bluuebunny/crossref_metadata_2025_split huggingface dataset:
1222-P: Adipose Tissue Antilipolytic Insulin Sensitivity Protects against Whole-Body Insulin Resistance and Lowers Acylcarnitine Accumulation in Adults with Obesity
Authors: SCHLEH MICHAEL W. , RYAN BENJAMIN J. , AHN CHEEHOON , LUDZKI ALISON , VARSHNEY PALLAVI , GILLEN JENNA B. , HOROWITZ JEFFREY F. 
Published: June 2021

The aims of this study were; 1) to assess clinical and subclinical factors associated with insulin-stimulated glucose uptake and 2) compare skeletal muscle lipid profile (untargeted lipidomics) in a sub-cohort of insulin sensitive vs. insulin resistant subjects. 66 obese adults (F=46 [BMI=34±3kg/m2], M=20 [BMI=33±2.9 kg/m2]) with homogeneous body composition completed a 2h hyperinsulinemic-euglycemic clamp, and stable isotope dilution methods to assess glucose rate of disappearance (Glucose Rd: index of insulin sensitivity), fatty acid rate of appearance (FA Ra), and hepatic glucose production (Glucose Ra) under basal and hyperinsulinemic conditions. We also performed an array of metabolic measurements (e.g., hepatic and visceral fat accumulation [via MRI], fat oxidation, lipid profile, circulating cytokines). Covariate analysis (LASSO) identified insulin-mediated suppression of FA Ra, basal glucose Ra, and fat oxidation as the cluster of measurements best predicting Glucose Rd (r=0.76, p&lt;0.01). Insulin-mediated suppression of FA Ra was also the strongest independent predictor of Glucose Rd (r=0.51; p&lt;0.01). As a result of greater adipose tissue anti-lipolytic response to insulin, lower FA delivery to skeletal muscle may improve insulin-mediated glucose uptake via lower muscle lipid accumulation. Importantly, we found the accumulation of several long-chain acylcarnitine species (measure of incomplete β-oxidation: C18:0,18:1,20:1,20:3) to be lower (p&lt;0.05) in muscle samples from an insulin sensitive sub-cohort (Glucose Rd &gt; 8.5 µmol/(min•FFM•[Insulin]); n=10) compared with an insulin resistant sub-cohort (&lt; 7.2 µmol/(min•FFM•[Insulin]); n=8).
In conclusion, our findings indicate that greater adipose tissue anti-lipolytic response to insulin is an important predictor of insulin-mediated glucose uptake - and acylcarnitine accumulation in skeletal muscle may mediate this effect.

Disclosure
M. W. Schleh: None. B. J. Ryan: None. C. Ahn: None. A. Ludzki: None. P. Varshney: None. J. B. Gillen: None. J. F. Horowitz: None.

Funding
National Institutes of Health (R01DK077966, P30DK089503, T32DK007245, F32DK117522); Canadian Institutes of Health Research (DFS146190, 338735)
1223-P: Effects of Bariatric Surgery on Quality of Life, Body Image, and Sex Life in Obese Women
Authors: DI GIOIA LUDOVICO , PERRINI SEBASTIO , BRAUN ANTONIO , ROSSI ERICA , GIORDANO FIORELLA , GUARINI FRANCESCA , SICILIANO EDOARDO , CIGNARELLI ANGELO , LEONARDINI ANNA , NATALICCHIO ANNALISA , LAVIOLA LUIGI , BERTOLINO ALESSANDRO , GIORGINO FRANCESCO 
Published: June 2021

Bariatric surgery and consequent weight loss improve metabolic and anthropometric parameters in obese subjects. However, a detailed assessments about the impact of bariatric surgery on quality of life (QoL), body image perception, and sex life is lacking. The aim of this study was to assess the QoL, body image satisfaction and sexual function in 389 female patients with obesity (age 40±10 years, pre-surgery weight 120.4±17.7 kg) before and at least 6 months after bariatric surgery (60% sleeve gastrectomy, 40% gastric bypass). All participants were asked to complete the following online self-report questionnaires seven days before and six months after bariatric surgery: the Body Uneasiness Test (BUT) to assess self-perception of body image, the Short Form-12 (SF-12) to QoL as per the physical (PCS) and mental (MCS) domains, and the Female Sexual Function Index (FSFI) to screen for sexual dysfunctions in women. After bariatric surgery, patients lost 44.5±16.5 kg (p&lt;0.001), with an increase of the PCS (53.3±7.2 vs. 31.9±21.4, p&lt;0.001) and MCS (50.5±8.8 vs. 39.6±12.5, p&lt;0.001) scores, that fell within the normal range of healthy individuals. All patients showed a significant improvement of the global score index domain of the BUT (1.9±1.1 vs. 3.7±0.9, p&lt;0.001). The youngest patients (18-39 years old) who lost at least 40% of the baseline weight obtained a normalization of their body image concern domain results, reaching the reference range for healthy non-obese subjects. After bariatric surgery, patients also had a significant improvement of the FSFI (26.8±9.7 vs. 19.6±8.8, p&lt;0.001), with an increase of non-dysfunctional, sexually active women from 26.2% to 78.2%. Significant correlations were found between the extent of weight loss and the improvement of all the psychometric parameters. Bariatric surgery is an efficient and safe treatment for obesity, and the physical gains related to weight loss are also mirrored by significant improvements in mental and physical health and sexual function.

