bluuebunny/crossref_metadata_2025 huggingface dataset:
1916-P: Postprandial Glucagon Metabolism in Healthy Subjects: Use of 13C 15N Glucagon
Authors: RUCHI FNU , YADAV YOGESH R. , ROMERES DAVIDE , SAWLEH SAFIA , BENSON LINDA M. , JOHNSON KENNETH L. , SCHIAVON MICHELE , MAN CHIARA DALLA , COBELLI CLAUDIO , MCCORMICK DANIEL J. , BASU RITA , BASU ANANDA
Published: June 2020

Glucagon metabolism in humans is poorly understood and is currently under active investigation. We have recently developed a new isotope dilution method using nonradioactive, stable human glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon fluxes. To estimate postprandial glucagon turnover using this novel technique, we present data from the first 5 healthy subjects (3 males, age 26.2±7.9 years, BMI 25.4±2.6 kg/m2, fasting plasma glucose 4.7±0.2 mM, HbA1c 5.1±0.2 %) done thus far. After IRB approval and informed consent, subjects presented to the clinical research unit in the morning after an overnight fast. A catheter was inserted in a forearm vein for glucagon tracer infusion and another catheter placed in the contralateral hand and the hand kept in a heated box for periodic draws of arterialized venous samples for measurements of glucagon tracer (tandem mass spectrometry), glucagon and glucose concentrations during the study. A mixed meal (75 grams carb, 15% protein, 35% fat; 8 kcal/kg) was ingested at time 0 and the glucagon tracer infusion rate adjusted to mimic the anticipated changes in postprandial circulating glucagon concentrations for 6 hours. Systemic glucagon appearance rate (Ra glucagon) was calculated by the isotope dilution method. Fig 1 shows the Ra glucagon in all subjects. These initial data show that postprandial glucagon turnover can be calculated in humans applying this novel technique.

Disclosure

F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. M. Schiavon: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca.

Funding

National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
1918-P: YWHAB Inhibits Hepatic Gluconeogenesis through Suppression of Glucagon Signaling Pathway
Authors: WEI LI , JI LINLIN , ZHU CHAOYU
Published: June 2020

Aims/Introduction: Hyperglycemia serves as a central factor in the development and progression of metabolic diseases. Since the glucagon receptor and its antagonism have been reported to be associated with the development and progression of hyperglycemias, the factors and proteins involved in the regulation of glucagon activity and signaling are still unclear.

Materials and Methods: We examined the role of YWHAB in vivo (in hepatocyte-selective Ywhab knockout and overexpressing mice) and in vitro (in mouse primary hepatocytes and human HepG2 cells).

Results: In this study, we found that YWHAB was down-regulated in ob/ob mice and db/db mice. To establish function of YWHAB in glucose metabolism in vivo, we generated hepatocyte-selective Ywhab knockout mice. The knockout mice displayed impaired blood glucose homeostasis in isolated mouse primary hepatocytes, as well as the increase in glucagon-mediated hepatocytic glucose production. Overexpressing YWHAB markedly decreases the expression of key enzymes in gluconeogenesis and inactivates the glucagon signaling. Similarly, the magnifying effect on glucagon signaling of Ywhab knockout in mouse primary hepatocytes were significantly changed by the treatment of PKA inhibitor H89.

Conclusions: The regulatory role of YWHAB in hepatocytes can protect against the glucagon-induced glucose production by attenuating the activation of cAMP/PKA and the expression of key enzymes in gluconeogenesis. Thus, YWHAB is a new target site identified in the control of glucagon signaling and associated metabolic diseases.

Disclosure

L. Wei: None. L. Ji: None. C. Zhu: None.

Funding

National Natural Science Foundation of China (81870603)
192-OR: Association between Gestational Diabetes and the Risk of Short Interpregnancy Intervals
Authors: ANGUZU RONALD , EGEDE LEONARD E. , SHOUR ABDUL R. , PALATNIK ANNA
Published: June 2020

Objective: Short interpregnancy intervals are associated with a number of adverse perinatal outcomes and their prevention is a public health priority. Among women with a history of gestational diabetes (GDM), short interpregnancy intervals further decrease the timeframe for postpartum glucose optimization and testing for type 2 diabetes prior to the next conception. The objective of this study was to evaluate whether women with GDM have higher rates of short interpregnancy intervals.

Methods: Data from the 2011-2017 National Survey on Family Growth were analyzed. Study sample included 28,443 women aged 18-44y. Primary outcome was short interpregnancy intervals, defined as pregnancies conceived within 18 months after a previous birth. The rates of short interpregnancy intervals were compared between women with and without GDM using bivariate analysis. Multivariable logistic regression was done to assess independent association between GDM and short interpregnancy intervals.

Results: Out of 28,443 women included in the analysis, 2,827 (9.9%) had diagnosis of GDM. Short interpregnancy intervals rates were higher in women with GDM compared to controls (56.4% vs. 43.6%, p<0.001). In bivariate analysis, GDM significantly increased the odds of short interpregnancy intervals compared to controls (OR=1.43, 95% CI 1.22-1.66). After controlling for maternal age, body mass index, race/ethnicity, marital status, education, insurance, family income, contraception use and history of sexually transmitted infections, GDM remained to be independently associated with a higher rate of short interpregnancy intervals (aOR=1.49, 95% CI 1.26-1.76).

Conclusion: Women with GDM have higher rates of short interpregnancy intervals. Reducing short interpregnancy intervals in this population will not only reduce perinatal risks of short interpregnancy intervals but will also allow time for adequate preconception counseling for screening and management of type 2 diabetes prior to future pregnancy.

