systemic insulin sensitivity and glucose tolerance were observed. Remarkably, a significant reduction in AT M1-like pro-inflammatory macrophages was found, indicating that Totum-63 can modulate macrophage recruitment/polarization and lower HFD-induced AT inflammation. Altogether, our results strongly suggest that Totum-63 reverses hepatic steatosis and insulin resistance in obese mice at least partly by dampening meta-inflammation, constituting a promising new approach for alleviating NAFLD and metabolic dysfunctions in established T2D.

Disclosure

H.J. van der Zande: None. A. Zawistowska-Deniziak: None. F. Otto: None. V. Chavanelle: Employee; Self; Valbiotis. S. Peltier: Board Member; Self; Valbiotis. P. Sirvent: Board Member; Self; Valbiotis. B. Guigas: Advisory Panel; Self; Valbiotis. Research Support; Self; Valbiotis.
2012-P: The Mouse Thermoneutral Zone Is Actually a Thermoneutral Point
Authors: SKOP VOJTECH , GUO JUEN , LIU NAILI , XIAO CUIYING , HALL KEVIN D. , GAVRILOVA OKSANA , REITMAN MARC
Published: June 2019

The mouse is widely used to study diabetes and obesity. Understanding thermal biology is essential for translating observations from mice to humans. For example, mice expend large amounts of energy to maintain body temperature, while humans do not. The thermoneutral zone (TNZ) for humans is defined as the ambient temperature (Ta) range where metabolic rate is at a minimum. Here we explore the mouse TNZ, focusing on its neglected upper boundary. Total light-phase energy expenditure (TEE) was quantitated by indirect calorimetry at various Ta, while also continuously measuring core body temperature (Tb). Broken line regression with nonlinear mixed model was used for data analysis. In wild type C57BL/6J mice, TEE decreased linearly with increasing Ta until a plateau was reached. The Ta at the break point (TNZ lower bound, called the Tlc) was 28.91 ±0.15 °C. Importantly, no increase in TEE was observed at Ta up to ∼4 °C above the Tlc. Tb was constant at cool Ta and began to rise at Ta = 28.95 ±0.12 °C. Thus, the Ta at which Tb starts to increase coincides with the Tlc and was not accompanied by an increased TEE. The generality of this unexpected observation was explored in multiple mouse models, including germline deletion of three temperature-sensing channels (TrpV1, TrpM8, TrpA1), neonatal ablation of Trpv1+ neurons, diet-induced obesity, and leptin deficiency. Over 12 cohorts (in total 66 mice), there was no difference between the Tlc and start of Tb increase (0.06 ±0.22 °C). Our novel results suggest a general property of mouse thermal physiology. Unlike humans, mouse Tb starts to increase right at the Tlc. There is no range of Tas over which both TEE and Tb are constant. The results suggest that the mouse TNZ is not the “zone” of textbooks, but rather is a fraction of a degree, a point.

Disclosure

V. Skop: None. J. Guo: None. N. Liu: None. C. Xiao: None. K.D. Hall: None. O. Gavrilova: None. M. Reitman: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK075063)
2029-P: A Simple Proximal Intestinal Bypass Surgery Directly Improves Insulin Sensitivity and Insulin Secretion in Mice
Authors: JANG HYE-MIN , HA NA-HEE , SONG MUN-GYU , LEE HYE-JIN , JIN BO-YEONG , KIM DONG-HOON , KIM NAM HOON
Published: June 2019

Objectives: To verify foregut hypothesis, we conducted simple bariatric surgery to evaluate the effects of those operations on body weight, glucose tolerance and insulin sensitivity in mice.

Methods: We applied operation techniques which involved gastrojejunostomy (GJ), GJ with duodenojejunal exclusion (GJDE), and sham operation (control). Jejunostomy site was located in the mid-jejunum with 1.0 cm pore size. Three different fed conditions were applied; 1) C57BL/6 mice fed with 60% high-fat diet (HFD) before and after surgery (n=8). ICR mice had been fed with chow diet, followed by 2) 45% HFD (n=9), and 3) 60% HFD (n=12) after surgery.

Results: In HFD fed C57BL/6 mice, body weight following operations was significantly reduced during first 2 weeks in GJDE and GJ mice compared to control mice, thereafter the difference was gradually attenuated. OGTT and ITT at 5 and 7 weeks after surgery showed that glucose levels were significantly lower, and insulin sensitivity was significantly improved in GJ and GJDE mice compared to control. In addition, in response to high glucose administration, insulin level was significantly increased in GJ and GJDE mice. In lean ICR mice, body weight in GJ and GJDE operated mice (45% HFD after surgery) were significantly lowered than that of control mice since 3 weeks after surgery. There were no difference in glucose tolerance between groups until 7 weeks, however, AUC glucose were significantly lower in GJDE mice than GJ and control mice after 10 weeks. ITT also showed GJDE mice were more insulin sensitive than GJ and control mice. GJ and GJDE operated mice with 60% HFD after surgery also showed similar results indicating delayed improvement in insulin sensitivity with proximal intestinal bypass.

Conclusion: This simple operation of proximal intestinal bypass demonstrated its effects on improvement in glucose tolerance and insulin sensitivity in mice. Mice preconditioned with HFD before surgery was also benefited by improvement in insulin secretion.

