bluuebunny/crossref_metadata_2025 huggingface dataset:
1969-P: Moderate Dosage of Benzyl Butyl Phthalate Synergizes the High-Fat Diet Induced Diabesity in Male Mice
Authors: KAY MATTHEW K. , ZHANG JIAN , POWELL CATHERINE , PARK MIN HI , SONKAR RAVI , MERUVU SUNITHA , CHOUDHURY MAHUA
Published: June 2020

There has been a sudden and rapid degradation in global metabolic health over the last decade, due to the progression of the obesity and diabetes epidemic. Exposure to endocrine disrupting chemicals (EDCs) used in plastic manufacturing may be contributing to this increase in metabolic disorders. Previous studies are concentrated on evaluating toxicity of these EDCs in the context of reproductive biology. However, virtually none have been performed with a range of exposure levels in both genders, especially in the context of an obesity-causing Western diet. In this study, we determined that butyl benzyl phthalate (BBP), a common EDC and food packaging plasticizer, mixed into chow (CD) (4% kcal from fat) and high fat diets (HFD) (60% kcal from fat) at varying concentrations (4 µg/kg body weight/day, 169 µg/kg body weight/day, 3 mg/kg body weight/day, 50 mg/kg body weight/day) produced a number of detrimental and sex-specific metabolic effects in C57Bl/6 male and female mouse populations after 16 weeks. Males exposed to moderate (3 mg/kg body weight/day) concentrations of BBP in an HFD were especially affected, with significant increases in body weight due to increases in liver, adipose tissue, kidney, and testes size. Other doses did not show any significant changes when compared to only CD or HFD alone. Furthermore, moderate dosage in HFD showed significant increases in fasting blood glucose, glucose tolerance, and insulin tolerance when compared to HFD alone. This group alters several molecular markers, which regulate hepatic gluconeogenesis and their transcriptional regulators, lipid metabolism, hepatic lipid synthesis, insulin signaling pathways, and inflammation. The female population did not show an intense effect as males even though they consumed similar amounts of food. Overall, these data establish a dose which can be used for a BBP induced metabolic research model, suggesting that a moderate dosage level of EDC exposure can contribute to widely ranging metabolic effects.

Disclosure

M.K. Kay: None. J. Zhang: None. C. Powell: None. M. Park: None. R. Sonkar: None. S. Meruvu: None. M. Choudhury: None.
197-LB: microRNA Expression Profiles and Progression from Normoglycemia to Prediabetes in a Biracial Cohort
Authors: OWEI IBIYE , DOKUN AYOTUNDE O. , STENTZ FRANKIE B. , DAGOGO-JACK SAMUEL
Published: June 2020

Background: MicroRNA (miRNA) profiles are associated with diabetes risk, but data on prediabetes are scant.

Methods: We studied participants (age 49.7 ±5.42 y; BMI 28.6 ±5.77 kg/m2) in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study, whose primary outcome was progression from normoglycemia to prediabetes (IFG/IGT) during 5-y follow up. We analyzed miRNA expression in participants with incident prediabetes (Progressors, n=10) and a matched group of Nonprogressors (n=10). Total RNA was extracted from plasma. NGS sequencing libraries were prepared using QIAseq miRNA Library Prep Kit and RNA sequencing was performed by QIAGEN Genomic Services. Over 12 million reads per samples were performed. To minimize false discovery, Benjamini-Hochberg corrected p-values were used to assess the significance of differential miRNA expression.

Results: Based on entries in mirbase_20, we identified 226 known miRNAs that were expressed at >1tags per million (TPM) and 151 known microRNAs that were expressed at >10 TPM in all samples analyzed. 25 miRNAs were differentially expressed in baseline plasma from Progressors to prediabetes vs. Nonprogressors (P=0.04- <0.0001). The top 5 most upregulated miRNAs in Progressors (vs. Nonprogressors) were miR 216a-5p, miR 217, miR 211-5p, miR 149-5p and miR 204-5p (log fold-change 3.61 to 6.49, P<0.0001). The top 5 most downregulated miRNAs in Progressors (vs. Nonprogressors) were miR 34c-5p, miR 550a-3p, miR 3200-3p, miR 144-5p and miR 144-3p (log fold-change -2.26 to -3.79, P= 0.0009-<0.0001). The most differentially expressed miRNA (miR 216a-5p; 6.49-log-fold higher in Progressors) is linked to the regulation of 78 genes, of which. 30 are involved in glucose, lipid, endocrine and metabolic pathways.

Conclusions: Plasma miRNA expression profile at baseline distinguished progressors to prediabetes from nonprogressors during longitudinal follow-up in the POP-ABC study. miR 216a-5p may be a novel biomarkers of early dysglycemia.

Disclosure

I. Owei: None. A.O. Dokun: None. F.B. Stentz: None. S. Dagogo-Jack: Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US. Stock/Shareholder; Self; Dance Biopharm Holdings, Inc., Jana Care Inc.

Funding

National Institutes of Health (R01DK067269)
1970-P: Mesenchymal Stromal Cells (MSCs) Upregulated with Both Mitochondrial and Cytosolic Antioxidants Improve Fatty Liver Disease in Diet-Induced Obesity (DIO) Mouse Model
Authors: NANDULA SESHAGIRI RAO , KUNDU NABANITA , SEN SABYASACHI
Published: June 2020

Introduction: Elevated oxidative stress by reactive oxygen species and mitochondrial dysfunction have been implicated in diabetes and obesity leading to insulin resistance (IR). Based on our previous study, we investigated to see the effect of two anti-oxidants (one mitochondrial, SOD2 and another one cytosolic, catalase) upregulated together in MSCs and delivered intra peritoneally (IP) in DIO mouse model.

Methods: C57BL/6J male mice (4-6weeks old) were obtained from the Jackson Lab. Obesity, glucose intolerance, and insulin resistance were induced by feeding the mice a high-fat diet (HFD) for 13 weeks. Mouse adipose-derived MSCs and adenovirus constructs containing GFP (Null, SOD2 and Catalase), were purchased Commercially. Glucose tolerance test (GTT), liver and fat depots H& E staining were performed and liver triglycerides (L-TG) were quantified.