Disclosure

R. Anguzu: None. L.E. Egede: None. A.R. Shour: None. A. Palatnik: None.
1935-P: Loss of µ-Crystallin Increases Adipose Tissues with Inhibitory Effects on Adipocyte Differentiation through ß-Catenin-Dependent Mechanisms in High-Fat Diet Fed Mice
Authors: OHKUBO YOHSUKE , NISHIO SHIN-ICHI , SHIMADA YASUHO , KUBOTA SATOSHI , KITAHARA JUNICHIRO , SHIBATA YUSUKE , KITAJIMA KOHEI , SEKIDO TAKASHI , SUZUKI SATORU , KOMATSU MITSUHISA
Published: June 2020

The 3,5,3’-triiodo-L-thyronine (T3) binding protein, μ-crystalin (CRYM), regulates intracellular thyroid hormone action by controlling the concentration of T3 in the cytoplasm. As thyroid hormone plays a pivotal role on metabolic homeostasis, CRYM may have influence on cellular metabolic processes. Loss of CRYM caused obesity in high fat diet (HFD) with glucose intolerance, fatty liver and hypertrophy of epididymal adipocyte, we have previously reported (BBRC 2019;508:914-920). Although the previous study has shown that the amount of HFD which CRYM knock out (KO) mice ate was larger than the one wild type (WT) mice did, the precise metabolic mechanisms has not been determined. In this study, we assessed the metabolic effects of CRYM expression by pair-feeding. We have found that the ratio of adipose tissue to body weight in CRYM KO mice significantly increases compared to those of WT mice (WT 0.034±0.009, CRYM KO 0.044±0.008 (mean±SD), p=0.04) in the pair-feeding test. However, there were no significant difference of body weights between two groups (WT 31.8±2.0g, CRYM KO 31.3±1.5g(mean±SD)). The microarray examination using visceral adipocytes of HFD fed mice showed that the several genes related to lipid metabolisms up-regulated in CRYM KO mice. Among them, the gene expression of the WNT1 inducible signaling pathway protein 2, inhibiting adipose differentiation, was significantly up-regulated in pair-feeding HFD CRYM KO mice (Z-score 2.18). In addition, the Lrp4, fzd10 and wnt10a genes, as adipogenesis inhibitors through a β-catenin-dependent mechanism, elevated in free feeding HFD CRYM KO mice. Collectively, our data suggests that lack of CRYM causes visceral adipose tissue hypertrophy not only because of appetite, but also maybe because of inhibitory effects on adipocyte differentiation in a caloric excess environment.

Disclosure

Y. Ohkubo: None. S. Nishio: None. Y. Shimada: None. S. Kubota: None. J. Kitahara: None. Y. Shibata: None. K. Kitajima: None. T. Sekido: None. S. Suzuki: None. M. Komatsu: None.
1939-P: Sex Dimorphism in Erythropoietin Regulation of Fat Mass
Authors: LEE JEEYOUNG , ROGERS HEATHER , NOGUCHI CONSTANCE T.
Published: June 2020

Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. In male mice and ovariectomized female mice on high fat diet (HFD), EPO treatment increased hematocrit, improved glucose tolerance and attenuated body weight gain via reduced fat mass. Estradiol supplementation abrogated the EPO effect on body weight in ovariectomized female mice, providing evidence for estrogen related gender specific EPO action in metabolic regulation. To determine estrogen response in metabolic regulation with EPO treatment, we use the estrogen receptor α knockout (ERαKO) mice and mice with targeted deletion of estrogen receptor alpha in adipose tissue (ERαadipoKO). Male and female ERαKO mice on HFD exhibit increased fat mass and glucose intolerance. EPO treatment on HFD increased hematocrit in both wild type (WT) and ERαKO mice and reduced gain in fat mass in male mice as well as female ERαKO mice but did not affect fat mass in female WT mice. The improvement in glucose tolerance and insulin tolerance with EPO treatment during HFD was significantly greater in female ERaKO mice compared with female WT. We previously demonstrated that specific deletion of EPO receptor in adipose tissue in mice decreases glucose tolerance and insulin sensitivity and increases susceptibility to diet-induced obesity. Although no decrease in body weight was observed in female WT and ERαadipoKO with EPO treatment on HFD, female ERαadipoKO also showed significantly improved glycemic control with EPO treatment compared with WT control. EPO treatment decreased white fat associated gene expression, Psat1 and Wdnm-1like in subcutaneous fat pads from both female ERαKO mice and ERαadipoKO on HFD but not WT female mice. These results confirm the role of estrogen in the sex-differential EPO effect on fat mass regulation and suggest cross talk between EPO and estrogen signaling in metabolic homeostasis and fat mass regulation via estrogen response in white adipose tissue in female mice.

Disclosure

J. Lee: None. H. Rogers: None. C.T. Noguchi: None.
1942-P: Vertical Sleeve Gastrectomy Confers Metabolic Improvements by Reducing Intestinal Bile Acids and Lipid Absorption in Mice
Authors: DING LILI , TIAN JINGYAN , HUANG WENDONG
Published: June 2020

Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the mechanisms through which changes in BA content and signaling contribute to the metabolic effects of VSG remain poorly understood. Therefore, in this study, we aim to systematically evaluate the roles of FXR in VSG and determine the underlying mechanism by which bile acids mediate the beneficial effects of VSG. Our data demonstrated that both intestine- and liver-specific farnesoid X receptor (Fxr) knockout mice retained VSG effects and VSG did not appear to increase FXR activation in the liver or intestine, indicating that hepatic or intestinal FXR is dispensable for the metabolic improvement of VSG. We further found that VSG altered gut microbiota composition and reduced intestinal BA levels in mice, resulting in lower intestinal fat absorption and concomitant metabolic improvements similar to those observed in Fxr null mice. We then confirmed these findings in sterol 27-hydroxylase knockout (Cyp27a1-/-) mice, which exhibited low intestinal BAs and fat absorption, did not experience metabolic improvements after VSG. Our findings reveal that reductions in intestinal BAs and lipid absorption may underlie the metabolic benefits of VSG.