Disclosure

H. Jang: None. N. Ha: None. M. Song: None. H. Lee: None. B. Jin: None. D. Kim: None. N. Kim: None.
2030-P: BS-016, a Novel Oleanolic Acid Derivative, Exerts Antidiabetic and Anti-Obesity Effects in Preclinical Studies
Authors: DU YONG
Published: June 2019

There is an urgent need for innovative treatment targeting multiple pathways of type 2 diabetes such as weight loss, insulin sensitization and beta cell proliferation. Natural products have been shown to have the potential to treat diabetes. Here we develop a novel compound from oleanolic acid with improved bioavailability and efficacy. BS-016 reduces blood glucose and induces a sustained weight loss in DIO mice, producing 15% weight loss in combination study. In db/db diabetic mice, BS-016 lowers plasma glucose and improves glucose homeostasis. In vitro studies show BS-016 promotes insulin sensitivity by activating PPAR gamma and increases energy expenditure. Taken together, these results indicate BS-016 is a promising agent for treating diabetes and obesity.

Disclosure

Y. Du: None.
2034-P: The Role of 14-3-3zeta in the “Beiging” of White Adipose Tissue
Authors: DIALLO KADIDIA , LIM GARETH E.
Published: June 2019

Adipocyte hypertrophy and hyperplasia is a hallmark of obesity, and treatments that induce the oxidation of lipid stores may represent a potential therapy. When stimulated by cold or beta-adrenergic agonists, adipocytes in inguinal white adipose tissue (iWAT) can convert to beige cells, which resemble brown adipocytes. This process can reduce body weight in rodents and improve glucose homeostasis through increased Ucp1-dependent lipid oxidation. 14-3-3?, a molecular scaffold we found to be essential for adipogenesis, regulates the enzymatic activities of tryptophan and tyrosine hydroxylases, both of which influence beiging. Thus, the aim of the current study is to investigate whether 14-3-3? influences the beiging process. Compared to control mice, acute (3 hr) and chronic (72 hr) cold (4 C) exposure in male transgenic mice over-expressing 14-3-3? led to improved cold tolerance due to significantly increased Ucp1 mRNA and protein in iWAT. Following chronic exposure, they were also able to maintain their body weight by increasing their food intake. Consistent with these data, analysis of adipocyte area revealed a decrease in the size of inguinal adipocytes in transgenic mice, suggesting increased lipid oxidation. In contrast, gonadal adipocytes were larger in transgenic mice, which may explain their ability to maintain their body weight. Systemic 14-3-3? knockout mice had significantly lower levels of Ucp1 mRNA in iWAT and BAT but did not display differences in tolerance to acute cold. Depletion of 14-3-3? by siRNA in brown adipocytes did not impair isoproterenol-mediated induction of Ucp1 mRNA, suggesting that 14-3-3? is not required for Ucp1 expression in this cell type. In future studies, we will examine if 14-3-3? influences the responsiveness of iWAT to chronic β-adrenergic stimuli and assess the impact of 14-3-3? overexpression in brown adipocyte function. Collectively, our results point to a novel role of 14-3-3? in the beiging of inguinal adipocytes and increase our understanding of how beiging is regulated.

Disclosure

K. Diallo: None. G.E. Lim: None.

Funding

Canadian Institutes of Health Research; Fonds de la recherche en santé du Québec; Centre de recherche du CHUM; Montreal Diabetes Research Center
2037-P: Characterization of Novel Unimolecular Amylin-Adrenomedullin Dual Agonists
Authors: DALBOEGE LOUISE S. , MAGOTTI PAOLA , BUCH-MÅNSON NINA , BECH ESBEN M. , FINK LISBETH N. , PEDERSEN SØREN LJUNGBERG , FOSGERAU KELD
Published: June 2019

Amylin and Adrenomedullin both belong to the calcitonin peptide family. While amylin plays an important role in maintaining glucose and energy homeostasis, adrenomedullin is primarily known for its beneficial vasoactive effects.

We hypothesize that combining the glucoregulatory and anti-obesity properties of amylin with the cardioprotective effects of adrenomedullin could be an effective treatment strategy to address type 2 diabetes, obesity and cardiovascular diseases in one molecule. Here we report the design and receptor potencies of unimolecular peptide agonists with dual activity at the amylin and adrenomedullin receptors.

Using solid-phase peptide synthesis, an array of hybrid peptides was rationally designed by substituting amino acids essential for amylin activity into the native adrenomedullin sequence. The pharmacokinetic profile was optimized by lipidation with a C20 diacid. Functional activities of the analogues were measured using a cAMP accumulation assay in cells overexpressing the human amylin receptor subtype 3 (hAMY3-R) or human adrenomedullin receptor subtype 1 (hAM1-R).

All analogues were full agonists on both receptors. hAMY3R potencies were comparable to human native amylin, whereas hAM1-R potencies ranged from equipotent to 100-fold less potent compared to human native adrenomedullin.

In summary, we have synthesized novel hybrid amylin-adrenomedullin peptide agonists with dual activity at the hAMY3R and hAM1-R. Ongoing studies address in vivo efficacy and potency of amylin-adrenomedullin dual agonists in rodent models of obesity and diabetes.