Results: A significant reduction in L-TG levels were observed in the mice that received Catalase+SOD2-MSCs (2-fold) compared to Null-MSC, which was less than noted either with catalase or SOD2-MSCs alone. This is consistent with the findings of the corresponding liver fat histology. The systemic inflammatory maker plasma TNF-α levels in mice injected with the combination antioxidants showed 1.5 fold decrease compared to Null-MSC though SOD2-MSCs or catalase-MSCs almost demonstrated a decrease compared to Null-MSC. GTT showed an improvement with combination therapy with total area under the curve (AUC) value less than other groups.

Discussion: Our results indicate that MSCs with upregulated both Catalase and SOD2 anti-oxidants were more effective in reducing systemic inflammation (plasma TNF-α) and liver triglyceride content in DIO mice. MSC mediated delivery of combination of antioxidants, intra-peritoneally is safe and can be used as an efficient tool for treating obesity, prediabetes and NAFLD.

Disclosure

S. Nandula: None. N. Kundu: None. S. Sen: None.
1971-P: Activation of Adipocyte Gq Signaling Causes Improved Whole-Body Glucose Homeostasis
Authors: KIMURA TAKEFUMI , PYDI SAI PRASAD , WANG LEI , CUI YINGHONG , GAVRILOVA OKSANA , WESS JÜRGEN
Published: June 2020

Objective: Obesity and type 2 diabetes have emerged as severe threats to human health worldwide. Adipocytes play a key role in the regulation of whole-body glucose and energy homeostasis. The aim of this study was to examine the metabolic effects of selective activation of Gq signaling in adipocytes in vivo.

Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive designer G protein-coupled receptor (Gq DREADD = GqD) which couples to Gq selectively in adipocytes (adipo-GqD mice). Notably, DREADDs can only be activated by an exogenous agent (CNO) that is otherwise pharmacologically inert. We also created a mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Mice consuming either regular chow or a high-fat diet were subjected to a series of metabolic tests.

Results: CNO-mediated activation of GqD in adipo-GqD mice caused significant improvements in glucose homeostasis and suppressed lipolysis, while adipo-Gq/11 KO mice showed opposite metabolic phenotypes (impaired glucose metabolism and enhanced lipolysis). In agreement with these findings, CNO treatment of GqD-expressing 3T3-F442A adipocytes resulted in enhanced glucose uptake and inhibited CL316,243-induced lipolysis.

Conclusion: Studies with newly generated mouse models allowed us to evaluate the metabolic relevance of adipocyte Gq signaling in vivo. Most strikingly, Gq activation in adipocytes led to improved glucose homeostasis and reduced lipolysis in mice. These findings are of considerable relevance for the development of novel antidiabetic drugs.

Disclosure

T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.

Funding

Japan Society for the Promotion of Science
1973-P: Single-Nuclei Transcriptomics of Human Adipose Tissue Identify Distinct Adipocyte Progenitor Subpopulations in Type 2 Diabetes
Authors: STRIEDER-BARBOZA CLARISSA , FLESHER CARMEN G. , GELETKA LYNN M. , OROURKE ROBERT W. , LUMENG CAREY N.
Published: June 2020

Altered adipocyte function underlies type 2 diabetes (DM) pathogenesis. We hypothesized that adipocyte dysfunction in visceral adipose tissue (VAT) in DM originates from distinct adipocyte progenitor cell (APC) subpopulations. VAT was collected from bariatric surgery patients with (HbA1c>6.5) and without DM (NDM, HbA1c<5.7). Single-nuclei RNA sequencing was performed in VAT nuclei (n= 1 NDM, 2 DM) using 10X Genomics. Transcriptionally distinct cell subpopulations were identified by DEG: mature adipocytes (ADIPOQ, LEP), endothelial cells (VWR), immune cells (F13A1, MSR1), and two major APC subpopulations (S1: FABP4, ADIRF, ITLN1 and MSLN; S2: APOD, CFD and WISP2). S2 was uniquely identified by the upregulation of extracellular matrix accumulation and fibrosis markers: LUM, DCN, FBN1, and COL1A1, 3A1, 6A1 and 6A3. S2 had higher expression of APC and committed preadipocyte markers, such as PLIN1, GNAI1, CXCL14, CP, and CRISPLD2, while S1 had higher mesothelial-like cell markers GPM6A, PKHD1L1, LRRN4, CXADR, SLPI, and UPK3B. We FACS-isolated S1 and S2 from VAT CD31-CD45- cells (n= 3 NDM, 5 DM) using the surface marker TM4SF1, which was abundantly expressed in S1, but not S2. TM4SF1 expression (qPCR) was 50% higher in S1 (TM4SF1+) than in S2 (TM4SF1-). TM4SF1 immunostaining of human SVF confirmed distinct APC subpopulations. S1 corresponded to 15 ± 3% and S2 to 69 ± 2% of CD31-CD45- cells. In DM compared to NDM, S2 fraction was increased by 12% while S1 was decreased by 45%. We tested the metabolic function of S1 and S2 sorted from 5 DM VAT. Both subpopulations differentiated into lipid-filled adipocytes upon adipogenic induction in vitro. However, S2 compared to S1, manifested decreased proliferation and increased intracellular lipid accumulation and lipolytic response, consistent with a pro-hypertrophic, lipolytic adipocyte phenotype in DM. Our data suggest that distinct APC subpopulations in human obese VAT contribute to adipose tissue dysfunction in DM.