Disclosure
L. Di gioia: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic. A. Bertolino: None. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. S. Perrini: None. A. Braun: None. E. Rossi: None. F. Giordano: None. F. Guarini: None. E. Siciliano: None. A. Cignarelli: None. A. Leonardini: None.
1234-P: Impact of Treatment Adherence to Observed Weight Loss in the GLOW Study
Authors: URBAN LORIEN E. , APOVIAN CAROLINE , ARONNE LOUIS , LEIDER HARRY 
Published: June 2021

Adherence to weight management treatments is suboptimal. The Gelesis Loss Of Weight (GLOW; NCT02307279) pivotal trial data were used to assess treatment adherence impact on weight loss. The primary objectives of the GLOW study were to assess the effects of an oral superabsorbent hydrogel (OSH) on weight loss (targeted difference of ≥ 3%) and ≥ 5% weight loss responder status in subjects with a body mass index of 27-40 kg/m2. A total of 436 subjects were randomized to 3 capsules twice per day of OSH or placebo taken with 500 mL (16 oz) of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. There were 172 OSH- and 152 placebo-treated subjects who completed the study. Capsules counted at each study visit every 2-4 weeks were used to calculate overall percent treatment adherence (PTA) after the final visit. The PTA impact on weight loss was assessed using ANCOVA models with baseline BMI, fasting glucose and sex as covariates. A logit model with the same covariates was also used to assess the impact of PTA ≥ 95% or &lt; 95% in subjects who achieved ≥ 10% or &lt; 10% weight loss at 24 weeks. In the OSH group, mean PTA for was 97.61% ± 4.68% (SD) ranging from 70% to 111%, and all but 1 subject had PTA ≥ 80%. A significant interaction of ≥ 5% weight loss responder status and PTA was found (P=0.039); therefore, separate ANCOVA models were fit. PTA predicted weight loss at week 24 among the OSH group ≥ 5% responders, but not the ≥ 5% non-responders. Also, a PTA increase of 1 day/week predicted an additional 3.5% weight loss (β = 0.-25 ± 0.11 SE, P=0.024). PTA did not predict weight loss in the placebo group. OSH-treated subjects with ≥ 95% PTA were 4 times more likely to achieve ≥ 10% weight loss compared to those with &lt; 95% PTA (P=0.027, odds ratio=4.27, 95%CI=1.18 to 15.41). These findings suggest that OSH has a binary impact on the treated subjects rather than a uniform effect. Increased PTA during OSH treatment predicted increased weight loss in patients responding to therapy with ≥ 5% weight loss, and not in non-responders or the placebo group.

Disclosure
L. E. Urban: Employee; Self; Gelesis. C. Apovian: Board Member; Self; Abbott, Allergan plc, Gelesis, Novo Nordisk, Nutrisystem, Tivity Health, Xeno Bioscience, Zafgen, Inc. L. Aronne: Other Relationship; Self; Allurion, Eisai & Janssen Pharmaceuticals, ERX Pharmaceuticals, Gelesis, Jamieson Wellness, Myos Corp, Intellihealth Corp, Novo Nordisk, Pfizer Foundation, Real Appeal, Research Support; Self; Astrazeneca, Aspire Bariatrics. H. Leider: Employee; Self; Gelesis.
1241-P: Inhibition of MiR-146a-5p Prevents Mitochondrial Dysfunction and ß-Cell Apoptosis, and Improves Insulin Secretion
Authors: KRISHNAN PREETHI , SYED FAROOQ , WEAVER STACI A. , LEE CHIH-CHUN , EVANS-MOLINA CARMELLA 
Published: June 2021