Disclosure

L.S. Dalboege: None. P. Magotti: None. N. Buch-Månson: None. E.M. Bech: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. S.L. Pedersen: None. K. Fosgerau: Stock/Shareholder; Self; Gubra.
2038-P: Rice Endosperm Protein Intake in Childhood Suppresses the Development of High-Fat Diet-Induced Metabolic Disorders and Kidney Disease during Adulthood in Mice
Authors: HIGUCHI YUKI , HOSOJIMA MICHIHIRO , KABASAWA HIDEYUKI , KUWAHARA SHOJI , KASEDA RYOHEI , ARAO HITOSHI , TANAKA TAKAHIRO , NARITA ICHIEI , SAITO AKIHIKO
Published: June 2019

Introduction: Obesity is associated with lifestyle diseases such as type 2 diabetes and organ complications including kidney disease. Childhood diet has a great influence on the development of obesity and its related disorders. Rice endosperm protein (REP) has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. Therefore, we aimed to clarify the effects of REP intake during childhood on the development of high-fat-diet (HFD)-induced obesity and its related disorders during adulthood in mice.

Methods: Four-week-old male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP for 6 weeks (childhood), and subsequently, an HFD containing casein or REP for 12 weeks (adulthood). Mice were then tested for oral glucose tolerance and subjected to the analyses of growth status, biochemical parameters, kidney histology, and fecal gut microbiota by 16S rRNA gene sequencing. Antibacterial activity of REP-derived peptides against gut microbiota was evaluated in vitro.

Results: Mice fed REP in childhood showed less increase in body weight, total fat mass, blood pressure, serum total cholesterol, triglyceride, and lipopolysaccharide (LPS)-binding protein, and better glucose tolerance than those fed casein in childhood followed by HFD with casein or REP. Furthermore, HFD-induced glomerular hypertrophy, mesangial expansion, and vacuolar formation in proximal tubules were suppressed in mice fed REP than those fed casein in childhood. The intake of REP in childhood ameliorated dysbiosis caused by HFD. Additionally, REP-derived peptides showed antibacterial activity against E. coli, a major producer of LPS.

Conclusion: These results indicate that the intake of REP during childhood can inhibit the progression of HFD-induced metabolic disorders and kidney disease in adulthood, probably through the effects of REP on gut microbiota.

Disclosure

Y. Higuchi: None. M. Hosojima: Research Support; Self; Astellas Pharma Inc., Biotech Japan Corporation, Daiichi Sankyo Co.,Ltd., Eli Lilly Japan K.K., Forica Foods Co.,Ltd., Kameda Seika Co.,Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisc Pharma Ltd., Sato Foods Industries Co.,Ltd., Taisho Toyama Pharmaceutical.Co.,Ltd., Takeda Pharmaceutical Co.,Ltd. H. Kabasawa: Research Support; Self; Astellas Pharma Inc., Biotec Japan Corporation, Daiichi Sankyo Company, Limited, Forica Foods CO.,LTD., KAMEDA SEIKA CO., LTD., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K, Novo Nordisc Pharma Ltd, Sato Foods Industries CO.,LTD., Taisho Toyama Pharmaceutical.CO.,LTD., Takeda Pharmaceutical Company Limited. S. Kuwahara: None. R. Kaseda: None. H. Arao: None. T. Tanaka: None. I. Narita: None. A. Saito: None.
204-LB: Lifestyle Risk Behaviors among Stroke Survivors With and Without Diabetes
Authors: BAILEY RYAN R. , PHAD ALLISON , MCGRATH RYAN , FORD ANDRIA , TABAK RACHEL G. , SERRANO NATALICIO H. , HAIRE-JOSHU DEBRA
Published: June 2019

Objective: History of stroke or diabetes increases risk for cardiometabolic conditions, which can be exacerbated by the presence of modifiable lifestyle risk behaviors. The purpose of this study was to evaluate lifestyle risk behaviors among stroke survivors with and without diabetes to inform future research and healthcare intervention. Specifically, we compared the prevalence of three lifestyle risk behaviors (i.e., consuming ≤1 fruit and ≤1 vegetable daily, physical inactivity, and overweight/obesity) and total number of lifestyle risk behaviors among stroke survivors, stratified by diabetes status.

Methods: Cross-sectional data from the 2013 and 2015 Behavioral Risk Factor Surveillance System (BRFSS) were examined. Weighted and age-adjusted prevalence estimates and adjusted odds ratios (AOR, adjusted for sociodemographic characteristics) with 95% confidence intervals (CIs) were calculated to compare prevalence and odds of individual and total number of lifestyle risk behaviors between stroke survivors with and without diabetes.

Results: Prevalence and AORs were higher in stroke survivors with diabetes compared to stroke survivors without diabetes for consuming ≤1 fruit and ≤1 vegetable daily (58.8% vs. 53.7%; AOR: 1.14, CI: 1.02-1.28), physical inactivity (65.7% vs. 54.6%; AOR: 1.41, CI: 1.26-1.58), overweight/obesity (87.2% vs. 63.1%; AOR: 2.42, CI: 2.12-2.79), 2 lifestyle risk behaviors (41.1% vs. 36.7%; AOR: 1.16, CI: 1.03-1.30), and 3 lifestyle risk behaviors (35.7% vs. 21.8%; AOR: 1.54, CI: 1.36-1.74).