Disclosure

C. Strieder-Barboza: None. C.G. Flesher: None. L.M. Geletka: None. R.W. ORourke: None. C.N. Lumeng: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115190, DK090262)
1984-P: Promoting Weight Loss in Diabetes: An Insulin-Sparing Approach
Authors: GORANTLA YAMUNA , SONNABEND HAJERAH , HWANG JESSICA
Published: June 2020

Background: One of the first treatment goals in type 2 diabetes management is 5-7% weight loss. However, weight loss while on insulin is rarely achieved because it requires a complex interplay of lifestyle changes, self-monitoring of blood sugars, and anticipation of hypoglycemia with resultant lowering of insulin doses. In fact, patients often gain weight on insulin therapy. Putative mechanisms include improvement of glycemic control at expense of low blood glucose, anabolic effect of insulin increasing fat storage and defensive eating habits due to fear of hypoglycemia. Here we present a motivational case of weight loss in type 2 diabetes.

Clinic Case: Patient was a 51 year old woman with insulin-dependent diabetes since 1993 who lost 88 pounds in 2 years. Her medications consisted of 70/30 mixed insulin (total daily dose = 150 units), Metformin and a GLP-1 receptor agonist. Over the course of 2 years she started eating smaller portions of food with resultant hypoglycemia. Her total daily dose of insulin is now 50 units per day, weight has decreased from 332 pounds to 244 pounds and A1c has improved from 8.7% to <6%.

Conclusion: Maintaining patients on high doses of insulin encourages a pattern of over-eating (feeding their insulin) and sedentary lifestyle. There is a need for best practice guidelines on how to safely de-escalate insulin doses as patients start insulin-sparing medications or institute lifestyle changes for the benefit of weight loss.

Disclosure

Y. Gorantla: None. H. Sonnabend: None. J. Hwang: None.
1985-P: The Relationship between Body Shape and Cardiovascular Disease in People with Metabolically Healthy Obesity
Authors: PARK JUNG HWAN
Published: June 2020

Background: Although obesity is a significant risk factor of metabolic disorders, some people have metabolically healthy obesity (MHO). Many studies reported inconsistent results about the development of cardiovascular disease (CVD) in individuals with MHO. This study aimed to evaluate the effect of body shape on CVD outcomes in individuals with MHO.

Methods: We analyzed the data of 8,416 participants from the Korean Genome and Epidemiology Study, a 10-year follow-up population-based cohort study. To evaluate the participants’ body shape, we calculated the Z-score of log-transformed A Body Shape Index (LBSIZ) and divided the participants into the following groups: metabolically healthy normal weight (MHNW), MHO, metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obesity (MUO). Then, each group was classified into four subgroups based on the LBSIZ quartile. A multivariate logistic regression analysis was performed to evaluate the effect of LBSIZ for CVD events according to obesity phenotypes. The graphical relationships between LBSIZ and CVD events were also evaluated with restricted cubic spline plots.

Results: During the 10-year study period, 696 CVD events occurred in the participants. In the multivariate Cox regression model, MHO individuals did not have an increased risk of CVD compared with MHNW individuals. However, the further analysis with LBSIZ showed that the MHO participants with 3rd and 4th LBSIZ quartiles had a significantly higher hazards ratio for CVD events, whereas those with 1st and 2nd LBSIZ quartiles did not have an elevated risk of CVD compared to the MHNW participants with 1st quartile. In the restricted cubic spline regression, LBISZ showed a linear relationship with CVD events regardless of obesity phenotypes.

Conclusion: The MHO individuals with a high quartile of LBSIZ have a significant increased risk for CVD events.

Disclosure

J. Park: None.
1989-P: Change of Bile Acids Metabolism after 12 Weeks of Internet-Derived Low-Energy Diet Intervention
Authors: ZHANG CHENGHUI
Published: June 2020

Objective: Bile acids not only play roles in dietary lipid absorption and cholesterol homeostasis, but also regulate triglyceride, cholesterol, energy and glucose homeostasis. We aimed to investigate the change of bile acids after 12 weeks of internet derived low energy diet intervention in overweight and obesity participants.

Methods: This was a prospective observational study of 39 overweight and obesity participants. A calorie restricted diet (800-1200kcal/day) with high-intensity consultant was provided to all the participants. Plasma Bile acids were measured in baseline and after 12 weeks by high-performance liquid chromatography-mass spectrometry.

Results: The levels of bile acids before and after intervention are presented in Table. Except for taurocholic acid and taurochenodeoxycholic acid, there seems to be a downward trend for other bile acids after intervention. However, only the changes of chenodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid had statistical significance. The level of conjugated bile acid was significantly increased and the conjugated/unconjugated bile acids ratio was decreased after intervention.

Conclusions: Participants undergoing calorie restricted diet showed changes in the level of conjugated bile acid and conjugated/unconjugated ratio. Further research is needed to see the relationship between these changes and clinical features.

Disclosure

C. Zhang: None.
199-OR: Improved Glycemic Outcomes with Medtronic Minimed Advanced Hybrid Closed-Loop Delivery: Results from a Randomized Crossover Trial Comparing Automated Insulin Delivery with Predictive Low Glucose Suspend in People with Type 1 Diabetes
Authors: COLLYNS OLIVIA , MEIER RENEE , BETTS ZARA , CHAN DENNIS , FRAMPTON CHRIS , FREWEN CARLA M. , GROSMAN BENYAMIN , HEWAPATHIRANA NIRANJALA , JONES SHIRLEY , KURTZ NATALIE , ROY ANIRBAN , SHIN JOHN , VIGERSKY ROBERT , WHEELER BENJAMIN J. , BOCK MARTIN DE
Published: June 2020

Background: The Medtronic Minimed® Advanced Hybrid Closed-Loop system (AHCL) includes an individualised algorithm with optional set points, automated correction bolus, and improved SmartGuard™ Auto Mode stability.

Methods: This dual-centre, randomized, open-label, two-sequence cross-over study in automated insulin delivery naïve participants (aged 7-80yrs), compared AHCL to Sensor Augmented Pump therapy with Predictive Low Glucose Management (SAP+PLGM). Each study phase was 4 weeks, preceded by a 2-4 week run-in, and separated by 2-week washout.