MicroRNAs (miRNAs) are small non-coding RNAs that function as modulators of gene expression. We previously identified upregulation of miR-146a-5p in pancreatic islets treated with proinflammatory cytokines and in human pancreatic sections from individuals with type 1 diabetes. While other studies have associated overexpression of miR-146a-5p with β cell apoptosis and defective insulin secretion, the molecular mechanisms through which these effects are mediated remain elusive. To this end, we transduced MIN6 cells with lentiviral vectors (i) overexpressing and (ii) inhibiting the expression of miR-146a-5p and developed stable cell lines resistant to puromycin. Monoclonal cell populations were developed by single clone selection and then treated with/without proinflammatory cytokines (IL-1β, IFN-γ and TNF-α) for 24 hours. Further characterization of the cells was performed using mRNA sequencing, western blot, RT-PCR of cognate targets and Seahorse mitochondrial functional assays. Overexpression of miR-146a-5p led to increased expression of cleaved caspase-3 and reduced insulin secretion under basal and cytokine-treated conditions, whereas inhibition of miR-146a-5p reversed these effects. Similarly, miR-146a-5p inhibition increased mitochondrial copy number, mitochondrial membrane potential, basal respiration rate, maximal respiration rate, spare respiratory capacity, and ATP production, suggesting a protective effect on the mitochondria, even upon exposure to proinflammatory cytokines. Consistent with these findings, bioinformatic analysis of sequencing data and validation of targets such as MAPT, MYRIP, NRG1, GPX1 also showed enrichment of pathways related to insulin secretion, apoptosis, mitochondrial function. Overall, findings from our study show for the first time that miR-146a-5p upregulation may alter β cell health through reduced mitochondrial function.

Disclosure
P. Krishnan: None. F. Syed: None. S. A. Weaver: None. C. Lee: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.
1245-P: Characteristic Distribution of GRP78 in Islets and Intraislet Ductal Cells of Diabetic C414A-CRY1 Transgenic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHRO , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: June 2021

Our preceding studies demonstrated that cysteine414 (zinc-binding site of mCRY1) - alanine mutant mCRY1 transgenic mice (TG mice) exhibit diabetes characterized by the reduction of β-cell proliferation caused by senescence-associated secretory phenotype (SASP)-like characters of β-cells. Not only pancreatic intraepithelial neoplasias (PanINs) with pancreatic duct glands (PDGs) but also intra-islet ducts emerged age-dependently in TG mice (Okano S. et al., 2019). Reportedly GRP78 (also called BiP) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and in lesions of acinar-to-ductal metaplasia (ADM) which is known as precursors of PanIN. As for the islet, GRP78 has been intensively studied with regard to the unfolded protein response (UPR) in the β cells. However, the details of in vivo distribution of GRP78, particularly in endocrine cells outside β cells, are still remain elusive. In this study, we conducted staining experiments for GRP78 in the pancreatic sections of well-matured mice to explore the relation between endocrine cells and intra-islet ducts. The results showed that the expression of GRP78 was higher in PanINs and PDGs than in normal ductal cells in TG mice, suggesting that GRP78 plays important roles in the maintenance of the atypical ductal lesions. In both wild-type and TG mice, GRP78 was observed in the whole islet. The expression of GRP78 was higher in β cells than in alpha and delta cells in both mice. Also, GRP78 was highly expressed in primary intra-islet ducts. Some of the GRP78 high-expressing primary intra-islet ductal cells were co-expressed with chromogranin A, which is known as an endocrine marker. Taken together, our results suggest that the direct trans-differentiation of endocrine cells (possibly β cells) to ductal cells is involved in the generation of the intra-islet ductal cells.

Disclosure
S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.

Funding
Japan Society for the Promotion of Science (19K07498); Tohoku University
125-LB: Differential Influences of Gastric Bypass and Sleeve Gastrectomy on Glucose-Reducing Effects of DPP-4 Inhibitor
Authors: HONKA HENRI , RAYAS MARIA S. , DEFRONZO RALPH A. , GASTALDELLI AMALIA , SALEHI MARZIEH 
Published: June 2021

