bluuebunny/crossref_metadata_2025 huggingface dataset:
1952-P: Vertical Sleeve Gastrectomy Induces Distinctive Gene Expression Changes in Glucose-Utilizing Peripheral Organs
Authors: AHN CHANG HO , MOON SUN JOON , CHO YOUNG MIN
Published: June 2020

Vertical sleeve gastrectomy (VSG) improves hyperglycemia and can achieve high rate of diabetes remission. To elucidate the molecular mechanism of VSG, we performed transcriptomic analysis of liver, fat, and muscle tissues in VSG mice compared to both sham and pair-fed sham controls. C57BL/6 mice fed high fat diet were randomly assigned to sham or VSG surgery. Sham-operated mice were fed ad libitum (Sham group) or pair-fed (Sham-PF group) matching their food intake to VSG-operated mice. Body weight, food intake, glucose and insulin tolerance were measured. Comparative transcriptomic analysis of liver, epididymal fat, and soleus muscle using RNA sequencing was performed. VSG decreased body weight and maintained the reduced body weight during the whole study period (up to 8 weeks after surgery). However, food intake was only reduced during the first 2 weeks after surgery in VSG than sham group. Glucose tolerance was improved by VSG after oral glucose load, but this improvement was attenuated after intraperitoneal glucose load. In addition, VSG increased insulin sensitivity than both Sham and Sham-PF group. Clustering and principal component analysis of the gene expression profiles of liver and adipose tissue revealed that Sham-PF was closer to Sham than VSG. The number of DEG was larger in comparison between VSG vs. Sham-PF than that between Sham-PF vs. Sham. The gene expression profile of muscle was not distinctive among the three groups. In pathway analysis, immune response was the common pathway enriched in all three tissues of VSG compared to Sham-PF. These results suggest that VSG induces organ specific changes of gene expression profile in both weight-loss dependent and independent ways. Interestingly, weight-loss independent changes were more robust than weight-loss dependent changes, which suggests that the improvement of hyperglycemia may be induced not only by weight-loss dependent mechanisms, but also by weight-loss independent mechanisms of VSG.

Disclosure

C. Ahn: None. S. Moon: None. Y. Cho: None.

Funding

Korean Ministry of Health and Welfare (HI14C1277)
1957-P: Intermittent Ketogenic Diet Ameliorates Diet-Induced Obesity and Fatty Liver with Improved FGF21 Signaling
Authors: GUO WANRONG , WANG WEI , LI WUGUO , LIANG HUA , XU FEN
Published: June 2020

Recently, ketogenic diet has been found to be effective on improving obesity. Fibroblast growth factor 21 (FGF-21) is an endocrine factor mainly synthesized in the liver and shown to impact the metabolism of multiple tissues. Here, we investigated the effect of intermittent ketogenic diet on obesity and the sensitivity of FGF-21. Eight-week-old C57BL/6 mice were subjected to a chow diet (CD group), a high fat diet (HFD group), an intermittent chow diet (iCD group) or an intermittent ketogenic diet (iKD group) for 16 weeks. The intermittent diet intervention began with an HFD and was alternated with a chow diet or a ketogenic diet biweekly. Although the average energy intake of iKD group was highest in the four groups, the body weight, fasting blood glucose, the body fat mass and the weight of liver, epididymal adipose tissues (eWAT), subcutaneous adipose tissue (sWAT) and brown adipose tissue (BAT) of iKD group were ameliorated remarkably when compared to HFD group. The insulin sensitivity of iKD group was greatly improved as well. Both the histological results and the quantification of liver triglyceride showed that hepatic steatosis was significantly alleviated in iKD group. Western blotting showed that lipid metabolism in liver was greatly improved by iKD. What’s more, the cold exposure test showed that the iKD group had the best cold tolerance in the four groups. The mRNA expression of FGF-21 was greatly upregulated and hepatic inflammation was ameliorated in livers of iKD group. HE staining showed that the adipocytes in eWAT and sWAT were smaller in iKD group. The whitening of BAT was also improved in iKD group. Both mRNA and protein levels of UCP1 and PGC1α were remarkably upregulated by iKD in eWAT, sWAT and BAT. The mRNA levels of FGFR1 and KLB, which are related to FGF-21 sensitivity, were observed to be improved in eWAT and sWAT. Our data demonstrated that iKD ameliorates diet-induced obesity and fatty liver, and improved insulin sensitivity and cold tolerance with improved FGF-21 signaling.

Disclosure

W. Guo: None. W. Wang: None. W. Li: None.
1961-P: Improved Glucose Control and Robust Weight Loss with a Long-Acting OXM-001
Authors: KAYED ASHREF , KATRI ANNA , ANDREASSEN KIM V. , KARSDAL MORTEN A. , HENRIKSEN KIM
Published: June 2020