Results: 59/60 people completed the study (mean age 23.3±14.4yrs). Overall time in target range (TIR) (70-180mg/dL) favoured AHCL over SAP+PLGM by 12.5±8.5% (p<0.001), with greater improvement overnight (15.7±12.0%, p<0.001) (Table 1). This was primarily due to reduction in hyperglycemia (-12.1±9.0% time spent >180mg/dL). Mean SG improved in AHCL by 10.0±7.4mg/dL (p<0.001). For each 1% lower baseline TIR, there was a 0.5% greater TIR improvement with AHCL (p<0.001). Auto Mode was active for 95.3±3.6% of the time.

Conclusion: AHCL with automated correction bolus showed significant improvement in glucose control compared to PLGM, in a population with a younger mean age reflecting a challenging demographic.

Disclosure

O. Collyns: None. R. Meier: None. Z. Betts: None. D. Chan: None. C. Frampton: None. C.M. Frewen: None. B. Grosman: Employee; Self; Medtronic. N. Hewapathirana: Other Relationship; Self; Sanofi. S. Jones: None. N. Kurtz: Employee; Self; Medtronic. A. Roy: Employee; Self; Medtronic. J. Shin: Employee; Self; Medtronic. R. Vigersky: Employee; Self; Medtronic. B.J. Wheeler: Research Support; Self; Medtronic. M. de Bock: None.
2003-P: Triiodothyronine and Free Thyroxine Levels Combined with Thyroid-Stimulating Hormone Are Associated with Glucose Metabolism in Obese Patients with Euthyroid Function
Authors: ZHANG JUNYI , LI GUIFANG , CHENG XIAOYUN , WANG XINGCHUN , JAYACHANDRAN MUTHUKUMARAN , HUANG YUEYE , QU SHEN
Published: June 2020

Purpose: To present thyroid hormones (THs) cutoff values to assess the association of THs and glucose metabolism in obese patients with euthyroid function.

Methods: This study investigated 445 obese patients (235 females and 210 males) with euthyroid function received treatment in the department of endocrinology of shanghai 10th people’s hospital from 2011 to 2019, with the median age of 29 years (interquartile range 22-35 years). The cut-offs for thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were 2mIU/L, 16mIU/L, and 5mIU/L, respectively.

Results: Fasting blood glucose (FBG) and 2h-glucose (BG120) were significantly higher in low FT3 (P<0.05) and high FT4 patients (P<0.05). In patients with TSH under 2mIU/L, a low FT3 group was robustly associated with higher FBG and BG120 levels (P<0.05). In patients with TSH under 1.5mIU/L, additional association with lower fasting and 2h-insulin (P<0.05) could be found. FT3 had no predictive value in high TSH patients. In patients TSH over 1.5 or 2mIU/L, a high FT4 group was robustly associated with higher FBG and BG120 levels (P<0.05). FT4 had no predictive value in low TSH patients. Patients with TSH over 2mIU/L, high FT4 group had a crude odds ratio of 2.65(95% Confidence interval 1.40-5.03, P=0.003) for FBG compared with low FT4 and remained significant after adjustments for age, gender and body mass index. Similar results could be obtained in patients with TSH over 1.5mIU/L.

Conclusions: A combination of TSH and FT4/FT3 instead of only one thyroid hormone indicator had predictive value of glucose metabolism in obese patients with euthyroid function.

Disclosure

J. Zhang: None. G. Li: None. X. Cheng: None. X. Wang: None. M. Jayachandran: None. Y. Huang: None. S. Qu: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Pujiang Program (2019PJD040); Effect of ApoC3 High Expression on Islet Cells and Related Molecular Mechanism (03.05.18.002)
2005-P: A Smartphone Intervention to Promote Time-Restricted Eating Reduces Body Weight and Blood Pressure in Adults with Overweight and Obesity
Authors: PRASAD MALINI A. , MANOOGIAN EMILY , ZURAIKAT FARIS M. , NAIR NANDINI , ST-ONGE MARIE-PIERRE , PANDA SATCHIDANANDA , LAFERRERE BLANDINE
Published: June 2020

Prolonged eating into late evening hours is associated with overweight (OW)/obesity (OB) and increases metabolic risk. Reducing the daily eating window, or time restricted eating (TRE), results in weight loss (WL) and improved metabolism. Our goal was to assess: 1) The eating patterns of adults with OW or OB and 2) The effect of 10h/d TRE, in persons who habitually eat for ≥14h/d, on WL and systolic (SBP) and diastolic (DBP) blood pressure.

Methods: In this open label study, eligible men and women with BMI ≥25kg/m2 were instructed to enter all caloric eating occasions (EO) via time-stamped photos using the validated MyCircadianClock smartphone application (app) for 2 weeks (run-in). No instructions were provided on food choice or calorie count. Upon completion of this run-in period, eligible participants entered a 3-mo personalized 10h/d TRE intervention administered remotely via the app. Adherence was defined as logging 2 or more EO/d, occurring at least 5h apart, and achieving a 4h reduction in eating window during TRE.

Results: Participants in the run-in period (n=30, 20% men) were 51.9±11.9y old, had a BMI of 31.1±7.3 kg/m2, waist circumference of 100.1±13.2 cm, SBP of 117.3±15.0 mmHg and DPB of 76.0± 10.5 mmHg. Logging into the app occurred on 10.9±3.2 days with a total of 61±30 [10-121] EO. The duration of the daily eating window varied greatly amongst participants (range: 8h02min - 23h26min) and ∼50% of them ate ≥14h/d. During the 3-mo TRE (n=12), login adherence was observed on 63% of days, with a mean of 3.4±1.7 EO/d; the mean eating duration decreased by 5.79±2.74 h/d (p=0.001). Weight decreased by 3.0± 2.7 kg (p=0.025). SBP and DBP also decreased by 21±11 mmHg (p=0.013) and 13±20 mm Hg (p=0.04), respectively.

Conclusion: TRE administered via a smartphone app is an effective and easy-to-implement intervention to reduce body weight and blood pressure in adults with OW and OB. These data need to be confirmed in randomized trials.