Conclusion: Individual and clustered lifestyle risk behaviors were present in greater proportions among stroke survivors with diabetes compared to those without diabetes. Because the co-occurrence of chronic conditions (i.e., multimorbidity) and multiple lifestyle risk behaviors increases risk for poor health and premature death, effective healthcare interventions and community programs are needed to promote health behavior change in stroke survivors.

Disclosure

R.R. Bailey: None. A. Phad: None. R. McGrath: None. A. Ford: None. R.G. Tabak: Other Relationship; Self; Envolve PeopleCare/Centene Corporation. N.H. Serrano: None. D. Haire-Joshu: Research Support; Self; Centene Corporation.

Funding

National Institutes of Health (P30DK092950, 5T32HL130357)
2041-P: Genetic Intervention in Kynurenine Pathway Alters Glucose Metabolism in Mice
Authors: YAMAMOTO TAKASHI , GOTODA TAKANARI
Published: June 2019

Most of tryptophan is metabolized to kynurenine (KYN) to synthesize NAD+, while a subsidiary pathway changes KYN to kynurenic acid (KYNA) by kynurenine aminoltransferases (KATs). We previously reported genetic association of a mutation in the gene encoding KAT-1, an isoform of KATs, with hypertension, adiposity and glucose intolerance in rats. Although it is widely known that KYNA negatively regulates central nervous system by antagonizing neuro-receptors, its physiological role in glucose metabolism remains unclear.

To explore such role, first, we have established KAT-1 knockout mice that showed decreased levels of KAT activity in liver and brain (p<0.01) and KYNA levels decreased significantly in brain and blood (p<0.05) and tending to decrease in liver. The KAT-1 knockout mice also showed significantly deteriorated glucose tolerance (p<0.05 at 60min after glucose i.p.) and insulin sensitivity (p<0.05 at 45, 60, 75 and 90min after insulin i.p.) as compared with wild littermates. Next, to establish mice with endogenously increased levels of KYNA, the hepatic gene encoding kynurenine mono-oxygenase (KMO), a rate-limiting enzyme for conversion of KYN to NAD+, was knocked down by shRNA adenovirus. The hepatic KMO knockdown in normal mice markedly increased endogenous KYNA levels in liver, blood and several other tissues, whereas the levels of 3-hydroxykynurenine, a downstream product of KMO, were decreased in liver (p<0.001). Finally, the hepatic KMO knockdown in diet-induced obese mice significantly ameliorated glucose intolerance and improved insulin sensitivity and pyruvate tolerance independently of food intake or body weight. Among the enzymes related to glucose metabolism, both the gene expression (p<0.01) and the enzymatic activity (p<0.05) of glucokinase were increased in the liver of the KMO knockdown group as compared with controls.

These results indicated that alterations in KYNA pathway influence glucose metabolism in vivo.

Disclosure

T. Yamamoto: None. T. Gotoda: None.
2049-P: Real-World Assessment of Orlistat and Liraglutide in Patients with Obesity: The XENSOR Study
Authors: GORGOJO-MARTINEZ JUAN J. , BELEN BASAGOITI-CARREÑO , SANZ-VELASCO ALBERTO , SERRANO-MORENO CLARA , FRANCISCA ALMODÓVAR-RUIZ
Published: June 2019

Data on comparative effectiveness among weight-loss medications (WLMs) in real-world studies (RWS) are limited. The aim of the XENSOR study was to assess in a real-world setting the effectiveness of two WLMs, orlistat and liraglutide, in patients with obesity and insufficient weight loss (WL) after a lifestyle modification program.

A retrospective RWS was conducted comparing clinical outcomes of orlistat 120 mg tid and liraglutide (up to 3 mg daily) in adult patients with BMI ≥ 30 kg/m² (or ≥ 27 kg/m² with at least a weight-related comorbidity) who had failed to lose at least 5% of their baseline weight (BW) after 6 months (mo) of lifestyle modification. The co-primary end points, assessed at 3-6 mo (visit 2) and at the end of the follow-up (visit 3), were weight change from baseline, proportion of patients who lost at least 5% of their BW and adjusted differences in WL between both drugs.

Five hundred patients, 400 in the group of orlistat (women 75%, mean age 47.0 y, mean BW 107.8 kg), and 100 in the group of liraglutide (women 73%, mean age 51.9 y, mean BW 105.1 kg), were included. Treatment with both drugs significantly reduced weight, FPG, systolic BP, LDL-C and ALT over a median follow-up period of 7 mo. WL with liraglutide at visit 3 (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), adjusted mean difference -4.7 kg (95% CI -6.4 to -2.9 kg). More individuals lost at least 5% of their BW with liraglutide (64.7%) than with orlistat (27.4%) at visit 3, p<0.0001. In the subset of patients with prediabetes at baseline, persistence of prediabetes or progression to T2DM was significantly lower with liraglutide (34.6%) than with orlistat (82.8%), p<0.0001. At 12 mo of follow-up, 61% of patients remained on liraglutide, compared to 46.8% on orlistat (p 0.011).

In summary, in this RWS, liraglutide showed a greater effectiveness in WL compared to orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.

