bluuebunny/crossref_metadata_2025_split huggingface dataset:
1897-P: BECN1, a Key Autophagy Protein, Regulates Adiponectin Secretion in Adipocytes by Interacting with the Exocyst Components
Authors: KURAMOTO KENTA , HE CONGCONG 
Published: June 2020

Autophagy is a lysosomal degradation pathway that plays pivotal roles in maintaining cellular homeostasis. Beclin1/BECN1 is a key autophagy protein that regulates the stability and kinase activity of the class III phosphatidylinositol 3-kinase complex. Dysregulation of autophagy results in the pathogenesis of a variety of diseases, including type 2 diabetes. However, the molecular mechanism of the autophagy machinery in metabolic regulation is poorly understood. To elucidate how autophagy and BECN1 are involved in energy homeostasis and insulin sensitivity, we generated a unique knock-in mouse model showing hyperactive autophagy. This mouse model carries a single amino acid substitution (F121A) in the BECN1 protein (BECN1F121A), which disrupts an inhibitory binding between BECN1 and BCL2, leading to constitutive activation of autophagy. Using this moue model, we discovered that in addition to a role in autophagic regulation, BECN1 also executes a non-degradative function. We found that in response to high-fat diet feeding, BECN1F121A mice show improved systemic insulin sensitivity, elevated adiponectin levels in the circulation, and enhanced adiponectin signaling in metabolic tissues, compared to wild type (WT) mice, despite that body weight and white adipose tissue weight are similar between the two genotypes. Using adipocyte-differentiated stromal vascular fraction cells, we further found that compared to WT BECN1, the BECN1F121A mutant interacts more strongly with components of the exocyst, a complex required for secretory vesicle docking at the plasma membrane. Finally, we demonstrated that the BECN1-exocyst interaction is mechanistically mediated through the coiled-coil domain of BECN1. Altogether, our findings suggest that BECN1 regulates adiponectin secretion through interacting with the exocyst in white adipose tissues, and highlight that autophagy proteins may play important non-degradative roles in energy metabolism.

Disclosure
K. Kuramoto: None. C. He: None.
190-LB: Exploring the Relationships between HbA1c Levels and Diabetes Care through NHANES Data, 2007–2016
Authors: YOUNG CLIPPER F. , VELASCO HECTOR E. 
Published: June 2020

Objective: To examine the relationships between diabetes care measures and HbA1c levels through analyzing the National Health and Nutrition Examination Survey (NHANES) data between 2007 and 2016.
Methods: This cross-sectional study involved subjective and objective data obtained from the CDC NHANES website. Data was then analyzed by STATA14 with ordered logistic regression models, controlling for age, race, gender, health insurance coverage. Subjective data included participants’ answers to the general and diabetes-related questionnaires, and the objective data was their HbA1c levels at the time of the interview/standardized clinical examination.
Results: Three of the eight regression analysis models showed statistically significant associations between HbA1c levels and identified diabetes care questions.

Conclusion: The levels of HbA1c in people with diabetes were associated with how long ago the participant checked-in with a diabetes specialist, whether having a doctor for diabetes care or not, and how often the participant saw a doctor within a year before the NHANES interview/examination. These findings suggest that connecting with healthcare professionals (Questions 1 - 3) showed significant relationships with HbA1c levels, but the same relationships were not observed between receiving or performing the actual diabetes care measures (Questions 4 - 8) and HbA1c levels.

Disclosure
C.F. Young: None. H.E. Velasco: None.
1903-P: Low Level of and Decrease in Serum Amylase (AMY) Increases the Risk of Type 2 Diabetes Mellitus (T2DM)
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , RISA IGARASHI , YAMADA MAYUKO H. , NEDACHI RINA , HATTA MARIKO , KODAMA SATORU , MORI YASUMICHI , MATSUBAYASHI YASUHIRO , ARASE YASUJI , SONE HIROHITO , YAMAMOTO-HONDA RITSUKO 
Published: June 2020