Disclosure

M.A. Prasad: None. E. Manoogian: Stock/Shareholder; Spouse/Partner; Abbott Laboratories. F.M. Zuraikat: None. N. Nair: None. M. St-Onge: None. S. Panda: Other Relationship; Self; Penguin Random House.
2008-P: Roux-en-Y Gastric Bypass Surgery Can Modulate ER Stress and Inflammation on Subcutaneous Adipose Tissue in Nondiabetic Patients with Obesity
Authors: FERRAZ-BANNITZ RAFAEL , WELENDORF CAROLINE R. , COELHO PRISCILA O. , SALGADO WILSON , NONINO CARLA B. , BERALDO REBECA A. , FOSS-FREITAS MARIA CRISTINA
Published: June 2020

Roux-en-Y gastric bypass (RYGB) is the most effective and durable treatment option for reducing adiposity and control abnormalities of metabolic syndrome in patient with severe obesity. Some studies have shown that the initial effect of RYGB on improving metabolic parameters is due to caloric restriction. However, the impact of RYGB on adipose tissue is still under debate. We evaluated 13 obese, nondiabetic patients (mean age 37 years, 100% women, BMI 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB. Changes in anthropometric, biochemical e gene expression were evaluated with ANOVA and Pearson’s correlation analysis. BMI, fat mass and blood pressure decreased after 3M and 6M (P≤0.05 for all) compared with baseline. Analysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3M and 6M Post-RYGB showed that interleukins (IL6, TNF-α, and MCP1) and endoplasmic reticulum stress (ERS) genes (EIF2AK3 and CALR) decreased during the follow-up (P≤0.01 for all). Nonetheless, genes involved in energy homeostasis (ADIPOQ and AMPK), cellular response to oxidative stress (SIRT1, SIRT3, and NRF2), regulation of adipogenesis (PPARγ), mitochondrial biogenesis (PGC1α) and amino acid metabolism (GCN2) increased from baseline to all other time points evaluated (P≤0.01 for all). We also observed a strong positive correlation between PGC1α, SIRT1, and AMPK with BMI at 3M (P≤0.01 for all) and ADIPOQ and SIRT1 with BMI at 6M (P≤0.01 for all). Our findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process, in a gene expression level, during the caloric restriction and weight loss period after RYGB in patients without diabetes.

Disclosure

R. Ferraz-Bannitz: None. C.R. Welendorf: None. P.O. Coelho: None. W. Salgado Jr.: None. C.B. Nonino: None. R.A. Beraldo: None. M. Foss-Freitas: None.

Funding

Ribeirao Preto Clinical Hospital-FAEPA
2009-P: Improvement in Renal Function Associated with Endobarrier (EB)–Induced Weight Loss
Authors: RYDER ROBERT E.J. , YADAGIRI MAHENDER , IRWIN SUSAN P. , BURBRIDGE WYN , ALLDEN RACHAEL , BASHIR TAHIRA , BLEASDALE JOHN , FOGDEN EDWARD , ANDERSON MARK , GUPTA PIYA SEN , COCKWELL PAUL
Published: June 2020

EB, a 60 cm proximal intestinal liner, endoscopically-implanted for up to 1 year, reduces weight and HbA1c. As the risk of progressive kidney-disease is increased by high BMI, we assessed the impact of EB on renal function. In 89 consecutive patients (aged 51.2 ± 8.0 years, 48.3% male, 55.1% europid, diabetes duration 10.8 (7.0-16.7) years, BMI 41.3 ± 6.9 kg/m2), mean ± SD HbA1c fell by 1.9 ± 1.8 %, from 9.4 ± 1.9 to 7.5 ± 1.2 % (p<0.001), weight fell by 15.0 ± 8.3 kg from 119.1 ± 26.3 to 104.1 ± 27.0 kg (p<0.001), systolic blood pressure (BP) from 138.4 ± 15.5 to 126.3 ± 16.9 mmHg (p<0.001) (Table 1a). With regard to renal function, mean ± SD serum creatinine improved by 5.0 ± 15.5 μmol/L from 88.9 ± 41.8 to 83.9 ± 42.1 μmol/L (p=0.003) and estimated-Glomerular-Filtration-Rate (eGFR - abbreviated MDRD equation) improved by 6.5 ±10.7 ml/min/1.73m2 from 83.6 ± 23.4 to 90.1 ± 25.7 ml/min/1.73m2 (p<0.001) (Table 1b). Eight patients had raised serum creatinine (>133μmol/L) prior to EB; after implantation in 6 of these, creatinine reduced and in 3 creatinine normalised. It was noteworthy, that the 6 patients with renal impairment who sustained improvement had large weight loss (mean 17.3 kg), whereas the patients without improvement had lower weight loss (mean 6 kg). As well as previously documented improvements, in weight, HbA1c and BP, EB was associated with improvements in renal function. These observational findings warrant further investigation.

Disclosure

R.E.J. Ryder: Consultant; Self; GI Dynamics Inc. Other Relationship; Self; Novo Nordisk A/S. M. Yadagiri: None. S.P. Irwin: None. W. Burbridge: None. R. Allden: None. T. Bashir: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None. P. Sen Gupta: None. P. Cockwell: Speaker’s Bureau; Self; Napp Pharmaceuticals.
2013-P: Lifestyle Intervention, Metformin, and Acarbose Treatments Differentially Impact Liver Fat Content, Serum Lipids, and Hormone Profiles in Obese Polycystic Ovary Syndrome Patients with Impaired Glucose Tolerance
Authors: LI SHENGXIAN , WANG YUYING , CAI JIE , LIU WEI , YIN HUIYONG , TAO TAO
Published: June 2020

Introduction: Polycystic ovary syndrome (PCOS) is often associated with obesity, insulin resistance, abnormal glucose tolerance, lipid metabolic disorders, and fatty liver. It remains unknown how current therapies impact these different components of PCOS.

Objective: We aim to evaluate the effects of lifestyle intervention (low calorie diet, LCD), metformin and acarbose treatment on fat mass, insulin sensitivity, hormone profiles, liver fat content and lipids profile in obese PCOS patients with impaired glucose tolerance (IGT).