Disclosure

J.J. Gorgojo-Martinez: Advisory Panel; Self; Abbott, AstraZeneca, Lilly Diabetes, Mundipharma, Novo Nordisk Inc., Pfizer Inc. Research Support; Self; Novo Nordisk Inc. Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. B. Basagoiti-Carreño: None. A. Sanz-Velasco: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc. C. Serrano-Moreno: Other Relationship; Self; Novo Nordisk A/S. F. Almodóvar-Ruiz: Other Relationship; Self; Novo Nordisk Inc.
205-OR: Sensitivity and Specificity of the PHQ-9 and PHQ-2 to Identify Depressive Symptoms in Teens with Type 1 Diabetes (T1D)
Authors: MARKER ARWEN M. , MCDONOUGH RYAN , EGAN ANNA , CLEMENTS MARK A. , PATTON SUSANA R.
Published: June 2019

ADA guidelines recommend regularly screening teens for depression. We examined sensitivity and specificity of the long and short-form of the Patient Health Questionnaire (PHQ) to identify depressive disorders in teens with T1D against a gold-standard diagnostic interview.

Teens (N=100; Mean age = 15.0 ± 1.7; 60% Male; 87% white; Mean HbA1c = 8.88 ± 1.8%) completed the PHQ-9 electronically. We used the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS DSM-5) depression module to determine whether the teen met criteria for any depressive disorder (DD; e.g., major depression, dysthymia, adjustment disorder-depressed mood, bipolar). We compared teens’ pre-existing PHQ cut-off scores (PHQ-9 ≥ 10; PHQ-2 ≥ 3) to KSADS results.

Per KSADS, 15% of teens met criteria for current DD, 11% endorsed past DD, and 25% endorsed past/present suicidal ideation (SI). Only 6% and 8% of teens exceeded PHQ-9 and PHQ-2 cut-off scores, respectively, and 10% endorsed current SI on PHQ item 9. Sensitivity and specificity outcomes are in Table 1.

The PHQ-9 and PHQ-2 showed low sensitivity and high false negative rates. Lower cut-offs or alternative screening measures may be indicated to reliably identify DD in teens with T1D. High rates of reported SI, even by teens who did not meet full criteria for DD, highlight the importance of screening for suicidality and/or treating subthreshold depressive symptoms.

Disclosure

A.M. Marker: None. R. McDonough: None. A. Egan: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. S.R. Patton: None.
2059-P: Higher Propensity to Store Energy in Thigh Subcutaneous Fat Associated with a Lower Risk of NDM and Better ß-Cell Function
Authors: HOU XUHONG , CHEN PEIZHU , WEI LI , BAO YUQIAN , JIA WEIPING
Published: June 2019

Background: The relationship between subcutaneous fat area (SFA) and diabetes mellitus (DM) is still not well described due to the fact that SFA has two aspects; it can buffer energy surplus and also reflect obesity severity.

Methods: 3967 subjects, from baseline survey data of the Shanghai Nicheng Cohort Study, were analyzed. Thigh subcutaneous fat area (TSFA), abdominal subcutaneous fat area (ASFA), and visceral fat area (VFA) were measured by magnetic resonance imaging. TSFA% and ASFA% were calculated as the ratio of TSFA and ASFA to the sum of VFA, ASFA, and TSFA, respectively and reflects the propensity to store energy in a given location. Diagnosis of newly diagnosed diabetes mellitus (NDM) as well as assessments of insulin sensitivity (Homeostatic Model Assessment of insulin resistance and ISI0,120 [GUTT]), and β-cell function (early-, first- and second-phase disposition indices) were made based on an oral glucose tolerance test.

Results: Compared to those without DM, TSFA%, ASFA%, and VFA% in men and women with NDM were 0.25 versus 0.21, 0.39 versus 0.38, and 0.36 versus 0.41; and 0.37 versus 0.32, 0.38 versus 0.37, and 0.26 versus 0.31, respectively. Before and after adjustment for potential confounding factors, each 1-SD increase in TSFA% was associated with a 37-47% and a 34-39% decreased likelihood of NDM in Chinese men and women, respectively (both P <0.05). Multivariable linear regression showed that TSFA% was mildly positively associated with all indicators of β-cell function and/or insulin sensitivity in women and mildly positively associated with DI1st in men. The favorable associations of NDM, insulin sensitivity, and β-cell function with TSFA% were stronger than with ASFA%.

Conclusion: TSFA% reflects the propensity to store energy in subcutaneous fat which is associated with a lower risk of NDM and better β-cell function in both genders.

Disclosure

X. Hou: None. P. Chen: None. L. Wei: None. Y. Bao: None. W. Jia: None.
2062-P: Improvement in Sphingolipids after Combined Weight Loss and Exercise Training in Adults with Obesity and Prediabetes
Authors: BROUSSARD JOSIANE L. , KAHN DARCY E. , NEWSOM SEAN A. , BROZINICK JOSEPH T. , BUI HAI , ROTH KENNETH D. , PERREAULT LEIGH , BERGMAN BRYAN C.
Published: June 2019

Serum lipids and sphingolipids circulate in plasma and are linked with insulin resistance and increased cardiovascular disease risk. We previously reported that dihydroceramides (DHCer) are elevated in people with insulin resistance compared to individuals with obesity and trained athletes. Despite associations with insulin resistance, little is known whether insulin sensitizing lifestyle interventions can improve sphingolipid profiles.