Disclosure

L. Ding: None. J. Tian: None. W. Huang: None.

Funding

NCIR01CA139158; Schaeffer Foundation (to W.H.); Hench Foundation (to W.H.); National Natural Science Foundation of China (81773961); Shanghai Pujiang Program (17PJ1408800 to L.D.)
1951-P: Glucose Effectiveness Fails to Compensate for Insulin Resistance after Fat Feeding in Dogs
Authors: ADER MARILYN , KOLKA CATHRYN M. , BERGMAN RICHARD N.
Published: June 2020

Glucose homeostasis involves actions of both insulin and glucose per se (“glucose effectiveness, SG”). While consumption of a high fat diet typically induces insulin resistance, it is unclear whether SG is altered by fat feeding. We quantified SG from the intravenous glucose tolerance test (IVGTT; n=36) or hyperglycemic clamp at basal insulin (HGC; n=5) in dogs, tested before and after 6 weeks fat feeding (+ 6 g/kg per day). SG from IVGTTs were quantified by minimal model (SG-MINMOD). In HGCs, glucose was sequentially raised to 125, 180, and 250 mg/dl during somatostatin (SRIF) and basal insulin replacement; SG-HGC was calculated as the slope of steady state glucose infusion rate and plasma glucose. Insulin sensitivity (SI) was calculated from IVGTTs and from euglycemic clamps. Fat feeding induced weight gain (28.8±0.4 to 31.2±2.5 kg; p<0.0001) and insulin resistance at both liver (p<0.0001) and periphery (p<0.0001). SG-MINMOD was reduced after fat feeding (0.036±0.002 vs. 0.041±0.002 min-1; p<0.001). The direct measure of SG from HGCs at basal insulin (SG-HGC) suggest similar diet-induced reduction (21%), although sample size was diminished due to SRIF breakthrough and resulting hyperinsulinemia in 2 animals. After fat feeding, there was no increase in glucose effectiveness that may be expected as compensation for diet-induced insulin resistance. Rather, glucose effectiveness decreased. These data indicate that obesity results in diminished actions of both insulin and glucose per se on glucose homeostasis.

Disclosure

M. Ader: None. C.M. Kolka: Research Support; Self; AstraZeneca. R.N. Bergman: None.

Funding

National Institutes of Health (DK29867, DK27619)
1958-P: Neonatal Il-4 Induces a Persistent Decrease in Adipocyte Maturation
Authors: YING TAMMY , SEALE PATRICK , SIMMONS REBECCA A.
Published: June 2020

Adipose tissue is a central node for the dynamic regulation of systemic metabolism and energy expenditure. Little is known about adipogenesis in the newborn which is the critical window of adipose tissue development. Emerging data suggest that immune cells, particularly innate immune cells, play an important role in de novo beige adipogenesis and beige fat thermogenesis in mature rodents. In previous studies we showed that administration of low levels of IL-4 in the first week of life to rat pups results in decreased adiposity and improved glucose tolerance in adulthood, suggesting that beige adipogenesis may be enhanced by neonatal IL-4 administration. Developing animals produce higher levels of IL-4 compared to mature animals and use a distinct pre-adipocyte compartment for adipogenesis. In this study, we analyze the effects of IL-4 on adipogenesis in the developing rat. We demonstrate that a short and transient IL-4 exposure in the neonate during postnatal days 1-6 induces acute beige adipogenesis in the inguinal white adipose tissue (iWAT) that is associated with the upregulation of Ucp1 (n=6). Concurrently, adipocyte maturation is decreased with Adipoq downregulated (n=6). Pre-adipocytes from 10 week old mature rats that had been treated with IL-4 as neonates were differentiated in vitro and also show a decrease in Adipoq compared to controls (n=6). These data demonstrate that neonatal IL-4 induces a long term decrease in the maturation potential of pre-adipocytes. Interestingly, these adult differentiated pre-adipocytes show no change in Ucp1 expression after neonatal IL-4 exposure compared to control (n=6). Thus, neonatal IL-4 induces only acute beige adipogenesis, but impairs adipocyte maturation long term. Phenotypically, neonatal IL-4 resulted in decreased iWAT (n=7) and decreased fasting blood glucose in 10 week old animals (n=6) compared to control. Our studies show that the neonatal period is critical for adipocyte development and may influence the later onset of obesity.

Disclosure

T. Ying: None. P. Seale: None. R.A. Simmons: None.

Funding

National Institutes of Health (DK114054)
1972-P: Adipose Tissue–Derived Exosomal MicroRNA Regulates Placental Glucose Uptake in Gestational Diabetes Mellitus Pregnancies
Authors: JAYABALAN NANTHINI , SCHOLZ-ROMERO KATHERIN , GUANZON DOMINIC , LAI ANDREW , MCINTYRE DAVID , LAPPAS MARTHA , SALOMON CARLOS
Published: June 2020

Adipose tissue exosomal miRNAs (exomiRs) serve as a signalling molecule that is involved in conveying intercellular message signalling. In this study, we aimed to profile the adipose tissue exomiRs in patients with normal glucose tolerant (NGT) and gestational diabetes mellitus (GDM). Omentum were obtained from BMI-matched NGT (n=10) and GDM (n=10) women at delivery (>37 weeks gestation). Isolated exosomes were characterised based on size distribution and protein enrichment. Total exosomal RNA was isolated by miRNeasy (Qiagen) according to manufacturer’s instructions. Illumina TrueSeq Small RNA kit was used to construct a small RNA library. Finally, the resulting sequencing FASTQ files were analysed using miRDeep2 to identify both known and novel miRNAs. A selected exomiR mimic was overexpressed in the human primary trophoblast (PHT) cells and its effect on glucose uptake was evaluated using 2-NBDG. We identified a total of 1209 miRNAs with 18 miRNAs were significantly differentially expressed in GDM exosomes. Comparatively, 12 miRNAs were upregulated while 6 were downregulated in the exosomes from GDM pregnancy compared to normal pregnancy. Consequently, has-miR-515-5p was selected to be investigated in further functional studies, following validation of its expression using real-time PCR. The QRT-PCR analysis of placental tissue showed a significant increase in the expression of GDM placenta compared to NGT placenta. In PHT cells, the overexpression of miR-515-5p significantly stimulated the glucose uptake (p<0.0001) compared to control group. The proteomics analysis of miR-515-5p overexpressed PHT cells showed differential expression of proteins that are associated with glycolysis. These findings suggest adipose tissue exosomal miR515-5p mediated placental glucose uptake could contribute to an excessive placental nutrient transfer GDM, which could instigate consequences, such as fetal overgrowth.