The two most commonly performed bariatric surgical procedures, gastric bypass (GB) and sleeve gastrectomy (SG), induce diabetes remission before any significant weight loss. While the role of entero-insular axis after SG remains unknown, weight-independent glycemic effects of GB have been attributed to larger systemic appearance of glucose and incretin effect. We examined the effect of increasing endogenous incretins 2-3 fold with a DPP-4 inhibitor on glycemic effects of GB and SG. Glucose and islet-cell secretory responses were measured in 4 subjects with a history of GB, 4 with SG and 4 non-surgical controls (CN) during 50-gram oral glucose ingestion with and without 200 mg sitagliptin orally on two separate days. GB, SG, and CN groups were matched for BMI, FFM, HbA1c, age, fasting glucose and insulin levels; GB and SG were matched for weight loss and time postsurgery; none had diabetes. Compared to SG-treated subjects and controls, subjects with prior GB had lower prandial glycemia (AUCGlucose 3hr) (P &lt; 0.001), and higher AUCGlucagon 3hr (P &lt; 0.0001). The expected differences in prandial insulin response pattern to glucose ingestion among surgical and controls was observed; however, AUCInsulin 3hr and AUCC-peptide 3hr were similar between groups. Sitagliptin did not change AUCGlucose 3hr in GB-treated subjects, whereas the prandial glucose response was reduced by 21 ± 13 % in SG-treated and non-surgical controls by sitagliptin. Enhanced endogenous incretins diminished early glucagon (AUCGlucagon 1hr) in all 3 groups (P &lt; 0.05), improved β-cell glucose sensitivity in CN (P &lt; 0.05), but it had no effect on beta-cell function in GB or SG subjects. Sitagliptin had no effect on insulin clearance or insulin sensitivity in fasting or fed states. These findings indicate that glucose metabolism after SG, similar to non-operated controls, is enhanced by incretins, which are at maximum in GB group and thus not influenced by DPP-4 inhibition.

Disclosure
H. Honka: None. M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None.

Funding
National Institutes of Health (TR002646); National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)
1251-P: Pancreatic ß-Cell Specific Deletion of Complement 1q Like-3 Secreted Protein Improves Glucose Tolerance by Increasing Insulin Secretion
Authors: RAHMAN MOSTAFIZUR , ALSHARIF HAIFA , TROMBLEY JOHN E. , PATHAK ASMITA , BHATNAGAR SUSHANT 
Published: June 2021

Secreted proteins are important metabolic regulators in the healthy and disease states. Using network biology approaches, our laboratory identified that complement-1q like-3 (C1ql3) secreted protein has a role in affecting pancreatic islet function. We demonstrated that the recombinant C1ql3 protein inhibits insulin secretion in response to stimulation by exendin-4 (an agonist for the stimulatory Gs-coupled GLP-1 receptor) from human and mouse islets. C1ql3 is expressed in β-cells but not in α- or δ-cells of mouse islets. Its expression is also conserved in human islets. Our goal is to investigate the role of β-cell C1ql3 in whole-body glucose homeostasis. We generated mice with β-cell-specific deletion of C1ql3 (βKO) by crossing C1ql3fl/fl and RIP-Cre+ mice. Preliminary data show that C1ql3 βKO mice have increased body weight with no change in fasting plasma glucose levels than the control mice. The glucose clearance was significantly improved after oral glucose challenge, whereas no difference in insulin action was observed in the C1ql3 βKO vs. control mice. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. The expression-coupled secretion of C1ql3 from islets is increased with obesity. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased insulin secretion from islets of C1ql3 βKO Leptinob/ob compared to Leptinob/ob control mice. These findings identify that C1ql3 in an autocrine manner inhibits insulin secretion from β-cells to regulate whole-body glucose homeostasis. Our work identifies a novel C1ql3-signaling pathway that may contribute to the observed β-cell dysfunction in obesity and type 2 diabetes.

Disclosure
M. Rahman: None. H. Alsharif: None. J. E. Trombley: None. A. Pathak: None. S. Bhatnagar: None.
1253-P: Markers of Beta-Cell Death and Insulin Secretion in Ketosis-Prone Diabetes (KPDM)
Authors: VELLANKI PRIYATHAMA , OLADEJO OMOLADE , FAYFMAN MAYA , DAVIS GEORGIA , MIGDAL ALEXANDRA , STAIMEZ LISA R. , SMITH ALICIA K. , UMPIERREZ GUILLERMO E. 
Published: June 2021