Oxyntomodulin has proven to be very promising with regards to weight loss and improved glucose control, however it has a very short half-life. There is a need of more potent and longer-lived molecules and therefore, we have identified a novel Oxyntomodulin analog known as OXM-001, with a better pharmacological efficacy. In vitro potency of OXM-001 was determined in both GLP-1/Glucagon receptor cell lines using β-Arrestin readout. Zucker Diabetic Sprague Dawley male rats (ZDSD) were treated with vehicle and OXM-001 (100 nmol/kg) every third day (n=6/group). The OXM-001 effects on body weight, food intake, FBG, fasting insulin and HbA1C were examined for three-weeks. HFD female C57BL/6J mice were administrated vehicle, OXM-001 (10 and 30 nmol/kg) and pair-fed to OXM-001 (50 nmol/kg) every third day and MEDI0382 (10 and 30 nmol/kg) everyday (n=8/group). Body weight, food intake and oral glucose tolerance test (OGTT) were assessed during the one-month study. OXM-001 showed to be more potent than stabilized Oxyntomodulin, both over a short 3h stimulation and a long 24h potency test. In ZDSD rats, OXM-001 significantly reduced FBG and HbA1C compared to vehicle group. Furthermore, OXM-001 improved fasting insulin due to the weight loss effect. In C57BL/6J mice, OXM-001 (30 and 50 nmol/kg) significantly reduced weight in a dose-depended manner (12.4% and 23.5% compared to vehicle) and was associated with a decreased energy intake. Both OXM-001 doses showed superiority in weight loss compared to MEDI0382. Interestingly, the pair-fed to OXM-001 lost 16.2 % of its body weight compared to vehicle, showing a superiority of the OXM-001 (50 nmol/kg) to the pair-fed group. Both OXM-001 doses improved glucose control compared to MEDI0382 during the OGTT.

In conclusion, OXM-001 significantly lowered the body weight and improved glucose tolerance in prediabetic rats and fat mice, more potent than MEDI0382, and may therefore represent a possible treatment opportunity for obesity-related co-morbidities.

Disclosure

A. Kayed: None. A. Katri: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience.
1965-P: The Extracellular Matrix Modulates Adipocyte Thermogenic Capacity
Authors: GONZALEZ PORRAS MARIA A. , STOJKOVA KATERINA , VAICIK MARCELLA K. , GODDI ANNA A. , COHEN RONALD N. , BREY ERIC
Published: June 2020

Obesity is characterized by an increase in adipose mass and is the leading risk factor for type 2 diabetes. Increasing adipose thermogenic capacity, by activation of brown or beige fat, could be a treatment for metabolic diseases. Nevertheless, many approaches fail in maintaining transformed adipose tissue in vivo, in part, due to the limited understanding of how environmental factors control cell fate and maintenance. We have shown that mice with a null mutation in the laminin α4 exhibit resistance to obesity, enhanced expression of thermogenic fat markers (UCP1) in subcutaneous white adipose tissue (sWAT), increased energy expenditure and enhanced insulin sensitivity. The knockout (KO) of Lama4 results in complex changes in overall ECM composition. We used liquid chromatography/tandem mass spectrometry (LC/MS) to evaluate ECM composition in sWAT from wild type (WT) and KO mice. In addition to the expected absence of Lama4, collagen 1A1 (Col1A1) and collagen 3A1 (Col3A1) were significantly lower in KO mice. Also, integrins α7 (ITα7) and β1 (ITβ1) were dramatically reduced. Immunohistochemical staining confirmed lower levels of Itα7 in KO compared to WT mice (P<0.0001). Knocking down Itα7 with siRNA promoted UCP1 expression (P=0.003) in vitro. In addition, culture of ADSC on Lama4, Col3A1 and Col1A1 coated surfaces had lower UCP1 expression (P<0.0001). Finally, mRNA levels of ITα7 and Lama4 decreased following 12 days of beige differentiation in human ADSC (P<0.0001). These results demonstrate that ECM can regulate adipocyte thermogenic capacity. Specifically, Lama4, Itα7, Col1A1 and Col3A1 are involved in the modulation of metabolic function in adipocytes. A better understanding of the mechanisms underlying these interactions allows for the potential to specifically manipulate these cells to improve systemic energy metabolism and glucose homeostasis.

Disclosure

M.A. Gonzalez Porras: None. K. Stojkova: None. M.K. Vaicik: None. A.A. Goddi: None. R.N. Cohen: None. E. Brey: None.
1977-P: Whole-Exome Sequencing Followed by Functional Analysis to Identify Variants That May Influence Body Mass Index (BMI) via a Role in Adipogenesis
Authors: MULLER YUNHUA L. , DAY SAMANTHA E. , KOROGLU CIGDEM , KOBES SAYUKO , HANSON ROBERT L. , KNOWLER WILLIAM C. , KIM HYE IN , HOUT CRISTOPHER VAN , GOSALIA NEHAL , SHULDINER ALAN R. , BOGARDUS CLIFTON , BAIER LESLIE
Published: June 2020

To identify variants that potentially impact human body fat via a role in adipogenesis, we analyzed whole-exome sequence data from a population-based sample of 6809 American Indians with longitudinal measures of BMI. A total of 623,236 exonic variants were detected and those that met the following criteria were prioritized for functional analysis: 1) non-synonymous, stop-gain or frameshift that occurred in ≥5 individuals; 2) a Combined Annotation Dependent Depletion (CADD) score ≥10 (top 10% of deleterious variants); 3) evidence for association with maximum BMI in adulthood (n=6002) or maximum BMI z-score in childhood (n=4882) (P<0.001, adjusted for age, sex, birth year and the first five genetic principal components) and 4) maps to a gene highly expressed in adipose tissue with literature support for a possible role in adipogenesis. The 20 variants which met these criteria had frequency of the BMI-risk allele ranging from 0.0004-0.025 and were characterized in differentiating OP9 cells for a role in lipid accumulation. Variants in PTPRF (P891L), LAMTOR1 (E37K), CCNY (P107R) and ATG5 (I65V) affected triglyceride content, where cells expressing the BMI-risk allele had increased triglycerides as compared to the wild type allele (9.1-20.5%, P=0.05-3x10-4, n=6-10 transfections). Heterozygous carriers for these variants had a higher BMI in adulthood (39.7-54.2 vs. 36.3kg/m2, P=0.05-5x10-4) and/or higher BMI Z-score in childhood (1.2-3.0 vs. 0.3SD, P=0.01-2.1x10-5) as compared to non-carriers. Two of these 4 variants had supportive evidence in other studies; E37K in LAMTOR1 directionally replicated in its association with BMI in GoDarts (P=0.04, n=2902), while I65V in ATG5 associated with waist (P=0.02) or hip circumference (P=0.02) in T2D-GENES (n=12954).