Twenty-one individuals with obesity and prediabetes (18F; 46± 2y; 35.0± 0.9 kg/m2; fasting glucose: 113.8± 9.4 mg/dl, 2h OGTT: 143.0± 19.4 mg/dl) participated in a 3-month lifestyle intervention of combined weight loss and exercise. Insulin sensitivity (SI) was assessed by hyperinsulinemic-euglycemic clamps and both targeted and shotgun lipidomics were conducted before and after intervention.

BMI and body fat percentage were reduced by 11+1% (mean± SEM) and 9± 1% after intervention (p<0.0001 for both). VO2 peak and SI increased by 14± 3% and 66± 12% following the intervention (p<0.0001 for both). Total serum triacylglyceride, diacylglyceride, DHCer and glucosylceramide were significantly reduced following intervention (p<0.05 for all). Reductions in specific species of ceramide (C18:0), lactosylceramide (C24:0), DHCer (C18:0, C24:1, C24:0) and glucosylceramide (C16:0, C22:0, C23:0, C24:1, C24:0) were also apparent. Of these lipids, glucosylceramide C20:0 and C22:0 were negatively associated with SI (r=-0.491, p<0.05 and r=-0.580, p<0.01, respectively). Furthermore, sphingomyelin C14:0, C16:1, C20:0, C21:0, C22:0, C23:0, C24:3 and C24:4 were negatively associated with SI.

These data show that serum sphingolipids species previously linked to insulin resistance in humans can be improved with insulin sensitizing lifestyle interventions. Decreases in serum sphingolipids may explain increased SI and decreased cardiovascular disease risk associated with weight loss and exercise training.

Disclosure

J.L. Broussard: Advisory Panel; Self; National Institutes of Health. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Sleep Research Society, Society in Science-The Branco Weiss Fellowship. D.E. Kahn: None. S.A. Newsom: None. J.T. Brozinick: Employee; Self; Eli Lilly and Company. H. Bui: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. B.C. Bergman: Advisory Panel; Spouse/Partner; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc.

Funding

American Diabetes Association (1-14-CE-05 to B.B.); National Institutes of Health (RR-00036, K01DK110138); Colorado Nutrition Obesity Research Center (P30DK048520)
2064-P: Effectiveness of Computer or Phone Interventions on Increasing Exercise and Weight Loss in Obese and Overweight Adults: A Meta-analysis
Authors: PU YUELI , GUO MAN , MA XIU M. , CHEN QING , TENG FANGYUAN , ZHANG TING , LIU CUIPING , XU YONG
Published: June 2019

Aim: The aim of this meta-analysis is to evaluate the effectiveness of the phone- or computer-based intervention on weight loss and improvement in diet and physical activity levels in obese or overweight adults.

Methods: We searched RCTs indexed in PubMed, Embase and CENTRAL from inception through May 1, 2018. A meta-analysis was conducted of RCTs involving participants receiving mobile devices included modern and portable devices.

Results: Eighteen RCTs enrolling 2,567 adult participants from 4 countries (America, Australia, England and Germany) were included. The mean difference (MD) for the effect of using mobile phones or computers on reduction in body weight, BMI, and waist circumference were −1.25 kg (95% CI −1.71 to −0.79, p<0.05), −0.30kg/m2 (95% CI −0.58 to -0.01, p=0.04), and −1.13 cm (95% CI −2.11 to −0.14, p=0.03), respectively, and raising in physical activity weekly was 420.07 kcal (95% CI 67.54 to 772.61, p=0.02), while basing on mobile devices can not significantly reduce daily energy intake (MD −61.05, 95% CI −205.22 to 83.12, p=0.41). Subgroup analyses suggested that use of computers or phones was associated with significant changes in body weight of −1.67 kg and −0.85 kg compared with the control group, respectively. Another subgroup analysis found that the United States, Australia and European countries (England and Germany) lost 1.52 kg, 1,98 kg and 0.33 kg, respectively.

Conclusion: Compared to control group, this meta-analysis indicated that intervention group based on mobile devices had potential effect on a decrease in body weight, waist circumference and a smaller decrease in BMI, and a moderate increase in weekly exercise, while no significant differences in daily energy intake among obese or overweight adults. Subgroup analyses revealed that compared with phone-based intervention, basing on computer significantly reduced body weight, and the United States lost more weight than Australia and European countries.

Disclosure

Y. Pu: None. M. Guo: None. X.M. Ma: None. Q. Chen: None. F. Teng: None. T. Zhang: None. C. Liu: None. Y. Xu: None.

Funding

National Natural Science Foundation of China (81800741)
207-OR: Intentional Insulin Omission for Weight Loss and Psychosocial Outcomes among Youth with Type 1 Diabetes: Findings from Routine Screening
Authors: PAPADAKIS JACLYN L. , ANDERSON LINDSAY M. , VESCO ANTHONY T. , EVANS MEREDYTH A. , WEISSBERG-BENCHELL JILL
Published: June 2019

Introduction: Research has found that up to 31% of youth with type 1 diabetes (T1D) restrict insulin in efforts to lose weight (Wisting et al., 2013), and that restricting or omitting insulin has been linked to higher HbA1c. However, less is known about psychosocial outcomes among youth who omit insulin. The purpose of the current study was to examine associations between intentional omission of insulin to lose or avoid gaining weight and psychosocial outcomes among youth with T1D.