Low serum AMY values were previously reported to be associated with incident T2DM. We further investigated that association in detail by showing the combined effects of chronological changes in AMY and baseline AMY as well as results of stratified analyses of baseline age and HbA1c.
Analyzed were 5306 individuals who had health examinations yearly for 7 y. We monitored changes in AMY values between baseline1 (first visit) and baseline2 (2 y later). Multivariate Cox analysis was conducted to evaluate the impacts of baseline2 AMY and change in AMY on incident T2DM in consideration of age and HbA1c. During the 5-y follow-up, T2DM occurred in 716 patients. Both low baseline2 AMY and decrease in AMY were independently associated with the development of T2DM. Compared with those whose baseline2 AMY ≥57 (Quintiles (Q) 2-5) and changes in AMY ≥90.4 (Q 2-5), those whose baseline2 AMY ≤56 (Q1) and changes in AMY ≤90.3 (Q1) had a significantly increased risk for T2DM (HR 1.60 [1.22-2.09]). Stratified analyses by age and baseline HbA1c levels showed that the increased risk for T2DM due to low baseline2 AMY or its change occurred only among those &lt;50 y old or with HbA1c levels &lt;5.6%.
These findings imply the clinical relevance of using AMY values and their chronological changes over time for evaluation of T2DM risk among individuals who are relatively young or have low HbA1c.

Disclosure
I. Ikeda: None. K. Fujihara: None. I. Risa: None. M.H. Yamada: None. R. Nedachi: None. M. Hatta: None. S. Kodama: None. Y. Mori: None. Y. Matsubayashi: None. Y. Arase: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. R. Yamamoto-Honda: None.
1915-P: High-but-Normal Serum Thyrotropin Levels Increased the Risk of Nonalcoholic Fatty Liver Disease in Euthyroid Subjects with Type 2 Diabetes
Authors: TANG XIXIANG , TAN YING , LI MEI , NIE YUANPENG , CHEN YANMING 
Published: June 2020

Aims: High-but-normal thyrotropin (TSH) is associated with visceral obesity, hyperlipidemia, insulin resistance in patients with type 2 diabetes (T2DM), which may lead to the occurrence of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the association between TSH levels and the incidence of NAFLD in euthyroid T2DM patients.
Methods: A total of 2289 T2DM patients with euthyroid function were included in this cross-sectional study conducted at the Third Affiliated Hospital of Sun Yat-sen University from January 2016 to December 2018. NAFLD was diagnosed by ultrasound. Thyroid function parameters, including the levels of TSH, free triiodothyronine (FT3) and free thyroxine (FT4) were analyzed. Multivariate logistic regression analyses were performed to evaluate the effect of TSH levels on the risk of NAFLD in T2DM patients.
Results: NAFLD was diagnosed in 940 subjects with T2DM (41.1%). The subjects were divided according to the inter-quartile of thyroid function parameters. The NAFLD prevalence rates show a positive correlation with the increasing TSH quartiles(Q1 to Q4: 34.8%, 37.5%, 44.9% and 47.0%, P&lt;0.01), but not with the FT3 or FT4 quartiles. In the multivariate logistic regression analysis, the highest TSH quartile (OR=1.610, 95% CI=1.131-2.289, P=0.008) was independently associated with the risk of NAFLD in patients with T2DM, after adjusting for multiple confounding factors. After additionally stratified by HbA1c levels, the highest TSH quartile level was still independently associated with the risk of NAFLD in euthyroid T2DM patients.
Conclusion: High-but-normal serum TSH is a significant independent risk factor for increased incidence of NAFLD in T2DM patients with euthyroid function, thus providing a novel insight for treating NAFLD.

Disclosure
X. Tang: None. Y. Tan: None. M. Li: None. Y. Nie: None. Y. Chen: None.

Funding
Research and Development Plans in Key Areas of Guangdong Province (2019B020227003); National Natural Science Foundation of China (81770826); National Key Research and Development Program of China (2017YFA0105803)
1917-P: Alpha-Cell Function in Patients with Type 1 Diabetes Is Compromised with Different Levels of Residual C-Peptide
Authors: ZHANG LINGYU , SHI YUWEN , HUANG YITING , HU QIZHEN , QIN YAO , ZHANG MEI 
Published: June 2020

Objective: It is poorly understood α-cell function changes to respond to the different detectable C-peptide levels in patients with type 1 diabetes (T1D). This study aims to investigate the relationship between glucagon secretion and declining β-cell function in patients with T1D.
Methods: Eighty-seven subjects [68, autoimmune type 1 diabetes (T1AD); 4, fulminant type 1 diabetes (FT1D); 15 healthy controls] were enrolled. All participants underwent a 100g steamed bread meal tests (SBMT). T1AD patients were divided into C-peptide negative (CPN), C-peptide middle (CPM) and C-peptide high (CPH) group based on peak C-peptide levels. Both fasting and postprandial of glucose, C-peptide and glucagon were measured. Glucagon among groups were compared by a linear mixed-effects model. The relationship between C-peptide, glucose and glucagon responses was evaluated by regression analysis.
Results: At baseline, fasting glucagon concentrations were comparable between CPN, CPM and CPH group (F=0.099, P=0.906). After SBMT, 180min-glucagon in CPN group were higher than in CPM (P=0.004) and in CPH group (P&lt;0.001). The iAUC30-180 of glucagon was lower in CPH than in CPN (P=0.001) and in CPM group (P=0.034), whereas the iAUC0-30 glucagon did not differ among CPN, CPM and CPH group (F=1.246, P=0.295). The same results were observed in iAUC of glucagon/glucose. After adjustment for age, BMI and diabetes duration, the iAUC30-180 glucagon in T1AD was inversely related to peak C-peptide and positively related to peak glucose levels (Radj2=0.315, P&lt;0.001); however, the iAUC0-30 glucagon in T1AD was only positively related to 30min-glucose (Radj2=0.466, P&lt;0.001).
Conclusions: This study demonstrates α-cell function in patients with T1D are compromised with different levels of residual C-peptide. Glucose is also a contributor factor for postprandial hyperglucagonemia.