In conclusion, whole-exome sequencing followed by in vitro analysis of lipid accumulation in OP9 cells has identified coding variants that may impact BMI via a role in adipogenesis.

Disclosure

Y.L. Muller: None. S.E. Day: None. C. Koroglu: None. S. Kobes: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. C. Van Hout: Employee; Self; Regeneron Genetics Center. N. Gosalia: None. A.R. Shuldiner: Employee; Self; Regeneron Genetics Center. Stock/Shareholder; Self; Regeneron Pharmaceuticals. C. Bogardus: None. L. Baier: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
1978-P: Glucose-Lipid Metabolism in Obesity with Elevated Prolactin Levels and Alteration of Prolactin Levels after Laparoscopic Sleeve Gastrectomy
Authors: QU SHEN , WANG XINGCHUN
Published: June 2020

Prolactin (PRL) exerts favorable actions on obesity, besides lactation and reproduction. To explore those actions we investigated the metabolism in obesity with increased PRL and the change in PRL levels after laparoscopic sleeve gastrectomy (LSG). Patients with obesity were divided into two groups: obesity with normal PRL (OB, n=123) and with mildly elevated PRL (OB+PRL↑, n=108). Markers of glucose-lipid metabolism and chronic low-grade inflammation were measured. 115 obese patients (OB, n=64; OB+PRL↑, n=51) underwent LSG. PRL and metabolic markers at 6 and 12 months after LSG were measured. Results showed that blood glucose (BG) at five points of oral glucose tolerance test, blood lipid (total cholesterol (TCH), low-density lipoprotein cholesterol (LDL-C), triglyceride) and tumor necrosis factor-α were lower in OB+PRL↑ than OB group (all P<0.05). PRL was negatively associated with neck circumference, waist-to-hip ratio, systolic pressure, heart rate, basal metabolic rate (BM), alkaline phosphatase (AKP), TCH and LDL in all obesity (all P<0.05). PRL levels were positively associated with weight, hip circumference and BM in males while negatively associated with alanine transaminase, glutamic oxaloacetic transaminase, AKP, BG30min, BG60min, free fatty acid and TCH in females (all P<0.05). PRL was descended in OB+PRL↑ (P=0.015) while increased in the OB group at 12 months after surgery(P=0.009). Increased PRL was associated with the change in TCH(P<0.05).

In conclusion, we found that the increased PRL levels in obesity results in better glucose-lipid metabolism and lower chronic low-grade inflammation. LSG led to increased PRL in obesity and decreased PRL in obesity with mildly elevated PRL. Improved lipid metabolism was associated with increased PRL after surgery.

Disclosure

S. Qu: None. X. Wang: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
1979-P: Thyroid Hormone Associated with Acanthosis Nigricans and Fat Distribution in Obese Patients Nigricans and Fat Distribution in Obese Patients
Authors: QU SHEN , WANG XINGCHUN
Published: June 2020

Obesity exhibits subclinical hypothyroidism (SH) and acanthosis nigricans (AN) easily as an associated complication. We aimed to elucidate the triad interlink between the thyroid hormone levels, fat distribution and AN. In this cross-sectional study, 202 obese men and 239 obese women were enrolled. Anthropometric measurements, glucose-lipid metabolism, thyroid hormone levels, and fat distribution were measured. SH was defined by thyroid-stimulating hormone (TSH) less than 2.5 mU/L. Results showed that the prevalence of AN was significantly higher in the obese group with SH than without SH (47.3% vs. 36.9%, P=0.035). The number of obese women with SH was larger than men (38.1% vs. 28.2%, P=0.029). Obese women have higher TSH levels, lower free triiodothyronine (FT3) and free thyroxin (FT4) than obese men (all P<0.01). In all obesity, FT3 was significantly positively associated with weight, NC, WC, WHR, SBP, DBP, FINS, UA and negatively with HDL-C (all P <0.05). FT4 was significantly positively associated with weight, BMI, NC, WC, SBP, DBP, UA, HGB and FBG (all P <0.05). TSH was negatively correlated with FBG and HGB (all P <0.05). FT3 was positively correlated with Peripheral fat mass, total lean mass and negatively with Total Fat% and Trunk/peripheral fat mass (P=0.025;P=0.029;P<0.001;P=0.034), FT4 was also positively with total lean mass and negatively with Total Fat%(P=0.008; P=0.017), and TSH was positively correlated with Total Fat%(P=0.032).

In conclusion, we found that obese patients with SH are more susceptible to AN. Relatively insufficient thyroid function with higher TSH may be a protective factor in obese women with a better metabolism. Thyroid hormone may be beneficial in improving fat distribution and building lean mass in patients with obesity.