Disclosure

N. Jayabalan: None. D. Guanzon: None. A. Lai: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. M. Lappas: None. C. Salomon: None.

Funding

Diabetes Australia; Fondo Nacional de Desarrollo Científico y Tecnológico (1170809)
198-LB: Pleiotropy Analysis of Adiposity, Glycemic, and Renal Traits in the Population Architecture Using Genomics in Epidemiology (PAGE) Consortium
Authors: HIGHLAND HEATHER M. , DOWNIE CAROLINA , DIMOS SOFIA F. , GRAFF MARIAELISA , POLFUS LINDA M. , DARST BURCU F. , BALDASSARI ANTOINE R.M. , SITLANI COLLEEN , HOWARD ANNIE GREEN , KOOPERBERG CHARLES L. , LOOS RUTH , MATISE TARA , MOTTL AMY K. , NORTH KARI E. , AVERY CHRISTY L. ,   THE PAGE CONSORIUM
Published: June 2020

A shared genetic susceptibility underlies diabetes, adiposity, and kidney phenotypes, yet few studies have leveraged this common genetic architecture in an attempt to clarify molecular functions, identify mechanistic common denominators, and prioritize variants for functional interrogation. We systematically interrogated evidence of a shared genetic architecture across adiposity (BMI [N=90,813], waist circumference[N=68,389], and waist to hip ratio [WHR, N=63,747]), type 2 diabetes (T2D, [N=98,686, Ncase=26,440], fasting glucose [FG, N=52,211], HbA1c [N=23,357], and fasting insulin [FI, N=48,395]), and kidney (eGFR [N=52,555] and chronic kidney disease [CKD, N=91,382, Ncase=10,883]) phenotypes in an ancestrally diverse study population (28% African American, 31% European ancestry, 28% Hispanic; 69% female; average age 56.9 (range 18-90)) within PAGE. We conducted a cross-trait meta-analysis using Adaptive Sum of Powered Score Tests (aSPU). We have identified 42 loci associated across these traits, (P<5e-8), including one preliminary novel cross-trait association for rs200812701, a nonsynonymous variant in KIF4B p.Ala491Val that was associated with BMI, waist circumference, and HbA1c. rs200812701 is rare (minor allele frequency [MAF]<0.1%) in all populations except Native Hawaiians (MAF=25%) and Asians (MAF=8%). Many of these loci are known for one trait, but the identification of shared genetic susceptibility for these loci is novel. For example, the PEPD locus is established for adiposity measures, namely WHR; however, this cross-trait association is driven more so by FI, T2D and eGFR. Our systematic interrogation of the shared genetic susceptibility underlying diabetes, adiposity, and kidney traits in an ancestrally diverse population has revealed novel loci and evidence of molecular functions and mechanistic common denominators underlying GWAS findings, demonstrating the utility of our approach.

Disclosure

H.M. Highland: None. C. Downie: None. S.F. Dimos: None. M. Graff: None. L.M. Polfus: None. B.F. Darst: None. A.R.M. Baldassari: None. C. Sitlani: None. A. Howard: None. C.L. Kooperberg: None. R. Loos: None. T. Matise: None. A.K. Mottl: None. K.E. North: None. C.L. Avery: Research Support; Self; Amgen.

Funding

American Diabetes Association (1-19-PDF-045 to H.M.M.); National Institutes of Health (T32HL007055, T32HL129982, R01HL142825)
1980-P: Broccoli Extract as a Supplement to Mitigate ER-Induced Inflammation in Adipocytes to Reduce Type 2 Diabetes Mellitus Risk
Authors: MURPHY ALICE , BARKER GUY , TRIPATHI GYANENDRA , MCTERNAN PHILIP G.
Published: June 2020

Background: Nutrient excess during obesity can contribute to type 2 diabetes mellitus (T2DM) risk via endoplasmic reticulum (ER) stress within adipose tissue. Investigating ’Superfoods’ such as broccoli that contain nutrients which may be able to combat this disruption is therefore important to potentially reduce the risk of developing T2DM in obesity.

Methods: Differentiated human adipocytes (Chub-S7, n=6) were treated with a broccoli extract (BE; hybrid Brassica oleracea var. italic; 10ng/ml) alone or in combination with tunicamycin (Tun; 750ng/ml), an inducer of ER stress. ER stress genes (ATF4, ATF6 and CHOP) were measured at three time points (24hr, 48hr, 72hr, n=3) using qPCR. ER stress proteins (BiP, P-eIF2α and eIF2α) were measured at 18 time points (0hr - 72hr) using Western Blot.

Results: Tun increased ER stress gene expression 4.5-fold (p<0.001), whilst BE+Tun reduced this expression by up to 64% (p<0.001). Similarly, Tun increased ER stress proteins 9.5-fold (p<0.05), whilst BE+Tun reduced expression by up to 94% (p<0.05). Transcriptomic analysis also highlighted positive significant changes in the mevalonate pathway with the use of BE in treated adipocytes (P<0,05), suggesting a possible mechanism of action.

Conclusion: These studies suggest that BE is able to alleviate ER stress in human adipocytes, possibly via mevalonate pathway activation, thus reducing the risk of subjects developing insulin resistance and T2DM. As such, there is the potential to develop a BE dietary supplement to reduce ER stress and reduce the impact of obesity on T2DM.