Methods: In a 12-week, randomized, open tag prospective clinical trial, we recruited thirty obese PCOS patients, and randomly divided them into three groups: LCD, metformin, and acarbose group. Body weight, adipose tissue distribution, and serum sex hormone levels were measured before and after treatment. MRI was used to measure the liver fat content (LFC) and abdominal fat mass (AFM); Insulin sensitivity and beta-cell function were evaluated by OGTT and two-step hyperglycemic clamp; Serum free fatty acids (FFAs) were measured by GC-MS.

Results: In all three groups, AFM and insulin secretion were significantly decreased as measured by MRI, OGTT and glucose clamp, respectively. LCD significantly improved the insulin sensitivity as determined by HOMA-IR, disposition index, and matsuda index. Metformin significantly improved hyperandrogenism. Interestingly, we found only acarbose significantly decreased triglyceride, FFAs, and LFC.

Conclusion: All treatment modalities were effective in the treatment of PCOS women with obesity and IGT, only acarbose significantly decreased the triglyceride and FFAs, and ameliorated the LFC, suggesting that acarbose is an effective agent that could be used in PCOS patients with IGT and fatty liver.

Disclosure

S. Li: None. Y. Wang: None. J. Cai: None. W. Liu: None. H. Yin: None. T. Tao: None.
2016-P: Bariatric Surgery May Improve Glucose Control among Patients with Type 1 Diabetes
Authors: VENDRAME FRANCESCO , CASU ANNA , PRATLEY RICHARD E. , CALHOUN PETER
Published: June 2020

The prevalence of obesity in patients with type 1 diabetes (T1D) is increasing. Obesity and metabolic syndrome are risk factors which contribute to the development and progression of micro- and macrovascular complications. Several studies have shown the beneficial and durable effect of bariatric surgery in patients with type 2 diabetes, but data in patients with T1D are scarce. We evaluated the impact of bariatric surgery in adult T1D patients enrolled in the T1D Exchange Registry. Clinical characteristics, comorbidities, socioeconomic factors and laboratory data were obtained within 5 years before or after bariatric surgery. A linear mixed model was used to compare glycemic and clinical outcomes before and after surgery controlling for patient characteristics. Overall, data were available for 38 patients of which 34 were female, 31 were white non-Hispanic (2 missing race); age and T1D duration at time of surgery was 43±9 yrs and 22 ± 13 yrs. After bariatric surgery, patients had lower HbA1c (8.7±1.4 before vs. 8.1±1.3% after), BMI (37.3±10.2 vs. 33.0±7.2 kg/m2), and LDL level (88±27 vs. 79±19 mg/dL), but only BMI reached statistical significance (Table). Although limitations include a small number of subjects and lack of information on type of surgery, this is to date the largest sample size. Our results suggest evidence T1D bariatric surgery is associated with improvement in diabetes control, although more research is needed.

Disclosure

F. Vendrame: None. A. Casu: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Janssen Scientific Affairs, LLC., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals Incorporated, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)
2019-P: Gender Influence on Body Habitus for an Underserved Population with Type 2 Diabetes and Food Insecurity
Authors: BEVIER WENDY C. , GLANTZ NAMINO M. , LAREZ ARIANNA J. , KUJAN MARY A. , CONNEELY CASEY , CASTORINO KRISTIN N. , KERR DAVID
Published: June 2020

In the United States, type 2 diabetes (T2D) has a disproportionate impact on underserved populations, and this appears to be related to excess weight. Although reasons are likely multifactorial, it is unclear if there are gender-related influences on obesity risk for these populations. We compared body habitus by gender for 218 adults [84% Mexican-American, 152 females, mean (SD) age 56.2 (10.7) years, HbA1c 8.1 (2.0) %, BMI 31.2 (6.7) kg/m2, 45% uninsured, 42% food insecure (U.S. Household Food Security Survey)] with T2D participating in 2 clinical trials (NCT03830840 and NCT03940300). Comparisons were made for BMI, waist circumference (WC), relative fat mass (RFM), systolic blood pressure (SBP), HbA1c, and food security by gender (Table). Results expressed as mean (SD), unless specified. Significant associations (Spearman’s Rho) were found between WC and BMI (rs= 0.82) and WC and RFM (rs=0.66, both p<0.001) for all participants and when stratified by gender (p<0.001). There were no significant associations between HbA1c and RFM or BMI, except for BMI and HbA1c in males (rs=-0.31, p=0.02). Food insecure adults had higher HbA1c (%) levels than those who were food secure (median [IQR] 7.65 [6.98-9.35] versus 7.30 [6.40-8.63], p=0.02).

In conclusion, gender may be an important influence on body habitus for underserved populations with T2D. Food insecurity is also common and can impact glycemic control.

Disclosure

W.C. Bevier: None. N.M. Glantz: Research Support; Self; Abbott, Eli Lilly and Company. A.J. Larez: Research Support; Self; Eli Lilly and Company. M.A. Kujan: None. C. Conneely: None. K.N. Castorino: Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Mylan, Novo Nordisk Inc. D. Kerr: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; Glooko, Inc.