Disclosure

S. Qu: None. X. Wang: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
1986-P: Plasma Retinol Binding Protein 4 and Adipsin Levels Were Not Altered after Gastric Sleeve Surgery in Adult Male Population
Authors: ALSHUBRAMI SUAD , IQBAL MUHAMMAD , ALFADDA ASSIM , ALREGAIEY KHALID
Published: June 2020

Background: Bariatric or weight loss surgery provides the most substantial and sustainable weight loss in individuals with obesity. Caloric restriction and malabsorption are not the only mechanisms by which bariatric surgery reduces body weight and improves glycemic control. Alterations in the secretion and activity of hormones are also the contributory mechanisms in bariatric surgery. We evaluated the levels of retinol binding protein 4 (RBP4) and adipsin after gastric sleeve surgery and their relationship with insulin and lipid parameters.

Method: Thirty-three obese (BMI > 38.3) healthy male subjects age ranged from 25 to 50 years were selected for this study. Plasma levels of RBP4 and adipsin were analyzed before and six months after gastric sleeve surgery by ELISA, along with plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and lipid profile.

Results: Circulating RBP4 was not significantly changed by bariatric surgery (4382.85±7.03 ng before, and 4393.28±5.769 ng after surgery, P= 0.842), neither did adipsin (2949.68±8.16 pg before, and 2917.90±7.295 pg after surgery, P=0.535). As expected, there was a reduction in BMI, insulin levels and HOMA-IR after six months of surgery. Lipid profile analysis revealed that cholesterol, high density lipoproteins (HDL), and low density lipoproteins (LDL) levels were increased after surgery (4.26±0.027 to 5.12±0.026 mmol/L and 0.90±0.007 to 1.55±0.011 mmol/L and 2.62±0.02 to 2.98±0.022 mmol/L, P<0.001) respectively. However, there was no correlation between RBP4, adipsin and insulin and lipid parameters.

Conclusions: Our findings do not suggest a role for RBP4 and adipsin in the improvement of insulin sensitivity in obese male population after gastric sleeve surgery. Moreover, there was no correlation between their plasma levels and either BMI, glucose, insulin, or lipid profiles.

Disclosure

S. Alshubrami: None. M. Iqbal: None. A. Alfadda: None. K. Alregaiey: None.

Funding

King Abdulaziz City for Science and Technology (1-17-03-001-0026)
1988-P: Association between Screen Time Including Smartphone Use and Obesity and Its Associated Lifestyles in School Children in Japan
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , NEDACHI RINA , MORIKAWA SAKIKO Y. , ISHIGURO HAJIME , YAMADA MAYUKO H. , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , SONE HIROHITO
Published: June 2020

An increase in screen time (ST) is reportedly associated with insulin resistance and obesity in children. However, most studies are of TV viewing but not smartphone use. Also, little is known of the relationship between ST and diet. In this study, we clarified the relationships among ST including smartphone use, lifestyle factors including dietary content, and obesity. Cross-sectionally analyzed were 1393 children between 11-15 years of age. ST (min/day) was classified into 4 groups: <120, 120-179, 180-239, ≥240. The associations of each group with dietary content and obesity were investigated. Smartphone usage time significantly increase and sleep duration significantly decreased as ST increased, which was not the case for physical activity. There was no significant difference in energy intake between the 4 groups of ST either for boys or girls, but intake of protein, vegetables green and yellow, other vegetables, and fish and shellfish decreased significantly as ST increased, as did increase in beverage intake. In addition, the association with obesity was significantly increased in the ≥240 ST group compared to the <120 ST group (1.93[1.14-3.28]).

In conclusion, the increase in ST including smartphone usage was suggested to be associated with various unfavorable lifestyles including dietary habits that could be connected to obesity.

Disclosure

I. Ikeda: None. K. Fujihara: None. R. Nedachi: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
1998-P: Waist Circumference Change in the First Year of the Look AHEAD Trial Is Associated with Risk for Cardiovascular Morbidity and Mortality
Authors: OLSON KAYLONI L. , NEIBERG REBECCA H. , ESPELAND MARK , JOHNSON KAREN C. , KNOWLER WILLIAM C. , PI-SUNYER XAVIER , STAIANO AMANDA E. , WAGENKNECHT LYNNE E. , WING RENA R. ,   THE LOOK AHEAD GROUP
Published: June 2020

Look AHEAD found no difference between intensive lifestyle intervention (ILI) for weight loss and diabetes support and education (DSE; control) in cardiovascular (CVD) outcomes among individuals with overweight or obesity and type 2 diabetes (T2DM). This secondary analysis evaluated the association between change in weight and waist circumference (WC), a possible proxy for visceral adiposity, and risk for CVD outcomes. We classified Look AHEAD participants (n=4590) into one of four categories based on change in weight and WC from baseline to Year 1 (increase/increase, etc.) to examine the association between the categories and primary (myocardial infarction, stroke, hospitalized angina, CVD death) and secondary (primary outcomes and CABG/PTCA, hospitalized congestive heart failure, carotid endarterectomy, PVD, and total mortality) CVD outcomes from Year 1 to end of active treatment (median of 9 years). Cox proportional-hazards regression models were used to 1) compare ILI participants in the four categories to DSE and 2) evaluate the four categories within treatment groups using the group that decreased WC and weight as the reference. Compared to DSE, individuals in ILI who increased WC and weight and individuals who increased WC but decreased weight both had greater risk of secondary CVD outcomes (HR[95%CI]: 1.95 [1.33, 2.86] and 1.35 [1.02, 1.80] respectively). In analyses stratified by randomization group, DSE participants did not differ in cardiovascular events across categories. Individuals in ILI who gained WC (regardless of weight loss or gain), had increased risk of primary and secondary CVD outcomes compared to individuals in ILI who decreased weight and WC. Increased WC during weight loss treatment, regardless of weight loss or gain, is associated with greater risk for CVD outcomes in individuals with T2DM. This emphasizes the importance of measuring WC in clinical practice and testing interventions focused on decreasing WC.