Disclosure

A. Murphy: None. G. Barker: None. G. Tripathi: None. P.G. McTernan: None.

Funding

Engineering and Physical Sciences Research Council
1996-P: Heightened Sweet-Taste Preference Is Associated with Greater Hypothalamic Response to Glucose and Longitudinal Weight Gain
Authors: YUNKER ALEXANDRA G. , ALVES JASMIN , ANGELO BRENDAN C. , DEFENDIS ALEXIS W. , LUO SHAN H. , PAGE KATHLEEN A.
Published: June 2020

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking “sweets” can be associated with weight gain, but the influence of sweet taste preference (STP) on hypothalamic regulation of appetite is unknown. We tested the hypothesis that STP is associated with increased hypothalamic activation in response to glucose (a potential marker of obesity risk), and that greater STP and glucose-linked hypothalamic activation would predict greater weight gain. Forty-six (24 female) adults age 18-35 years completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 38. STP was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and ∼35 min after 75g glucose ingestion, and hypothalamic response to glucose was measured by calculating hypothalamic blood flow (BF) after minus before glucose ingestion. Linear regression was used to examine relationships between STP and the hypothalamic response to glucose and changes in BMI before and after adjusting for age, sex, BMI, mean cerebral BF, and baseline BMI. Baseline BMI was 27.61±5.13 kg/m2. STP scores ranged from 3% to 29.39% w/v. The hypothalamic response to glucose ranged from -14.64 to 15.63 ml/100g/min. Change in BMI ranged from -2.93 to 6.00 kg/m2. STP was positively associated with hypothalamic response to glucose (unadjusted: β=0.65, p<0.0001; adjusted: β=0.29, p=0.01). Greater hypothalamic response to glucose was positively associated with increases in BMI (unadjusted: β=0.07, p=0.04; adjusted: β=0.09, p=0.07). STP was positively associated with increases in BMI (unadjusted: β=0.09, p=0.0004; adjusted: β=0.09, p=0.0002). Our results suggest that heightened STP is associated with a greater hypothalamic response to glucose which may relate to greater susceptibility for weight gain.

Disclosure

A.G. Yunker: None. J. Alves: None. B.C. Angelo: None. A.W. DeFendis: None. S.H. Luo: None. K.A. Page: None.

Funding

National Institutes of Health (R01DK102794)
1997-P: Bidirectional Regulation of Energy Homeostasis Mediated by Estrogen Receptor a and ß in the Medial Amygdala
Authors: YE HUI , HE YANLIN , IBRAHIMI LUCAS , SCHAUL SARAH , LUO PEI , CARRILLO-SÁENZ LESLIE , LAI PENGHUA , PATEL NIRALI , KOTA MAYA , DIXIT DEVIN , XU PINGWEN
Published: June 2020

Compelling evidence has demonstrated that estradiol and estrogen receptor α/β (ERα/β) play key roles in the central regulation of energy balance and glucose homeostasis. Our previous research showed that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, therefore promotes energy expenditure and prevents diet-induced obesity (DIO). Interestingly, another estrogen receptor, ERβ, is also highly expressed in the MeA. To test the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood using AAV virus-mediated Cre-Lox site-specific recombination. We found that, when fed on a high-fat diet but not on a normal chow diet, compared to the control mice, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, which were associated with increased energy expenditure. We further showed that half of the ERαMeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Finally, we showed that chemogenetic activation of ERαMeA or ERβMeA neurons induces a similar increase in energy expenditure. Collectively, our results support a model that, estrogen acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO, whereas activating ERαMeA decreases and activating ERβMeA increases body weight.

Disclosure

H. Ye: None. Y. He: None. L. Ibrahimi: None. S. Schaul: None. P. Luo: None. L. Carrillo-Sáenz: None. P. Lai: None. N. Patel: None. M. Kota: None. D. Dixit: None. P. Xu: None.

Funding

National Institutes of Health (5R00DK107008-04)
2002-P: Waist-Hip Ratio: A Better Obesity Measure Index Represents Insulin Secretion among Obese Women with Different Glucose Metabolism Status
Authors: WU JING , WANG BIAN
Published: June 2020

Objective: To investigate the association of simple obesity measures (BMI, WC and WHR) with insulin secretion in obese subjects with normal glucose metabolism (NGM), prediabetes, and T2DM.

Research Design and Methods: 848 obese patients were recruited and divided into three groups (428 NGM, 248 prediabetes, and 172 T2DM). BMI, WC, and WHR were obtained. Insulin secretion was described by three beta cell function indices (HOMA-β, ΔI30/ΔG30 and AUCI60-120). Pearson correlation analysis and multiple linear regression analysis were used. In addition, 284 subjects estimated their body fat by dual x-ray absorptiometry. The joint relationship between obesity measures, body fat and insulin secretion were studied.

Results: As glucose metabolism spectrum changed from NGM to prediabetes and to T2DM, the correlation between WHR and insulin secretion declined (from r=0.286**, r=0.081, r=0.2** to r=-0.012, r=-0.072, r=-0.074 and to r=-0.173*, r=-0.175*, r=-0.171*; *P < 0.05, **P < 0.01). In contrast, BMI and WC showed a consistent association with insulin secretion (r>0). Similar relevant reversal was only found in female subjects. There were significant interactions of WHR and glucose status on insulin secretion in female subjects, in this adjusted model, WHR was associated with higher insulin secretion in NGM group (1.19±0.23**, 0.58±0.32, 0.82±0.26**) and lower in T2DM group (-0.77±0.34*, -1.78±0.47**, -1.36±0.39), not prediabetes (0.15±0.27, 0.08±0.38, 0.28±0.31). Adding HOMA-IR to the core model can increase the inverse associations. Elevated limb fat to trunk fat ratio had significantly lower insulin secretion levels, and the relationship between this fat ratio and WHR was considerably strong in female.

Conclusions: WHR and insulin secretion relationship is dependent on glucose status among obese women. As diabetes developed, higher WHR revealed lower insulin secretion, which may be attributed to more fat distributed in extremities.