Approximately 50% of obese Black individuals present with diabetic ketoacidosis (DKA) at new-onset of diabetes undergo remission from insulin (fasting blood glucose [FBG &lt;130 mg/dl, random BG &lt; 180 mg/dl and HbA1c &lt; 7% and off insulin therapy &gt; 1 week) with intensive insulin treatment due to improved pancreatic beta(β)-cell secretion. Controversy exists whether KPDM is type 1 or type 2 diabetes and whether β-cell death contributes to DKA and β-cell secretion. Circulating unmethylated to methylated insulin DNA ratio (unMeth/MethINS) levels were found to correlate with β-cell death and β-cell secretion in patients at high risk for type 1 diabetes. In this exploratory study, we hypothesized that increased circulating unMeth/MethINS ratio at presentation of DKA correlates with decreased β-cell secretion in KPDM. Obese Black individuals presenting with DKA without GAD-65 antibodies were recruited 3-4 days after discharge from the hospital (Visit 1, n=22) and at insulin remission (Visit 2, n=19). Serum circulating unMeth/MethINS levels were measured at Visit 1. β-cell secretion was measured with glucagon stimulation tests (GST) performed at Visit 1 and Visit 2 and calculated as 6-min (maximum[Max]) and Delta (Max-baseline) C-peptide levels. At Visit 1, mean age was 38 ± 12 years and 7 (32%) were female. Mean BMI was 39.4 ± 10.6 kg/m2 with mean baseline HbA1c of 12.4 ± 1.8%. C-peptide levels increased significantly from Visit 1 to Visit 2 and expressed as median with minimum and maximum: Max (Visit 1: 2.94 [0.65, 12.07] vs. Visit 2: 5.87 [1.83, 12.11] ng/ml, p=0.011) and Delta (Visit 1: 1.57 (0.24, 6.88) vs. Visit 2: 2.80 [0.46, 9.01], p=0.047). UnMeth/MethINS ratio at Visit 1 was not significantly correlated (Spearman) with C-peptide levels at Visit 1 (Max: r=0.02, p=0.93, Delta: r=0.04, p=0.84) or at Visit 2 (Max: r=-0.07, p=0.79, Delta: r=0.03, p=0.89). Our data shows that in patients with KPDM, markers of β-cell death are not correlated with insulin secretion indicating that KPDM is consistent with type 2 diabetes.

Disclosure
P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. O. Oladejo: None. M. Fayfman: None. G. Davis: None. A. Migdal: None. L. R. Staimez: None. A. K. Smith: None. G. E. Umpierrez: Research Support; Self; AstraZeneca, Dexcom, Inc., Novo Nordisk.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK111024, UL1TR002378, K23DK11324-01A1)
1262-PUB: Observational Study to Evaluate the Presence of Tubulopathy and Glomerulopathy in Indian T2DM Patients and to Correlate Their Presence with Established Risk Factors for Nephropathy
Authors: HANS PANKAJ , KUMAR MANISH 
Published: June 2021

Objective: Urinary cystatin C (UCC) is an emerging marker of DN. UCC has recently been suggested as an alternative marker in eGFR due to its favorable properties. This study was conducted to evaluate the presence of glomerulopathy and tubulopathy in patients with type 2 diabetes mellitus (T2DM) and to correlate them with established risk factors for nephropathy. We aimed at evaluating the level of UCC as a marker of tubulointerstitial damage in patients with T2DM in relation to the level of albuminuria and other parameters.
Methods: Sixty eight patients with T2DM (mean age, 47.44 ± 10.40 years) age- and sex-matched subjects were evaluated for UCC, serum creatinine (SCr), and urinary albumin-creatinine ratio (UACR) along with other parameters.
Results: Of the 68 patients enrolled in the study, 49 were male (72%) and 19 were female (28%). The mean duration of diabetes was 7.21 ± 4.03 years, mean HbA1c was 9.1 ± 1.3%, and mean body mass index (BMI) was 23.21 ± 3.11 kg/m2. Microalbuminuria was found in 17 (25%) cases and macroalbuminuria was found in 8 (11.8%) cases. The mean UACR of the study group was 113.42 ± 252.31 mg/g creatinine and mean UCC was 741.26 ± 1523.46 ng/ml. There was a statistically significant association between rising albumin excretion and BMI, duration of diabetes, SCr, UCC, and SBP and DBP. A significant negative correlation between eGFR and age of the patient and SCr and significant positive correlation between eGFR and BMI was noted. However, a negative correlation between eGFR and UCC failed to achieve statistical significance.
Conclusion: We thus conclude that UCC may be one of the early biomarkers of DN. the use of UCC measurement for early evaluation of renal involvement and may help initiation of timely treatment and prevent/delay renal complications of diabetes.

Disclosure
P. Hans: None. M. Kumar: None.