Disclosure

K.L. Olson: None. R.H. Neiberg: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. K.C. Johnson: None. W.C. Knowler: None. A.E. Staiano: None. L.E. Wagenknecht: None. R.R. Wing: None.

Funding

National Institutes of Health
200-OR: Effects of Glucose Target on the Performance of a Bihormonal Bionic Pancreas
Authors: TUFFAHA MARWA , BALLIRO COURTNEY A. , HILLARD MALLORY , EL-KHATIB FIRAS , SELAGAMSETTY RAJENDRANATH , DAMIANO EDWARD , RUSSELL STEVEN J.
Published: June 2020

We performed a non-blinded, random-order, cross-over study in 20 volunteers with type 1 diabetes comparing glycemic regulation by the bihormonal bionic pancreas (BHBP) at three glucose targets (130, 115, and 100 mg/dl). Subjects went about their daily routines during each 3-day test period. In the BHBP arms, lower glucose targets (130 to 115 to 100 mg/dl) were associated with correspondingly lower mean CGM glucose levels (156±12 to 146±14 to 135±14 mg/dl, p<0.005 for each comparison). There was no corresponding difference in percent time <60 mg/dl (0.6±1.0 % to 0.9±1.2% to 0.8±1.1%, p≥0.22 for each comparison). However, there was a corresponding significant increase in glucagon total daily dose (2.2±1.2 to 5.3±2.3 to 8.3±3.0 µg/kg/day, p≤0.001 for each comparison). Mean daily nausea scores reported on a 10 cm visual analog scale were low and not significantly different between BHBP arms (0.5, 0.8 and 1.1 cm for the 130, 115, and 100 mg/dl glucose targets, respectively, p>0.05 for each comparison). There were no significant differences between the different BHBP arms in average hypoglycemia symptoms per day, average hypoglycemia interventions per day, or average grams of oral carbohydrates taken by subjects to prevent or treat hypoglycemia. The 100 mg/dl glucose target had a higher satisfaction score when compared to the 115 and 130 mg/dl glucose targets (4.3 versus 4.15 and 4.18, respectively; p<0.005 for both comparisons). There was no significant difference in satisfaction score between the 115 and 130 mg/dl glucose targets. The results of the present study show that for the BHBP, the lowest glucose target in this comparison was associated with better glycemic control, no statistically significant increase in side effects, and greater user satisfaction than higher glucose targets.

Disclosure

M. Tuffaha: None. C.A. Balliro: None. M. Hillard: None. F. El-Khatib: Other Relationship; Self; Beta Bionics, Inc. R. Selagamsetty: Employee; Self; Beta Bionics, Inc. Stock/Shareholder; Self; Beta Bionics, Inc. E. Damiano: Board Member; Self; Beta Bionics, Inc. Employee; Self; Beta Bionics, Inc. Stock/Shareholder; Self; Beta Bionics, Inc. Stock/Shareholder; Spouse/Partner; Beta Bionics, Inc. S.J. Russell: Consultant; Self; Beta Bionics, Inc., ConvaTec Inc., Novo Nordisk A/S, Senseonics. Research Support; Self; Beta Bionics, Inc., Novo Nordisk A/S, Zealand Pharma A/S. Stock/Shareholder; Self; Companion Medical. Other Relationship; Self; Ascensia Diabetes Care, Roche Diabetes Care.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
2001-P: Glycemic and Energy Homeostasis Profiles in Women with Different Metabolic Phenotypes of Obesity in Nutritionist Health Study
Authors: RIBEIRO FRANCIELI B. , SOLAR ISABELA , FREITAS RENATA G. , HANADA ALFREDO S. , BARBOSA MARINA G. , XAVIER CAMILA M. , CROUCHAN NAJLA S.K. , SANTOS VINICIUS F.D. , NETO BRUNO G. , SILVA ISIS T. , FOLCHETTI LUCIANA G.D. , PITITTO BIANCA ALMEIDA , FERREIRA-VIVOLO SANDRA ROBERTA G. , VASQUES ANA CAROLINA J.
Published: June 2020

Objective: To compare components of glycemic and energy homeostasis in women with metabolically healthy normal weight (MHNW) and metabolically unhealthy (MUNW), metabolically unhealthy overweight/obese (MUO) and metabolically healthy (MHO) phenotypes.

Methodology: Cross-sectional study with 104 women (18-45 years): 30 MHNW, 17 MUNW, 27 MHO, 30 MUO. Overweight was considered BMI ≥ 25 kg/m² and metabolic health without of changes in blood pressure, glycemic, lipemic levels and cardiovascular disease. The standard mixed meal tolerance test and indirect calorimetry were performed (assessments at -15, 0, 30, 60, 120 and 180 min). The quantifications were: areas under the curve (AUC) for glucose, insulin, C peptide, glucagon and GLP-1; insulin sensitivity (IS) by oral glucose insulin sensitivity index; energy expenditure, respiratory quotient, and carbohydrate and lipid oxidation rate were measured at rest and after oral stimulation.

Results: The groups did not differ regarding age and HbA1c levels. IS was decreased in MUO compared to MHNW and MHO (p<0.001). Insulin AUC was lower in MUO compared to MHNW (p=0.02), and C-peptide AUC was increased in MHO and MUO compared to MHNW (p<0.001). Resting energy expenditure was increased in overweight individuals compared to lean individuals (p <0.01). The lipid oxidation rate at time 30 min. was lower in MHNW and MUNW compared to MUO (p <0.01).