Disclosure

J. Wu: None. B. Wang: None.
2006-P: Association between High Birth Weight and Later Higher BMI and Blood Pressure in 9-Year-Old Schoolchildren
Authors: HIRSCHLER VALERIA ,   CARIÑO STUDY GROUP, MOLINARI CLAUDIA , GARCIA CONCEPCION , LAPERTOSA SILIVA
Published: June 2020

Background: Studies have suggested that high birth weight (BW) is associated with later higher BMI but its association with higher blood pressure (BP) should be further explored.

Objective: To determine the association between high BW with later higher BMI and BP in 9-year-old overweight/obese (OW/OB) schoolchildren.

Methods: Schoolchildren (n = 2567, 1157M) aged 8.7±2.1 years from 10 elementary schools in five states of Argentina were examined between April 2017 and September 2019. Mothers submitted children’s BW information. Body mass index (BMI) and BP were assessed by pediatricians.

Results: 1095 (42.7%) of the children were OW/OB. The prevalence of low (<2500grams), and high BW (>4000grams) was 6.6% (n=169) and 7.4% (n=190), respectively. There was a significant difference in mean BMI z-score in 9-year-old children between low BW, normal BW, and high BW (0.44, 0.73, and 1.05, respectively). OW/OB 9-year-old children with high BW had higher z-BMI (1.70 vs. 1.89, respectively) and higher systolic BP (97 vs. 100 mm Hg, respectively) than OW/OB 9-year-old children with normal or low BW. However, normal-weight 9-year-old children with high BW had similar BP than 9-year-old children with normal or low BW. Multiple linear regression analyses showed that systolic BP was significantly associated with age in 9-year-old normal-weight children (R2=0.07). However, systolic BP was positively associated with age and BW in 9-year-old-OW/OB children (R2=0.11). When systolic BP was replaced by diastolic BP similar results were obtained.

Conclusion: This study suggests that systolic BP was significantly associated with high BW in OW/OB 9-year-old children but not in 9-year-old normal-weight children. Children with high BW should be followed closely to prevent future cardiovascular disease.

Disclosure

V. Hirschler: None. C. Molinari: None. C. Garcia: None. S. Lapertosa: None.
2010-P: Adipocyte Clusterin Is a Link between Cardiometabolism and Alzheimer’s Disease
Authors: BRADLEY DAVID , LIU JOEY Z. , BLASZCZAK ALECIA M. , WRIGHT VALERIE P. , TARAWNEH RAWAN , LIU YUXI , RYU JAE CHEON , YOON SUNG OK , HSUEH WILLA
Published: June 2020

Background: Obesity heightens the risk for both cardiometabolic complications and Alzheimer’s disease (AD). Although the reasons have yet to be fully elucidated, weight loss improves cognition. Given this link, factors overproduced by obese adipose tissue are ideal candidates for novel investigation into AD pathogenesis. We have recently shown that clusterin from the adipocyte is related to multiple factors of the metabolic syndrome (insulin resistance, dyslipidemia, NAFLD, and atherosclerosis). Clusterin is also involved in CNS lipid trafficking and has been proposed as an AD biomarker.

Rationale: Our goals were to characterize the effect of high-fat diet (HFD) feeding on CNS clusterin and neuronal insulin signaling in an AD mouse model (5XFAD); and furthermore, determine the relationship of adipocyte clusterin with neurocognition and insulin sensitivity in obese humans at baseline and following bariatric surgery.

Methods: We treated 5XFAD and WT mice with normal chow and HFD for 4 mo., measured CNS clusterin, and determined its effect on neuronal insulin signaling. We next measured subcutaneous adipocyte (SAd) clusterin expression, and performed neuropsychological evaluation and a hyperinsulinemic-euglycemic clamp procedure in obese human subjects (n=11) before and after sleeve gastrectomy.

Results: In the 5XFAD mice, HFD increases brain clusterin levels compared to WT, and in primary cortical neurons clusterin attenuates insulin signaling in a dose-dependent manner. In humans, SAd clusterin is related to hepatic insulin resistance, higher fasting glucose, and reduced working memory/attention. After sleeve gastrectomy SAd clusterin expression is reduced, with a significant inverse association between clusterin and working memory/attention and hepatic insulin sensitivity.

Conclusions: Our data suggests that SAd clusterin is a potential player in AD pathology, providing a critical link between excess adiposity, T2D, insulin resistance, and heightened AD risk.

Disclosure

D. Bradley: None. J.Z. Liu: None. A.M. Blaszczak: None. V.P. Wright: None. R. Tarawneh: None. Y. Liu: None. J. Ryu: None. S. Yoon: None. W. Hsueh: None.

Funding

American Diabetes Association (1-16-ICTS-049 to W.H.); National Institutes of Health (KL2TR001068, R01HL135622)
2011-P: Cognitive Function Improves after Vertical Sleeve Gastrectomy, and Cognitive Gains Are Associated with Reduced Inflammation
Authors: MOHEET AMIR , RUBIN NATHAN , EBERLY LYNN E. , IKRAMUDDIN SAYEED , LUCIANA MONICA
Published: June 2020

Obesity (OB) is associated with cognitive impairments, though the mechanisms are not well understood. OB-related chronic systemic inflammation has been postulated to contribute to cognitive dysfunction. Inflammation improves after vertical sleeve gastrectomy (VSG) and could be a potential mechanism for cognitive improvement. We examined cognitive functions in morbidly obese adults without diabetes (n 10, mean age 35 ± 4 yrs, BMI 46±11, A1C 5.3±0.4) before and 6 months after VSG. Blood inflammatory markers including IL 6 and CRP were quantified at both assessments. Paired t-tests were used to index pre versus post VSG changes. Spearman correlations quantified associations between cognition and inflammatory markers. There were post VSG improvements in bilateral fine motor skills (Grooved Pegboard, dominant 73 ±21.2 vs. 61 ±8.0, p 0.003, non-dominant 81 ± 24 vs. 67±9 p 0.01), working memory (backward digit span 5.2 ±1.8 vs. 6.1±1.2, p 0.18; NIH Toolbox List Sort Working Memory 102 ± 14 vs. 108 ± 11, p 0.069), and Fluid Reasoning (NIH Toolbox 94 ± 18 vs. 102 ±17, p 0.048). Depression levels (Beck Inventory) significantly decreased; levels were sub-clinical prior to VSG. Functions that remained stable pre to post VSG included estimated nonverbal and verbal IQ (Matrix Reasoning and Picture Vocabulary Tasks), verbal learning (Rey Auditory Verbal Learning Test), basic attention (Digit span forward), and self-reported impulsivity. When pre-to-post VSG changes in cognitive performance was correlated with pre-to-post VSG changes in systemic inflammation (IL6 and CRP levels), decreased inflammation was associated with improvements in working memory and other fluid abilities (r’s from .4 to .8). These findings are novel and show that cognitive function improves after VSG in obese subjects without diabetes and inflammation may contribute to cognitive alterations in OB.