Disclosure
L. Zhang: None. Y. Shi: None. Y. Huang: None. Q. Hu: None. Y. Qin: None. M. Zhang: None.

Funding
National Natural Science Foundation of China (81670756, 81974103), Provincial Key Research and Development Foundation of Jiangsu (BE2018748)
192-LB: The Interaction between Health-Related Social Needs, Diabetes, and Health Outcomes
Authors: FRANKLIN STEPHANIE , HAGAN ANGELA , HANSEN PETER , HAUGH GIL , LONG CHARRON 
Published: June 2020

Health-related social needs (HRSN), such as housing instability, food insecurity, and poor transportation or social support, adversely affect health. In diabetes, where evidence links health behaviors, which are influenced by social/environmental factors, to disease onset and progression, a deeper understanding of the degree to which specific HRSN, or multiple needs, affect health may be crucial to achieving one’s best health. HRSN for adults with Medicare Advantage coverage (n=33,690) who responded to an abridged version of the Accountable Health Communities screener developed by the Centers for Medicare and Medicaid Services were evaluated. Overall, 56% (n=18,925) of people with diabetes reported one or more HRSN. A higher percentage of people with diabetes screened positive for financial strain (47%), food insecurity (31%), and poor housing quality/safety (24%) compared to those without diabetes (38%, 24%, and 19%, respectively). As the HSRN burden increased, healthcare utilization and cost also increased while compliance with certain quality indicators decreased. Our findings highlight the interplay between clinical and social needs and indicate that an increased awareness and incorporation of patients’ HRSN into clinical care may be essential for achieving optimal health in patients with diabetes. As more practices move to value-based arrangements, data on HRSN, combined with proven interventions, will help drive better health outcomes.

Disclosure
S. Franklin: Employee; Self; Humana. A. Hagan: None. P. Hansen: Employee; Self; Humana. G. Haugh: Employee; Self; Humana. C. Long: Employee; Self; Humana.
1920-P: First Oral MC4R Agonist for the Treatment of Rare Genetic Obesity
Authors: PARK HEE DONG , YEO SUJIN , PARK HYUNSEO , PARK JIN-SOOK , HONG PETER S. 
Published: June 2020

Melanocyte-stimulating hormones, neuropeptides induced by Pro-opiomelanocortin (POMC) in the hypothalamus, act as the endogenous ligands of Melanocortin 4 receptor (MC4R). They decrease appetite by MC4R activation, leading to weight loss. Dysfunction of genes in MC4R pathway is known to cause rare genetic obesity such as POMC deficiency, leptin receptor deficiency, Bardet-Biedl syndrome and Alström syndrome. Therefore, MC4R agonists have the potential to be therapeutic agents for such genetic obesities. Compound LB(LB) is an orally available, small molecule MC4R agonist under clinical development. In vitro activity of LB toward MC4R and selectivity over MC1R, MC3R and MC5R were measured by radio-ligand binding, luciferase, cAMP and β-arrestin assays. LB showed a high potency and selectivity toward MC4R. In vivo efficacy of LB was tested in high fat diet-induced obese mice, rats and KK-Ay mice. Following repeat-dose to obese rodents, LB led to appetite suppression and weight loss comparable to or higher than setmelanotide. To evaluate in vivo pharmacokinetic properties, a single dose of LB was administered to mice, rats, dogs and monkeys. The GLP toxicology program of LB was comprised of general toxicity studies in rats and monkeys up to 4 weeks, genotoxicity and safety pharmacology studies. The IND-enabling toxicology studies demonstrated good safety profiles in the rats and monkeys. LB showed no significant safety issue in the genotoxicity and safety pharmacology studies. Comprehensive in vitro and in vivo studies demonstrated that LB is potent and selective MC4R agonist. LB is safe and well-tolerated compound, as demonstrated in GLP toxicity studies. In addition, the observed efficacy and safety profiles of LB are well described by the preclinical pharmacokinetic properties of LB such as a great penetration to brain tissue.
In conclusion, these nonclinical studies suggested that LB can be a safe and effective drug for the patients with genetic obesity.