Conclusion: In young and normoglycemic women, there was lower IS and insulin secretion for the MUO phenotype. The greater rate of lipid oxidation in this group compared to the lean ones may be a reflection of the lower IS, and the inability to switch the use of energy substrate to the higher carbohydrate availability after oral stimulation. BMI is not an ideal indicator of the presence or absence of metabolic health. However, even in MHO individuals’, physiological adaptations may happen to maintain the metabolic parameters within normal range.

Disclosure

F.B. Ribeiro: None. I. Solar: None. R.G. Freitas: None. A.S. Hanada: None. M.G. Barbosa: None. C.M. Xavier: None. N.S.K. Crouchan: None. V.F.D. Santos: None. B.G. Neto: None. I.T. Silva: None. L.G.D. Folchetti: None. B. Almeida Pititto: None. S.G. Ferreira-Vivolo: None. A.J. Vasques: None.

Funding

Fundação de Apoio a Pesquisa do Estado de São Paulo (2017/10185-9)
2014-P: Obesity Phenotypes and Subclinical Atherosclerosis among Whites, African Americans, and South Asians: The Genestar and Masala Studies
Authors: AL-SOFIANI MOHAMMED , VAIDYA DHANANJAY , KANAYA ALKA M. , YANEK LISA , MONGRAW-CHAFFIN MORGANA , KANDULA NAMRATHA R. , BECKER LEWIS , KRAL BRIAN G. , BECKER DIANE , MARUTHUR NISA M. , LEE CLARE
Published: June 2020

Background: Whether obesity in the absence of cardiometabolic abnormalities increases the risk of subclinical atherosclerosis remains debatable.

Methods: We compared coronary artery calcium (CAC) across obesity phenotypes in 505 Whites and 306 African Americans (AAs) from the Genetic Study of Aspirin Responsiveness (GeneSTAR); and 875 South Asians (SAs) from MASALA (Mediators of Atherosclerosis in South Asians Living in America). Using BMI and the International Harmonized Definition of metabolic syndrome, participants were categorized as Metabolically Healthy Non-Obese (MHNO), Metabolically Healthy Obese (MHO), Metabolically Unhealthy Non-Obese (MUNO), and Metabolically Unhealthy Obese (MUO).

Results: The prevalence of any detectable CAC was similar in MHNO versus MHO among all ethnic groups (Whites 35 versus 30%, AAs 30 versus 23%, SAs 29 versus 26%; respectively, all p>0.05). In contrast, the prevalence of CAC was the highest in the MUNO and MUO groups in all ethnic groups. After adjusting for potential confounders; the odds of CAC in MUNO and MUO compared to MHNO were significantly higher in Whites and SAs; but not in AAs.

Conclusion: Metabolically unhealthy Whites, AAs, and SAs had higher CAC scores regardless of obesity status suggesting that metabolic health is more closely associated with atherosclerosis than obesity alone especially in Whites and SAs.

Disclosure

M. Al-Sofiani: Speaker’s Bureau; Self; Novo Nordisk Inc. D. Vaidya: None. A.M. Kanaya: None. L. Yanek: None. M. Mongraw-Chaffin: None. N.R. Kandula: None. L. Becker: None. B.G. Kral: None. D. Becker: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. C. Lee: Employee; Self; Eli Lilly and Company.

Funding

National Institutes of Health (R01HL093009, K24HL112827); National Center for Research Resources (UL1RR024131, M01-RR000052); National Heart, Lung, and Blood Institute (U01HL72518)
2018-P: Whole-Genome Sequence Identifies Potentially Functional Variants in Cytochrome B5 Type A (CYB5A) that Associate with Obesity in Southwest American Indians
Authors: DAY SAMANTHA E. , TRAURIG MICHAEL , PIAGGI PAOLO , KUMAR PANKAJ , KOBES SAYUKO , HANSON ROBERT L. , BOGARDUS CLIFTON , BAIER LESLIE
Published: June 2020

Southwest American Indians (SAI) suffer from a high obesity prevalence. We previously reported that rs7238987, in cytochrome B5 type A (CYB5A), strongly associated with increased body mass index (BMI) in a population-based study of SAI. CYB5A plays a role in fatty acid oxidation (FAO) and reductions in FAO have been linked to weight gain. However, in vitro studies did not confirm a functional effect of this variant. Therefore, the goal of the current study was to assess variation across the entire CYB5A locus to identify the causal variant contributing to obesity in this population. Genotypic data from a custom Axiom genotyping array on 7,700 SAI was merged with whole-genome sequence data from 335 SAI to impute variation within and 10,000 bp surrounding the CYB5A gene. This region contained 316 variants with a minor allele frequency >0.01; 3 variants had a Combined Annotation Dependent Depletion (CADD) score >10 (top 10% most likely to be deleterious) and a BMI association P ≤ 0.001 (adjusted for age, sex, birth year and the first 5 genetic principle components). Among these potentially deleterious variants, the obesity-risk T-allele in rs548402150, also significantly associated (P = 0.00003) with decreased CYB5A expression in skeletal muscle from biopsy data (n=207). Therefore, rs548402150 was prioritized for functional studies. This C/T variation falls within a CTCF consensus site in the 5’-UTR, which could have the ability to effect gene expression levels. In vitro luciferase reporter assays were used to assess altered promoter activity in human skeletal muscle cells. A 30% decrease in luciferase expression was identified for the promoter carrying the obesity-risk T-allele compared to the non-risk C-allele (P = 0.003).