Funding

Eli Lilly and Company; U.S. Department of Agriculture (2018-01793)
2020-P: ß3-Adrenergic Receptors Regulate Lipolysis and Thermogenesis in Human Brown/Beige Adipocytes
Authors: CERO CHERYL , LEA HANNAH J. , ZHU KENNETH Y. , CYPESS AARON M.
Published: June 2020

Activation of rodent brown adipose tissue (BAT) via pharmacological stimulation of β3-adrenergic receptors (β3-AR) leads to metabolic benefit, however in humans, the physiological relevance of BAT and β3-AR remain controversial. To investigate the role of the β3-AR in human brown adipocytes, first, we established a human primary supraclavicular adipocyte in vitro model that upon differentiation preserved the physiological properties brown adipose tissue with increased β-ARs, adipogenic, thermogenic and brown/beige markers. Next, we selective silenced β3-AR expression in differentiated primary brown/beige adipocytes using a lipofectamine-based non-viral transfection. 48h of transfection of siRNA targeting ADRB3 (siRNA-ADRB3) resulted in a 90% reduction in ADRB3 mRNA levels, relative to control siRNA-transfected cells (siRNA-Ctrl). siRNA-ADRB3 also reduced genes of fatty acid metabolism, thermogenesis (UCP1, 90% decrease), and mitochondrial mass. Functionally, lower cAMP levels, lipolysis, oxygen consumption rates and higher glycolysis were caused by silencing β3-AR receptor. Immortalized brown adipocyte (hBA’s), from a separate subject, displayed a similar decrease in lipolysis and cellular respiration. Mirabegron, the selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, that were lost after knockdown ADRB3. Similarly, selective subtype human β-AR agonists dobutamine (β1-AR agonist) and terbutaline (β2-AR agonist) treatment also increased lipolysis and thermogenesis, that were also attenuated when β3-AR was silenced. Thus, the β3-AR maintains multiple components of the human brown/beige adipocyte lipolytic and thermogenic cellular machinery. These findings indicate that ADRB3 and β3-AR agonists could be used to achieve metabolic benefit in humans.

Disclosure

C. Cero: None. H.J. Lea: None. K.Y. Zhu: None. A.M. Cypess: None.
2022-P: Partial-Body Cryotherapy Acutely Augments Resting Metabolism in Obese Women
Authors: CODELLA ROBERTO , NARDI MASSIMO DE , DELBARBA SUNDEEP , FACHERIS CARLO , LUZI LIVIO
Published: June 2020

Cryotherapy has been shown to reduce pro-inflammatory response, relieve pain and enhance muscles’ post-exercise recovery. Cryostimulation could be also proposed as an alternative strategy to trigger cold-induced thermogenesis in overweight/obese subjects. In this study, 16 obese (BMI: 32±4 kg/m2) women (43.4±4.8 years) underwent Partial-Body Cryotherapy (PBC) (-130°C x 150sec) for 5 days (1/day, h 07:00 AM). Resting energy metabolism (REE) was assessed by indirect calorimetry pre- and post-PBC on day 1 and day 5. Subjects were energy-controlled (physical activity and dietary intake). Before 5th-day PBC, REE was increased by 5.5% versus pre-1st-day PBC values (1755±265 vs. 1664±241 kcal/day; p=0.0005). With a similar design, in a larger sample of 80 subjects (F=61; M=19; 34.4±11.1 years; BMI: 24.4±4.8 kg/m2), REE augmented by 1.89% (p=0.02) after PBC of day 1. In a multivariate analysis, multiple regression output a positive relationship between cryostimulated REE and body weight (Spearman r=0.68; p<0.0001, Figure). Altogether, these preliminary data suggest that cold-induced thermogenesis could be explored as an alternative therapy to combat weight gain and obesity. Longitudinal studies could test chronic effects of cryotherapy, estimating the extent of the metabolic adaptations that could be favorably preserved.

Disclosure

R. Codella: None. M. De Nardi: None. S. Delbarba: None. C. Facheris: None. L. Luzi: None.
2025-P: Relation between Serum Uric Acid and Autonomic Function, Blood Pressure, and Visceral Obesity in Prediabetes and Type 2 Diabetes with Short Duration
Authors: DIMOVA RUMYANA , CHAKAROVA NEVENA , GROZEVA-DAMYANOVA GRETA , TANKOVA TSVETALINA
Published: June 2020

Aim: The present study assesses the relation between uric acid and cardiovascular autonomic function (CAF), blood pressure (BR) and visceral obesity at early stages of glucose intolerance.

Material and Methods: A total of 100 subjects - 50 males, mean age 47.4±14.2years, mean BMI 32.2±7.5kg/m2, divided into 3 groups according to glucose tolerance: 30 subjects with normal glucose tolerance (NGT), 37 with prediabetes and 33 with type 2 diabetes (T2D) with duration ≤5 years were included. Glucose tolerance was assessed by OGTT according to WHO 2006 criteria. Anthropometric indices, BP, HbA1c and plasma glucose were measured. Body fat distribution was estimated by a bioimpedance method (InBody 720, BioSpace). CAF was assessed by ANX-3.0 using frequency-domain analysis during standard clinical tests.

Results: Uric acid levels were higher in prediabetes and T2D (p<0.0001 and p=0.004, respectively) as compared to NGT. There was a decreased parasympathetic tone at rest (p=0.026 and p=0.001, respectively), deep breathing (p=0.025 and p=0.003, respectively), Valsalva maneuver (p=0.023 and p=0.003, respectively) and standing (p=0.012 and p=0.002, respectively) test in T2D in comparison to prediabetes and NGT. Sympathetic tone was diminished at rest (p=0.004), deep breathing (p=0.040) and standing (p=0.016) test in T2D as compared to NGT. Uric acid positively correlated with waist circumference (r=44, p<0.0001), visceral fat area (r=24, p=0.022), diastolic BP (r=0.023) and HbA1c (r=22, p=0.030); and negatively with sympathetic activity at rest (r=-23, p=0.024), deep breathing (r=-26, p=0.010) and standing (r=-21, 0=0.039) test and with parasympathetic activity during deep breathing test (r=-21, p=0.033).

Conclusions: It seems to be an increase in uric acid levels and a decline in CAF in prediabetes and T2D with short duration. Uric acid is probably associated with CAF, visceral obesity and BP at early stages of dysglycaemia.