Disclosure
H. Park: None. S. Yeo: None. H. Park: Employee; Self; LG Chem. J. Park: None. P.S. Hong: None.
1923-P: Ablating Mitochondrial Creatine Kinase Does Not Affect Energy Expenditure, White Adipose Tissue, Mitochondrial Respiration, or the Susceptibility to High-Fat Diet-Induced Obesity
Authors: POLITIS-BARBER VALERIE , PETRICK HEATHER L. , HOLLOWAY GRAHAM 
Published: June 2020

Introduction: Recently, creatine (Cr) mediated ’recycling’ of ADP was proposed to promote energy expenditure (EE) within white adipose tissue (WAT). We determined the influence of ablating mitochondrial creatine kinase (Mi-CK), an enzyme necessary to the proposed Cr cycling, to ascertain the biological importance of Cr-mediated EE in the development of high-fat diet (HFD)-induced obesity.
Methods: Female Mi-CK wild type (WT) and knock-out mice (n=6-8/group) were randomized to receive control (10% fat) or HFD (60% fat) for 8 weeks. Whole-body indirect calorimetry (EE, RER) and glucose tolerance were determined. Inguinal WAT (iWAT) and gonadal WAT (gWAT) were used to determine mitochondrial oxidative phosphorylation (OXPHOS) proteins and submaximal (100 μM ADP) and maximal (5 mM ADP) respiration in the presence and absence of Cr (0.01mM).
Results: In WT animals, HFD consumption increased body mass and whole-body fat oxidation, while decreasing rates of carbohydrate oxidation and glucose tolerance. HFD reduced mass-specific iWAT and gWAT submaximal and maximal ADP-supported respiration ∼50%. HFD also reduced WAT OXPHOS protein content ∼25%, however normalizing respiration to OXPHOS protein did not mitigate the observed HFD-induced reduction in respiration, suggesting an attenuation in mitochondrial-specific respiration. The presence of Cr did not drive respiration in any experiment, challenging the notion that Cr stimulates mitochondrial respiration. In further support of this finding, ablating Mi-CK did not influence HFD-induced weight gain, whole body EE, the development of glucose intolerance or respiratory function in either iWAT or gWAT depots.
Conclusion: Ablating Mi-CK does not affect HFD-induced phenotypic changes, suggesting Cr-mediated EE is not a primary determinant in the development of obesity-induced glucose intolerance.

Disclosure
V. Politis-Barber: None. H.L. Petrick: None. G. Holloway: None.

Funding
Natural Sciences and Engineering Research Council of Canada (400360)
1931-P: New Insights Into Lipoprotein Lipase Maturation in the ER
Authors: WU SHUANGCHENG , TORRES MAURICIO , QI LING 
Published: June 2020

Lipoprotein lipase (LPL) is a key enzyme responsible for the hydrolysis of triglycerides packed in lipoproteins, and defects in this process have been linked to the development of obesity-associated pathological conditions such as hyperlipidemia, atherosclerosis and stroke. However, our understanding of early events leading the maturation of nascent LPL protein remains limited. Here, we report a previously unappreciated crosstalk between ER-associated degradation (ERAD) and autophagy in controlling LPL maturation in the ER. Sel1L, an essential cofactor involved in ERAD, is required for the export of active LPL from the ER and prevents the formation of high molecular weight LPL aggregates. In the absence of Sel1L, autophagy is activated in adipocytes to limit the size of LPL aggregates in the ER. Deletion of autophagy in Sel1L-deficient adipocytes leads to the formation of large LPL foci in the ER. Thus, we conclude that Sel1L-Hrd1 ERAD and autophagy, most likely in the form of ER-phagy, synergistically control the biogenesis and aggregation of nascent LPL proteins. Ongoing studies aim to decipher how ERAD controls the activation of ER-phagy and how ER-phagy recognizes and degrades LPL aggregates.