In summary, the further exploration of CYB5A using imputed data has identified a potential casual variant for the observed decreased CYB5A expression and increased risk of obesity in this population.

Disclosure

S.E. Day: None. M. Traurig: None. P. Piaggi: None. P. Kumar: None. S. Kobes: None. R.L. Hanson: None. C. Bogardus: None. L. Baier: None.
2023-P: Effect of Combination Therapy with a ß3 Adrenergic Receptor and PPARγ Agonist on Adipose Beiging in Obese Humans
Authors: KERN PHILIP A. , MEMETIMIN HASIYET , ZHU BEIBEI , CONFIDES AMY L. , JOHNSON ZACHARY , VEKARIA HEMENDRA J. , WESTGATE PHILIP , SULLIVAN PATRICK G. , DUPONT-VERSTEEGDEN ESTHER E. , FINLIN BRIAN
Published: June 2020

Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately.

We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment.

Disclosure

P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None.

Funding

National Institutes of Health (DK112282)
2040-P: Chronic Activation of CREB by Islet Amyloid Increases Star (Steroidogenic Acute Regulatory Protein) Expression in Islets
Authors: HOGAN MEGHAN F. , ESSER NATHALIE , TEMPLIN ANDREW T. , CASTILLO JOSEPH J. , ZRAIKA SAKENEH , HULL REBECCA L. , KAHN STEVEN E.
Published: June 2020

Star, which we have shown to be produced in beta cells, is responsible for transport of cholesterol into mitochondria for the production of steroids. We previously found that Star is upregulated with islet amyloid deposition and this is associated with mitochondrial dysfunction. In steroidogenic tissues, StAR transcription is acutely regulated by cAMP Regulatory Element Binding protein (CREB).

To determine whether upregulation of Star expression by islet amyloid deposition is regulated by CREB activation, we studied the effects of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic islets in vitro (16.7 mM glucose for 144 hrs) and in vivo (high fat diet; HFD for 6 months).

In vitro phosphorylation of CREB (pCREB) and Star expression increased only with amyloid formation (Table; Expt 1a), as did expression of other known CREB target genes (Expt 1b). When islets were cultured with the amyloid inhibitor Congo red (CR; 200 μM), the increase of CREB target genes was abrogated (Expt 2), suggesting chronic activation of CREB is downstream of amyloid deposition. Amyloid deposition in vivo was also associated with upregulation of Star and other CREB target genes (Expt 3).

In summary, chronic CREB activation is associated with increased Star expression, suggesting a novel pathway for amyloid-induced mitochondrial dysfunction in beta cells.

Disclosure

M.F. Hogan: None. N. Esser: None. A.T. Templin: None. J.J. Castillo: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc.

Funding

American Diabetes Association (1-18-PDF-174 to M.F.H.); U.S. Department of Veterans Affairs (I01BX001060)
2060-P: RFX6, a Causative Gene of Mitchell-Riley Syndrome, Regulates ParaHox Genes in Early Endodermal Differentiation
Authors: NAKAMURA TOSHIHIRO , FUJIKURA JUNJI , ITO RYO , INAGAKI NOBUYA
Published: June 2020

Background: RFX6 was identified as a causative gene of Mitchell-Riley syndrome (MRS), an autosomal recessive disease associated with neonatal diabetes and morphological disorders in development of the endodermal lineage such as pancreatic hypoplasia and intestinal atresia. However, little is known of RFX6 regulation of other genes, especially in the early developmental stage of the endoderm.

Aim: To clarify the mechanism of human early development for clues to understanding the pathophysiological features of MRS.

Method: We established human induced pluripotent stem cell (hiPSC) reporter lines, RFX6 +/eGFP and RFX6 eGFP/eGFP, by homologous recombination using a bacterial artificial chromosome vector containing eGFP-pA-loxP-Pgk-NeoR-loxP cassette following 5’UTR of RFX6. Their locus specificity was validated by fluorescent in situ hybridization. We then compared gene expression at the primitive gut stage using the in-vitro differentiation method.

Results: We compared bulk gene expression between RFX6 +/+ with RFX6 eGFP/eGFP using RNA-seq. Among downregulated genes in the latter, we focused on PDX1 and CDX2, which are marker genes of posterior foregut and mid-hindgut, respectively. mRNA expression of these genes was significantly decreased in RFX6 eGFP/eGFP compared to those in RFX6 +/eGFP. Immunocytochemistry and FACS studies showed that most PDX1+ cells were GFP+ in RFX6 +/eGFP; however, the number of PDX1+GFP+ cells was highly decreased in RFX6 eGFP/eGFP while GFP+ cells were observed similarly to those in RFX6 +/eGFP. Regarding CDX2, most CDX2+ cells were GFP+ in RFX6 +/eGFP; however, CDX2+GFP+ cells were observed less frequently in RFX6 eGFP/eGFP than in RFX6 +/eGFP.

Conclusion: Our present findings show that RFX6 deficiency results in downregulation of the major ParaHox genes, PDX1 and CDX2, in early endodermal differentiation. These findings may underlie the association between the genetic and pathophysiological features of MRS.