Disclosure

A. Moheet: None. N. Rubin: None. L.E. Eberly: None. S. Ikramuddin: Other Relationship; Self; Reshape Life Sciences (formerly EnteroMedics). M. Luciana: None.

Funding

National Institutes of Health (R21NS101140)
2012-P: Effective Online CME Improves Obesity Diagnosis and Management
Authors: LARKIN AMY , CAPPARELLI CATHERINE C. , LEPKOWSKI ELIZABETH , LE ANNE
Published: June 2020

We sought to determine if online continuing medical education (CME) could improve the knowledge and competence of diabetologists/endocrinologists (D/Es) and primary care physicians (PCPs) related to diagnosis and management of obesity. The CME activity was a 30-minute online video panel discussion among 3 faculty. A repeated pairs pre-/post-assessment study design was used and chi-square test (P <.05 is considered significant) assessed educational effect for each activity. Cramer’s V was used to calculate the effect size (0.06-0.15 is a noticeable effect, 0.16-0.26 considerable, and >0.26 extensive). The activity launched August 29, 2019 and data were collected through October 3, 2019. In total, 110 D/Es and 507 PCPs completed all pre/post questions and were included in the study. • Overall, 16% of D/Es (P<.01 V=.146) and 23% of PCPs (P<.0001, V=.209) demonstrated improvement from pre to post. • 26% of D/Es (P<.0001; V=.345) and 31% of PCPs (P<.0001; V=.342) demonstrated improvement in diagnosing a patient with obesity. • 5% of D/Es (P=.60; V=.033) and 15% of PCPs (P<.0001; V=.107) demonstrated improvement in diagnosing a patient with obesity. • 29% of D/Es and 38% of PCPs reported an increase in confidence in effectively managing obesity. Continued educational gaps: • 69% of D/Es and 62% of PCPs need additional education on diagnosis and staging of obesity. • 21% of D/Es and 49% of PCPs need additional education on strategies for managing obesity. This study demonstrates the success of an online CME activity with discussion among 3 experts in the field on improving knowledge and competence related to obesity diagnosis and management. Additionally, continued gaps were identified for future educational targets.

Disclosure

A. Larkin: None. C.C. Capparelli: None. E. Lepkowski: None. A. Le: None.

Funding

Novo Nordisk
2015-P: Endobarrier (EB) in Diabetes/Prediabetes with Obstructive Sleep Apnoea (OSA) Study: The Final Results
Authors: YADAGIRI MAHENDER , KINNEY FIONA Y. , ASHMAN NATALIE , ADAMS JESSICA , WYRES MELANIE C. , SHARRATT EMMA S. , GREENWOOD CHERYL , LANG MICHAEL H. , BLEASDALE JOHN , FOGDEN EDWARD , ANDERSON MARK , WALTON CHRISTOPHER , GREENSTONE MICHAEL A. , RYDER ROBERT E.
Published: June 2020

Background/Aim: EB, a 60cm endoscopically implanted proximal intestinal liner is implanted for up to one year and then removed. We aimed to assess the extent to which patients with type 2 diabetes or prediabetes, obesity (BMI 30-45kg/m²) and moderate OSA requiring continuous positive airway pressure ventilation (CPAP) are able to discontinue CPAP following EB-related weight loss.

Method: We assessed Apnoea Hypopnoea Index (AHI), weight and HbA1c before and during EB treatment and following its removal in the 12 patients with moderate OSA requiring continuous positive airway pressure ventilation (CPAP) {75% female, 8/12 (66%) type 2 diabetes, 4/12 (34%) prediabetes, mean ± SD age 52.6±9.7 years, BMI 37.4±3.5 kg/m², median duration of OSA while on CPAP 9.0(7.0-15.0) months}.

Results: During the period of EB implantation, mean ± SD HbA1c fell by 1.26±0.7% from 7.9 ± 1.6 to 6.6 ± 0.9% (p=0.023), weight by 10.5±4.0 kg from 103.8± 14.1 to 93.3±13.7 kg (p<0.001) and AHI by 9.1±5.0 events/hour from 18.9±3.8 to 9.7±3.0 events/hour(p<0.001). Prior to EB, all patients had AHI in the National Institute for Health and Care Excellence (NICE) moderate OSA range (15-29.9 events/hour). During EB treatment the AHI of all 12 patients fell below 15 such that they no longer required CPAP according to NICE criteria. After EB removal, 10/12 (83%) patients attended follow up and at 12 months after removal, AHI remained below 15 in 5/10 (50%) patients but in the other 5 the AHI rose above 15 such that restarting CPAP was recommended. Two of these 5 patients, inspired by the desire to avoid CPAP, lost the regained weight and their AHI dropped below 15 again. Thus, 7/10 (70%) of patients were able to remain off CPAP 12 or more months after EB removal.

Conclusion: These results demonstrate major benefit of EB in moderate OSA, allowing patients to discontinue CPAP with maintenance of improvement at follow up in 70% and confirm previously demonstrated metabolic improvements in diabesity.