Disclosure

R. Dimova: Consultant; Self; Amgen, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Sanofi, Wörwag Pharma. N. Chakarova: None. G. Grozeva-Damyanova: None. T. Tankova: Board Member; Self; Amgen, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Servier.
2026-P: Efficacy of Internet-Based Intensive Weight Management or Exenatide Treatment on Weight Loss and Metabolism in Overweight/Obese PCOS
Authors: ZHENG SIYUAN , ZHANG YING , LI RENYUAN , XUE JIAO , SHEN HUANLING
Published: June 2020

To evaluate efficacy of internet-based intensive weight management or exenatide treatment on weight loss and metabolism in overweight/obese patients with polycystic ovary syndrome(PCOS). The study recruited 50 overweight/obese patients with PCOS into intensive lifestyle intervention group(ILI) for internet-based intensive weight management, which characterized with strict-energy and low-carbohydrate diets(1100-1400 kcal of total energy and less than 50g of carbohydrates per day), nutritional meal-replacement diets for lunch and dinner, online reporting followed by nutrionists, exercises, behavioral intervention and medication(metformin, 500mg Tid), for 3 months. 50 BMI matched subjects assigned to 3 months of exenatide injection (10μg bid)in our previous study were recruited as control group (EXE group). Oral glucose tolerance test were performed to assess glucose tolerance and insulin sensitivity. Anthropometric, glycolipid metabolic markers, sex hormone level and inflammatory state were measured and compared between two intervention. After 3 months of intervention, decreases of weight(ILI group 10.02 ± 3.06 kg vs. EXE group 6.15 ± 2.28 kg), BMI (ILI group 3.98±1.26 kg/m2 vs. EXE group 2.54±1.05 kg/m2), HOMA-IR(2.60 ± 2.37 vs. 1.06 ± 2.04), WC, FBG, FINS, TG and UA in ILI group were more statistically significant than EXE group. There were no significant differences in decreases of 2hPBG, 2hINS, testosterone and hs-CRP between two groups(P> 0.05). There were no statistically differences in improvements of total cholesterol, LDL-C, ALT, and AST in both groups (P> 0.05). It is suggested that internet-based intensive weight management in overweight/obese PCOS can significantly reduce weight, improve central obesity and insulin resistance. These effects were significantly better than exenatide treatment. However there were no significant differences in improvements of testosterone level and inflammatory state.

Disclosure

S. Zheng: None. Y. Zhang: None. R. Li: None. J. Xue: None. H. Shen: None.
203-LB: Redosing of Suboptimally Controlled Diabetic Mice with Human Neo-islets, 3D Aggregates of Mesenchymal Stromal and Pancreatic Islet Cells, Durably Restores Euglycemia: Relevance to the Treatment of Diabetic Humans
Authors: CHOWDHURY SABIHA S. , GOOCH ANNA , ZHANG PING , HU ZHUMA , WESTENFELDER CHRISTOF
Published: June 2020

We reported that the i.p. administration of allogeneic Neo-Islets (NIs; 3D aggregates of allogeneic, culture-expanded Islet cells (ICs) with immune- and cyto-protective Mesenchymal Stromal Cells (MSCs)), durably restores normoglycemia in autoimmune type-1 diabetic NOD mice through omental engraftment. Similarly, our ongoing, FDA-guided pilot study in insulin dependent pet dogs (INAD 012-0776) demonstrates that allogeneic canine NI therapy significantly improves both glycemic control and insulin needs (> 1.5 years), and this without eliciting an allo-immune response. The current study was undertaken in preparation of a Phase I Clinical Trial in order to determine whether NIs engineered from human cells (hNIs) could also reduce insulin need, and whether redosing of suboptimally controlled diabetic mice could fully restore euglycemia, as is frequently required in human recipients of islet transplants.

Hyperglycemia (blood glucose > 350 mg/dL x 3 days) was induced with streptozotocin in adult NOD/SCID mice and blood glucose levels were controlled with insulin pellets (Linbits) until i.p. hNI (2x10e5 hNIs/kg bw) or vehicle administration (n=6/group). Blood glucose levels, weights, ip glucose tolerance tests [GTT) were closely monitored.

While no mice in the hNI treated group died (vs. 4 in the control group), hNI therapy partially reduced glucose levels . Therefore, on day 64 post initial treatment, mice were re-dosed with hNIs (2x10e5 hNIs/kg bw) and followed together with controls as above. This second dose of hNI completely and durably restored euglycemia and normalized ip GTTs.

We conclude that this minimally invasive, safe and highly effective therapy supports our current pursuit of an IND for the conduct of a pioneering Clinical Trial in subjects with T1DM.

Disclosure

S.S. Chowdhury: Employee; Self; SymbioCellTech. A. Gooch: Employee; Self; SymbioCellTech. P. Zhang: Employee; Self; SymbioCellTech. Z. Hu: Employee; Self; SymbioCellTech. C. Westenfelder: Consultant; Self; SymbioCellTech.
203-OR: ADA Presidents’ Select Abstract: Landscape of Liver Cell Heterogeneity and Reprogramming during NASH Pathogenesis Revealed by Single Cell RNA Sequencing
Authors: XIONG XUELIAN
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is rapidly emerging as a prevalent liver disease that is associated with metabolic syndrome. NASH increases the risk for end-stage liver diseases such as cirrhosis and liver cancer and currently has no effective treatments. Despite this, the pathophysiological mechanisms underlying NASH initiation and progression remain poorly understood. We and others have previously established a diet-induced NASH model in mice that recapitulates key aspects of human NASH pathologies, including hepatic steatosis, liver injury, inflammation, and liver fibrosis in the context of obesity and insulin resistance. Here we performed single-cell RNA sequencing (sc-RNAseq) analysis on liver cells isolated from healthy and diet-induced NASH mice to map the landscape of liver cell heterogeneity and reprogramming during NASH pathogenesis. Our analysis revealed a highly interconnected ligand-receptor signaling network among different liver cell types that is disrupted during NASH progression. Hepatic stellate cells are emerging as a hub of signaling in the liver by secreting “stellakines” and respond to vasoactive hormones. Finally, we identified TREM2-expressing macrophages as a unique disease-associated macrophage population that is linked to NASH severity in humans. This work reveals the transcriptomic landscape of liver cells at single-cell resolution and uncovers key aspects of NASH-associated reprogramming of liver non-parenchymal cells.

Disclosure

X. Xiong: None.