Methods: Participants included 54 youth with T1D ages 12-17 (M age = 14.7, 55.6% female) and their caregivers, recruited during routine diabetes clinic visits. Youth and caregivers completed an annual psychosocial screening battery which included the PROMIS® depression and anxiety scales, the Problem Areas in Diabetes measure, and the Diabetes Family Conflict Scale. Youth also answered questions on their intentional omission of insulin to either lose or avoid gaining weight. Analyses were conducted via Pearson’s correlations, t-tests, and Chi-square tests.

Results: Intentional omission of insulin to lose or avoid gaining weight was significantly positively correlated with youth-report of depression, anxiety, diabetes distress, and diabetes-related family conflict. Compared to youth who do not intentionally omit insulin, those who do omit insulin were more likely to have clinically elevated levels of depression (p’s < .05). No differences for parent-reported psychosocial outcomes were found.

Conclusions: Results reveal that youth who intentionally omit insulin for weight purposes are at risk for poorer psychosocial outcomes, especially depression. Additional research is needed to understand the causal direction of these associations, and to examine the potential role of disordered eating behavior. Results also highlight how psychosocial screening during routine diabetes visits can identify youth and caregivers in need of behavioral health interventions.

Disclosure

J.L. Papadakis: None. L.M. Anderson: None. A.T. Vesco: None. M.A. Evans: None. J. Weissberg-Benchell: Consultant; Self; Roche Diabetes Care.
2070-P: Role of Education Attainment in Obesity: A Two-Sample Mendelian Randomization Study
Authors: ZHOU TAO , SUN DIANJIANYI , LI XIANG , HEIANZA YORIKO , QI LU
Published: June 2019

Lower educational attainment has been associated with an increased risk of obesity; however, the causality of educational attainment in relation to adiposity, body composition, and fat distribution remains to be established. We used two-sample Mendelian randomization (MR) analyses of summary statistics with participants number ranged from 330,762 to 1,131,881 to test the causal effects of educational attainment in body fatness phenotypes [e.g., BMI, body fat mass, and waist-to-hip ratio (WHR)]. A total of 1,196 available single nucleotide polymorphisms associated with educational attainment were included in the current analysis. Eight complementary MR methods were used to test the robustness of our results. The genetically-instrumented higher educational attainment was consistently associated with a lower BMI [β -0.42, 95% confidence interval (CI) -0.45 to -0.39], body fat percentage (-0.31, -0.33 to -0.28), body fat mass (-0.36, -0.39 to -0.33), and waist circumference (-0.31, -0.33 to -0.28). The causal relationships of higher educational attainment with lower body weight, fat-free mass, and hip circumference were less consistent. There was no causal relation between educational attainment and WHR (Figure 1).

In conclusion, our findings indicate low educational attainment may causally increase BMI, body fat and waist circumference.

Disclosure

T. Zhou: None. D. Sun: None. X. Li: None. Y. Heianza: None. L. Qi: None.

Funding

National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616); Boston Obesity Nutrition Research Center (DK46300); United States-Israel Binational Science Foundation (20110360); American Heart Association (0730094N to L.Q.)
2071-P: Changes in Serum Uric Acid Correlated with Sex Hormones Variations for Chinese Obese Patients Undergoing Sleeve Gastrectomy
Authors: ZHU CUILING , GAO JINGYANG , MEI FANGYUN , WANG XINGCHUN , ZHOU DONGLEI , QU SHEN
Published: June 2019

Background: Hyperuricemia (HUA) and sex hormone imbalance in obese patients can be reversed by bariatric surgery. However, the relationships between changes in serum uric acid (SUA) and sex hormones variations after bariatric surgery is unexplored. We aimed to investigate the correlations between changes in SUA and sex hormones variations after laparoscopic sleeve gastrectomy (LSG) in Chinese obese patients in relation to gender.

Methods: We enrolled 133 severely obese patients who underwent LSG in this study. SUA, sex hormones, and relevant metabolic parameters were compared pre- and 12 months post-LSG.

Results: At baseline, HUA was more common in males than in females. Twelve months after LSG, significant improvements in BMI and glucolipid metabolic indices were noted. SUA levels and the prevalence of HUA were declined significantly in both gender while the changes in SUA and percentage of SUA variations were significantly greater in females than in males (all P<0.01). In addition, we observed significant increase in estradiol (E2) and decrease in total testosterone (TT) in females and increase in TT in males (P=0.018, P=0.006, P <0.001, respectively). In a multiple regression model, after adjusting for age and changes in BMI, fasting insulin (FINS), and HOMA-IR, SUA reduction correlated significantly with increased E2 (β=-0.645, P=0.001) and decreased TT (β=0.503, P=0.014) in females, and increased TT (β=-0.909, P=0.008) in males.

Conclusion: LSG promotes more profound improvement of SUA levels in female obese patients than in males, and SUA reduction after surgery correlated significantly with different sex hormones changes in males and females.