Disclosure

T. Nakamura: None. J. Fujikura: None. R. Ito: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
207-OR: Liver-Preadipocyte Cross Talk Reverses Lipodystrophy-Induced Insulin Resistance
Authors: BRANDAO BRUNA , SAKAGUCHI MASAJI , BATISTA THIAGO M. , QIAN WEIJUN , KAHN C. RONALD
Published: June 2020

Insulin and IGF1 receptors (IR/IGF1R) control adipose tissue development. We previously demonstrated that mice with an inducible adipocyte-specific knockout of IR/IGFR (Ai-DKO) develop severe lipodystrophy, insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia. This phenotype resolves over 10-30 days due to proliferation of preadipocytes (PAds) and regeneration of adipose tissue. Here, we sought to identify circulating factors that trigger PAds proliferation by treating primary wild type PAds with serum from either WT or Ai-DKO mice. To exclude the hyperglycemia effect, we also incubated cells with serum from WT and Ai-DKO mice treated with the SGLT2 inhibitor Remogliflozin (Remo). Serum from either, chow or Remo-treated Ai-DKO mice, induced primary PAds proliferation of approximately 30%. Serum proteomics analysis revealed that Cathepsin D and multiple apolipoproteins, including C2 and C3, were significantly upregulated in Ai-DKO serum (FC>1 and FDR<0.1). Cathepsin D is known to induce fibroblast proliferation, however, when serum Cathepsin D was neutralized with its antibody, we observed an increase of 25% in PAds proliferation, indicating that, in this context, this protein has the potential to block proliferation. Apolipoproteins are mainly secreted by the liver. We found that ex-vivo liver culture conditioned media from Ai-DKO mice induced PAds proliferation in approximately 40% compared to control. Striking, this phenomenon was mimicked when PAds were treated with purified Apo C2 or C3. Taken together, our data suggest that loss of insulin signaling in mature adipocytes initiates a complex crosstalk between liver and preadipocytes resulting in PAds proliferation and adipose tissue regeneration. Further characterization of these factors will provide important insights into adipose tissue biology during insulin resistant states and contribute to reverse the metabolic syndrome associated with lipodystrophy.

Disclosure

B. Brandao: None. M. Sakaguchi: None. T.M. Batista: None. W. Qian: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.

Funding

National Institutes of Health (R01DK082659-11)
2071-P: C2CD4A, Pancreatic Beta-Cell Function, and Type 2 Diabetes Susceptibility
Authors: KUO TAIYI , ACCILI DOMENICO
Published: June 2020

To this day, intergenic single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) are still a geneticist’s nightmare, because these SNPs are steps away from revealing the disease causative gene, relevant tissue(s), and mechanism of action. For instance, fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes GWAS poses a significant challenge. The VPS13C-C2CD4A-C2CD4B locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1, a transcription factor, is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. To this end, we generated a genome-wide map of FoxO1 super-enhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. Super-enhancers mark genes underpinning β cell identity, and comparing super-enhancers in mouse and human bridge the mouse data to human relevance. When parsed against human super-enhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved super-enhancer in C2CD4A, a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of C2CD4A-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2cd4a regulates glycolytic genes, and notably represses key β cell “disallowed” genes, such as lactate dehydrogenase A, Aldolase B, and monocarboxylate transporter. We propose that C2CD4A is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.

Disclosure

T. Kuo: None. D. Accili: Board Member; Self; Lilly Diabetes. Other Relationship; Self; Forkhead BioTherapeutics Inc.

Funding

National Institutes of Health (K01DK114372)
2072-P: Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo
Authors: GEORGIADOU ELENI , CHABOSSEAU PAULINE L. , TOMAS ALEJANDRA , LECLERC ISABELLE , RUTTER GUY A.
Published: June 2020

Background and Aims: Mitochondrial metabolism of glucose is vital for the initiation of insulin secretion in pancreatic beta cells. Whether mitochondrial ultra-structure, and the proteins controlling their fission and fusion, are essential for glucose recognition is less clear. In the present study, beta cell-selective adult mouse restricted deletion of Mfn1 and Mfn2 was used to investigate the role of mitochondrial fusion in insulin secretion and glucose homeostasis in vivo and in vitro.

Methods: C57BL6 mice bearing Mfn1 and Mfn2 alleles with FloxP sites, were crossed to animals carrying an inducible Cre recombinase at the Pdx1 locus (PdxCreERT). After induction of recombination with tamoxifen, live beta cell fluorescence imaging of mitochondrial [Ca2+] and membrane potential were performed on isolated islets. Mitochondrial ultra-structure was measured using super resolution fluorescence and transmission electron microscopy. Intraperitoneal glucose tolerance, and insulin secretion in vivo and in vitro, were measured using standard techniques.

Results: Mitochondrial length was strongly (to 77±0.9% of controls, p<0.0001) and selectively diminished in beta cells from Mfn1/2 KO mice. KO animals displayed higher fasting glycaemia than control animals at 11-12 weeks (8.6 vs. 6.4 mmol/L, p>0.05). An increase in circulating glucose levels was also observed (p<0.05 at 30 min and p<0.01 at 60 min) and was linked to a considerable (>five-fold) decrease in plasma insulin (5-15 min, p<0.0001) post-intraperitoneal glucose injection. Mitochondrial Ca2+ accumulation and membrane potential were significantly reduced (p<0.01) in response to high glucose in KO animals.

Conclusions: Mitochondrial fusion and fission cycles are indispensable in the beta cell in order to preserve normal mitochondrial bioenergetics and glucose sensing, and may be disrupted in some forms of diabetes.

Disclosure

E. Georgiadou: None. P.L. Chabosseau: None. A. Tomas: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.

Funding

UK Wellcome Trust (WT098424AIA, 212625/Z/18/Z); UK Medical Researh Council (MR/R022259/1, MR/J0003042/1, MR/L020149/1, MR/L02036X/1, MR/N00275X/1); Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA16/0005485)