Disclosure

M. Yadagiri: None. F.Y. Kinney: None. N. Ashman: None. J. Adams: None. M.C. Wyres: None. E.S. Sharratt: None. C. Greenwood: None. M.H. Lang: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None. C. Walton: Speaker’s Bureau; Spouse/Partner; Celgene, LEO Pharma, Novartis Pharmaceuticals Corporation. M.A. Greenstone: None. R.E. Ryder: Consultant; Self; GI Dynamics Inc. Other Relationship; Self; Novo Nordisk A/S.
2024-P: A Qualitative Study in Obesity to Explore Clinically Meaningful Change on Patient-Reported Outcome (PRO) Measures
Authors: POON JIAT LING , MARSHALL CHRIS , JOHNSON CHLOE , PEGRAM HANNAH , HUNTER MAILE , KAN HONGJUN , AHMAD NADIA
Published: June 2020

Background: Obesity is a chronic disease with significant impacts on health-related quality of life (HRQoL) specifically physical functioning (PF), which is increasingly assessed using PRO measures in clinical trials. A review of existing literature suggested that further qualitative research was required to establish patient-perceived clinically important change (CIC) thresholds for two PRO measures used in obesity studies: the acute 36-item Short Form Health Survey (SF-36v2) and Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL-Lite-CT).

Objective: To explore the level of change on the SF-36v2 (acute) and IWQOL-Lite-CT that individuals living with obesity consider to be meaningful, noticeable and indicative of treatment success.

Methods: Semi-structured interviews were conducted in the U.S. with adults who have overweight or obesity (Body Mass Index [BMI] ≥ 27 kg/m2). Open-ended concept elicitation (CE) questions allowed participants to discuss the amount of body weight loss needed to have a noticeable improvement on PF. Cognitive tasks were later used during cognitive debriefing (CD) to explore what participants considered a CIC on each PRO measure.

Results: A total of 33 participants were interviewed (mean BMI: 37.6 kg/m2 [27.4 to 56.6 kg/m2] mean age: 45 years [19 to 81 years]). In CE, participants identified 5-10% weight loss as the threshold for having a noticeable improvement on PF and contextualized meaningful weight loss by using real-life examples (e.g., climbing stairs without becoming breathless). In CD, the majority of participants considered a 1-point change at the item level to be indicative of meaningful improvement on both PRO measures.

Conclusions: The combined CE and CD approach facilitated better understanding of meaningful change by participants, providing evidence that a 1-point change, the smallest detectable change on both the SF-36v2 (acute) and IWQOL-Lite-CT, is a CIC in people with overweight or obesity.

Disclosure

J. Poon: Employee; Self; Eli Lilly and Company. C. Marshall: Other Relationship; Self; Eli Lilly and Company. C. Johnson: Other Relationship; Self; Eli Lilly and Company. H. Pegram: Other Relationship; Self; Eli Lilly and Company. M. Hunter: Other Relationship; Self; DRG Abacus. H. Kan: Employee; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company.
2031-P: Obesity and Insulin Resistance Alter the Biodistribution of Whole Body Insulin-Stimulated Glucose Disposal
Authors: KOH HAN-CHOW , VLIET STEPHAN VAN , LAFOREST RICHARD , GROPLER ROBERT , KLEIN SAMUEL , MITTENDORFER BETTINA
Published: June 2020

Insulin-stimulated whole-body (WB) glucose disposal (GD) is thought to occur predominately in skeletal muscle (SM). Studies in animals suggest adipose tissue (AT) could also be an important site of GD, especially in people with obesity and insulin resistance. The interrelationship between adiposity, insulin sensitivity, and organ-specific insulin-stimulated GD is not known. We evaluated WB, SM, and AT insulin-stimulated GD by using the hyperinsulinemic-euglycemic clamp procedure together with [6,6-2H2]glucose infusion and 18F-deoxyglucose positron emission tomography in healthy lean people (n=13, age: 39±12 yrs, BMI: 23±2 kg/m2; body fat: 31±7%, mean±SD) and 27 people with obesity, who were then characterized as insulin sensitive (OIS, n=9, age: 48±10 yrs, body fat: 45±10%) or insulin resistant (OIR, n=9, age: 40±10 yrs, body fat: 48±4%) based on the top and bottom tertile values for WB insulin-stimulated GD. WB insulin-stimulated GD was 60% lower in the OIR (1,636±283 µmol/min) than both the OIS and Lean groups (P<0.01), without a difference between the OIS and Lean groups (4,188±758 and 3,855±1115 µmol/min). Total GD in subcutaneous AT was lower in the OIR than the OIS group (392±134 vs. 663±224 µmol/min) and greater in the OIS than the Lean (305±97 µmol/min, P<0.01) group. However, the contribution of AT to WB GD was greater in the OIR than the OIS and Lean groups (24±6%, 16±5%, and 9±4% of WB GD, P<0.01). GD rate in four major muscle groups (erector spinae, obliques, hamstrings, quadriceps) was 75% lower in the OIR (median [IQR]: 29 [23-35] µmol/kg muscle/min) than the OIS and the Lean groups (P<0.01), without a difference between the OIS and Lean groups (115 [89-139] and 102 [90-127] µmol/kg muscle/min). We conclude that: 1) a decrease in insulin-stimulated SM GD is responsible for the decrease in WB insulin-stimulated GD in the OIR group and 2) AT is a more important site of insulin-stimulated GD in people with obesity, particularly those with insulin resistance, than lean people.

Disclosure

H. Koh: None. S. van Vliet: None. R. Laforest: None. R. Gropler: None. S. Klein: Advisory Panel; Self; Danone Nutricia, Merck & Co., Inc. Research Support; Self; Johnson & Johnson, Pfizer Inc. Stock/Shareholder; Self; Aspire Bariatrics. B. Mittendorfer: None.

Funding

American Diabetes Association (1-18-ICTS-119 to B.M.); National Institutes of Health (DK115400, DK56341, DK020579, UL1TR000448)