Disclosure

C. Zhu: None. J. Gao: None. F. Mei: None. X. Wang: None. D. Zhou: None. S. Qu: None.

Funding

Shanghai Municipal Science and Technology Commission (17DZ1910603); Fundamental Research Funds for the Central Universities (1501219107); National Natural Science Foundation of China (81500650, 81700752, 81570782)
2073-P: Are Early Dumping and Postprandial Hypoglycemia after Roux-en-Y Gastric Bypass Related Events?
Authors: ØHRSTRÔM CAROLINE , WORM DORTE , KIELGAST URD , HOLST JENS J. , HANSEN DORTE L.
Published: June 2019

Introduction: Early dumping (ED) and postprandial hypoglycemia (PH) are often addressed as two separate complications after Roux-en-Y gastric bypass (RYGB) although symptoms overlap. We investigated the occurrence of ED in RYGB-patients with PH and potential mechanisms.

Methods: In a randomized cross-over study, 11 RYGB-patients with confirmed PH (blood glucose <3.9 mmol/L) underwent 6 separate 4-hour liquid mixed meal tests (MMT) in which continuous heart rate (HR) was recorded by Holter monitoring. The MMTs were preceded by the following: acarbose 50 mg (A), sitagliptin 100 mg (S), verapamil 120 mg (V), liraglutide 1.2 mg s (L), pasireotide 300 µg (P) and no treatment (NT). HR was averaged over 5 minutes intervals and calculated as peak values and incremental changes from baseline (ΔHR). ED was diagnosed as ΔHR ≥10 bpm during the first 60 minutes of the MMT. Associations between HR values and glucose, insulin, and GLP-1 concentrations were tested with the Spearman rank-order correlation and the effects of drug intervention were tested by use of linear mixed models.

Results: With NT, all patients had ΔHR ≥ 15 bpm within the first 35 minutes of the MMT (27 ± 3 bpm, mean ± SEM) corresponding to a 44 ± 4% increase in HR. Peak HR occurred at the same time as peak levels of glucose and GLP-1 (26 ± 2, 31 ± 2, 30 ± 2 minutes; p>0.23) and HR values were positively correlated with glucose, insulin and GLP-1 concentrations (r=0.44, r=0.41, r=0.56; p<0.0001). Intervention with P reduced both ΔHR, insulin and GLP-1 levels, A reduced ΔHR, hyperglycemia and insulin levels, and V reduced ΔHR and peak GLP-1 values (ΔHR: A 18 ± 3, V 18 ± 2, and P 11 ± 2 vs. NT 27 ± 3 bpm; p<0.001).

Conclusion: RYGB-patients with PH have postprandial HR increments suggestive of ED, indicating that PH and ED constitute a combined post-surgical complication. Insulin and GLP-1 are potential mediators driving the HR increments.

Disclosure

C. Øhrstrôm: None. D. Worm: None. U. Kielgast: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Sanofi. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. D.L. Hansen: None.
2076-P: Time Restricted Eating (TRE) Promotes Weight Loss, Alters Body Composition, and Improves Metabolic Parameters in Overweight Humans
Authors: CHOW LISA S. , MANOOGIAN EMILY , ALVEAR ALISON C. , WANG QI , PANDA SATCHIDANANDA , MASHEK DOUGLAS G.
Published: June 2019

TRE, restriction of the eating window, reduces weight in animals and humans. We performed a randomized clinical trial examining the effect of TRE on body composition and glycemic measures in overweight humans without diabetes. We hypothesized that TRE will reduce weight and alter body composition compared with unrestricted feeding (non-TRE).

21 overweight subjects [18F/3M, mean(SE), age: 44.7 years (2.7), BMI:34.6 kg/m2(1.7) with a prolonged eating window:15.6 hours (0.2)] were randomized to either 12 weeks of TRE [n=11 (goal 8 hours)] or non-TRE [n=10]. All oral intake was logged using the myCircadianClock smart phone application to remotely monitor TRE adherence. Subjects also underwent: 2-hour oral glucose tolerance test, 2-week continuous glucose monitoring (Freestyle Libre), and 2-week activity tracking (Actigraph Link) pre and post intervention.

Compared with the non-TRE group [eating window 15.2 hours (0.3)] post-intervention, the TRE group [eating window 10.4 hours (0.6)] decreased weight [-3.6 kg(0.6) vs. -1.4 kg(0.7)], visceral fat [-260 g(110) vs. 38 g(56)], lean mass [-1450 g(389) vs. -95.5 g(351)] and triglycerides [-23.6%(6.8) vs. -0.57%(7.6)] (all p≤0.05). Relative to baseline, the TRE group decreased: weight, fasting glucose, fat mass, lean mass, visceral fat, and fasting triglyceride levels (all p<0.05). This was not observed in the non-TRE group. TRE-related weight loss was associated with lower: fat mass [-4%(0.9)], visceral fat [-11%(4.0)], and lean mass [-3%(0.8)] relative to baseline (all p<0.05). All TRE-related effects were not significant after adjusting for weight loss. Neither intervention significantly altered physical activity.

In overweight subjects, TRE reduced weight and improved metabolic parameters (triglycerides, fasting glucose). However, the TRE-related weight loss included both lean and fat mass loss. Further investigation into the translational aspects of TRE to treat obesity-related disorders is warranted.

Disclosure

L.S. Chow: Research Support; Self; Eli Lilly and Company. E. Manoogian: None. A.C. Alvear: None. Q. Wang: None. S. Panda: Other Relationship; Self; PenguinRandomHouse. D.G. Mashek: Consultant; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company.

Funding

University of Minnesota Healthy Foods Healthy Lives (17SFR-2YR50LC)