Disclosure
S. Wu: None. M. Torres: None. L. Qi: None.
1934-P: Branched-Chain Amino Acids Are Poor Markers of Insulin Resistance in Women: The Federal Women’s Study
Authors: MATTA SAMANTHA , CRAVALHO CELESTE K. , VILLALOBOS-PEREZ ALFREDO , MEYERS ABBY , MABUNDO LILIAN , COURVILLE AMBER B. , SAMPSON MAUREEN L. , SUMNER ANNE E. , CHUNG STEPHANIE T. 
Published: June 2020

The data relating branched chain amino acids (BCAAs) with obesity and type 2 diabetes is conflicting but may be further clarified by examining its relationship to race/ethnicity and menopause. Therefore, we determined the relationship of BCAA with markers of insulin sensitivity (SI) in 122 federally employed women (49 White, 73 Black: 58 African American and 15 African Immigrant, age 44±10 (mean±SD) (range 24-62y); BMI 30.2±5.7 (range 20.3-45.2 kg/m2); 33% menopausal) using linear regression models adjusted for race and menopause. Fasting BCAAs were measured by nuclear magnetic resonance (NMR) spectroscopy, whole-body SI derived from the minimal model, basal hepatic insulin sensitivity (HISI) using [6,62H2]glucose, and hepatic and visceral adipose tissue (VAT) by proton NMR. BCAAs were similar in black and white women (leucine:104±30 vs. 114±37, valine:196±40 vs. 204±34, isoleucine:41±12 vs. 38±12 μmol/L, all P≥0.1) and did not differ by menopause (P&gt;0.5). Total and individual BCAAs were associated with lower whole-body SI (Figure), weakly associated with VAT (AdjR2=0.1, P=0.01), liver fat (AdjR2=0.01, P=0.01), and there was no association with HISI (P&gt;0.2). Overall, plasma BCAAs were not robust markers of insulin resistance in women of white or African ancestry and higher levels in women with insulin resistance may reflect a composite effect of dietary and metabolic processes.

Disclosure
S. Matta: None. C.K. Cravalho: None. A. Villalobos-Perez: None. A. Meyers: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. A.E. Sumner: None. S.T. Chung: None.

Funding
National Institutes of Health (to S.T.C., L.M., A.B.C.)
1938-P: The Gut Microbiota Is Critical for the Beneficial Metabolic Effects of Palmitic Acid Hydroxy Stearic Acids (PAHSAs) in Diet-Induced Obese Mice
Authors: LEE JENNIFER , RAHNAVARD ALI , WELLENSTEIN KERRY , NELSON ANDREW T. , CLISH CLARY B. , SIEGEL DIONICIO , KAHN BARBARA 
Published: June 2020

The gut microbiome contributes to host health and has therapeutic potential to treat metabolic disease. A newer class of lipids, PAHSAs, have antidiabetic effects in high-fat diet (HFD)-fed mice. We aimed to determine whether the gut microbiome contributes to the beneficial metabolic effects of PAHSAs and if these effects are transmissible by Fecal Microbiota Transplantation (FMT) in mice. In HFD-fed germ-free (GF) mice, PAHSA treatment for 35 days did not improve glucose homeostasis vs. vehicle-treated mice, in contrast to previous data in conventional HFD mice. Feces from conventional Chow fed mice with enhanced insulin sensitivity after PAHSA treatment for 21 days were used for oral FMT in HFD-GF mice. HFD-GF mice treated with feces from PAHSA-treated chow mice gained less weight, had reduced glycemia 5-hrs after food removal, and were more glucose tolerant and insulin sensitive than HFD-GF-mice that received feces from vehicle-treated Chow mice. Metagenome sequencing and metabolomics analysis performed on cecal contents from conventional Chow-fed PAHSA- and Vehicle-treated mice showed that 26 fatty acids (out of 600 metabolites) and several microbial species and their metabolic pathways correlated most highly with PAHSA-mediated insulin sensitivity. Also, Bacteroides thetaiotaomicron (Bt), a gut microbe associated with leanness in humans, and cecal C34:2 Phosphatidylethanolamine (PE), an abundant phospholipid class that is reduced in obese humans, were most strongly associated with the beneficial PAHSA effects. Initial studies with Bt treatment in male chow mice show improved glucose tolerance and lower glycemia 5-hrs after food removal vs. controls. Thus, the gut microbiota is necessary for the effects of PAHSAs to improve glucose homeostasis in HFD-fed mice. These effects can be conferred by FMT. PAHSA-associated microbes could provide novel gut-based therapeutic strategies to treat obesity and insulin resistance.

Disclosure
J. Lee: None. A. Rahnavard: None. K. Wellenstein: None. A.T. Nelson: None. C.B. Clish: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Harrington Discovery Institute, Janssen Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK114162-01A1, DK1NADK-057521-01 to J.L.); JPB Foundation (to B.K.)