bluuebunny/crossref_metadata_2025_split huggingface dataset:
1714-P: Higher Initial Diet Quality Predicts Shorter Weight Loss Period prior to an Involuntary Weight Loss Plateau
Authors: MELHORN SUSAN J. , SEWAYBRICKER LETICIA E. , GAO HUI , ROSALYNN DE LEON MARY , WEBB MARY , LYLE MEGHAN , BEATTY SARAH J. , KRATZ MARIO , SCHUR ELLEN 
Published: June 2023

It is currently unknown what factor(s) may promote entry into a weight loss plateau. Given intensive lifestyle interventions (ILI) for weight loss include changes in diet, we evaluated how diet quality impacts characteristics of a weight loss plateau. Daily weights were obtained remotely via electronic scale from 62 adults with obesity (73% female, mean age 42±11 y and BMI 37±5 kg/m2) undergoing a 24-week ILI. Periods (≥14 d) of active weight loss or plateau were identified by threshold regression modeling. Active weight loss was defined as a per day % weight change from baseline equivalent to ≥0.5 lb loss/wk and a weight loss plateau as ±0.25lbs/wk after a period of active weight loss (in which ≥3.5% weight loss was achieved). Three unannounced self-reported ASA24 dietary recalls were obtained at baseline and 3 mo. Diet quality was assessed by the healthy eating index (HEI)-2015. 53% reached a plateau after active weight loss (27% did not achieve &gt;3.5% weight loss, 19% re-gained directly after loss). Weight loss (i.e., plateau depth) was associated with longer time to plateau (β=–10d, P&lt;0.01). Higher baseline diet quality (total HEI) was associated with shorter time to plateau (β=–2.6d, P=0.03), but not overall depth of plateau (β=0.1%, P=0.28). Specifically, shorter time to plateau was related to lower baseline consumption of saturated fats (β=–15d, P=0.01) and greater plateau depth was related to lower baseline consumption of added sugars (β=1.3%, P=0.04). Mean diet quality improved minimally during ILI (ΔHEI 1.9±2.2). Lower baseline HEI correlated with greater improvement in diet quality at 3 mo (β=–0.5, P&lt;0.001, N=46), but ΔHEI did not associate with any plateau characteristics (time: β=1.1d, P=0.15; depth: β=–0.1%, P=0.16, N=25). Higher diet quality upon entry into an ILI predicted a shorter duration of weight loss prior to reaching a plateau, suggesting that individuals with healthy eating patterns may derive less sustained weight loss benefit from participation in an ILI.

Disclosure
S.J.Melhorn: None. L.E.Sewaybricker: None. H.Gao: None. M.De leon: None. M.Webb: None. M.Lyle: None. S.J.Beatty: None. M.Kratz: Other Relationship; Nourished by Science LLC. E.Schur: None.

Funding
National Institutes of Health (DK089036, DK1176223, K24HL144917); University of Washington (NORC, DK035816)
1717-P: Weight-Loss Differences with SGLT2 inhibitors, GLP-1 Receptor Agonists, and Repetitive Transcranial Magnetic Stimulation in Type 2 Diabetes and Obesity
Authors: FERRULLI ANNA , MASSARINI STEFANO , MACRÌ CONCETTA , SENESI PAMELA , TERRUZZI ILEANA , CANNAVARO DANIELE , LUZI LIVIO 
Published: June 2023

Weight loss in individuals with obesity (O) and type 2 diabetes (T2D) may improve glycemic control, prevent obesity-related comorbidities and, in some cases, induce remission of T2D. Glucose-lowering drugs such as SGLT2i and GLP-1 RAs are able to control simultaneously body weight and glucose levels; their use is recommended in individuals with O and T2D. Recently, we have demonstrated the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in promoting weight loss up to 1 year in individuals with O, with and without T2D. The aim of this retrospective comparative study was to compare the efficacy of SGLT2i, GLP1-RA and rTMS in reducing body weight in the long term in patients with O and T2D. Data obtained from 31 patients with O and T2D were retrospectively analyzed: 11 were treated for O with high frequency rTMS for 5 weeks, 8 subjects were treated for T2D with SGLT2i for 1 year, and 12 individuals were treated for T2D with GLP1-RA for 1 year. Changes in body weight and HbA1c in the 3 groups were analyzed with ANOVA, after 6 months (FU1) and 1 year (FU2) from the beginning of the treatment. The change in body weight between the 3 groups was significant at both FU1 [−3.2±1.8% (SGLT2i) vs −3.5%±1.5% (GLP1-RA) vs −6.3±4.0% (rTMS);p=0.026] and FU2 [−2.1±2.1% (SGLT2i) vs −2.1±4.2% (GLP1-RA) vs −6.7±4.7% (rTMS); p=0.017]. Glycated hemoglobin variation was higher in the SGLT2i and GLP-1 RA groups than in rTMS at FU1 [−11.7±25.1% (SGLT2i) vs −11.9%±13.2% (GLP1-RA) vs −8.9±10.4% (rTMS)] and at FU2 [−15.9±24.2% (SGLT2i) vs −7.8±11.9% (GLP1-RA) vs −5.6±9.0% (rTMS)], although not statistically significant. TMS was found to be more effective than SGLT2i and GLP1-RAs in promoting long-term weight loss in a population with O and T2D, likely due to a prevalent effect of rTMS on appetite control at the meso-cortico-limbic system’s level. These findings set the stage for a potential combined use of rTMS with SGLT2i or GLP1-RAs in treatment of O and T2D.

Disclosure
A.Ferrulli: None. S.Massarini: None. C.Macrì: None. P.Senesi: None. I.Terruzzi: None. D.Cannavaro: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis.

Funding
IRCCS MultiMedica (Ricerca Corrente)
1719-P: Nomogram for Predicting Remission of Metabolic Syndrome One Year after Sleeve Gastrectomy Surgery in Chinese Patients with Obesity
Authors: PAN YUNHUI , HAN XIAODONG , TU YINFANG , ZHANG PIN , YU HAOYONG , BAO YUQIAN 
Published: June 2023

Background: Sleeve gastrectomy (SG) is a widely used and effective treatment for patients with obesity and comorbid metabolic abnormalities. No specialized tool is available to predict metabolic syndrome (MS) remission after SG. We aimed to present a nomogram that evaluated the probability of MS remission 1 year after SG.
Methods: Patients who underwent SG were enrolled. Of these patients, those with baseline MS were analyzed at the end of follow-up. They were divided into a training set and a validation set. Multivariate logistic regression analysis was performed to identify independent predictors of MS remission 1 year after SG, and these predictors were employed to create a nomogram. Receiver operating characteristic (ROC) curve analysis was used to evaluate discrimination ability. Calibration was performed with the Hosmer-Lemeshow goodness-of-fit test. The net benefits of the nomogram were evaluated using decision curve analysis (DCA).
Results: Three hundred and eighteen patients (94 males and 224 females) with a median age of 34.0 years were analyzed at the end of follow-up. They were divided into a training set and a validation set with 159 individuals each. A combination of age, preoperative high-density lipoprotein cholesterol (HDL-c), presence of elevated triglycerides (TG) and the glycated hemoglobin (HbA1c) level independently and accurately predicted MS remission. The nomogram included all four factors. The model showed moderate discrimination in the training and validation sets (Area under curve 0.800 and 0.727, respectively). The Hosmer-Lemeshow X2 values of the nomogram were 8.477 (P=0.388) for the training set and 5.361 (P=0.718) for the validation set, both indicating good calibration. Moreover, DCA showed substantial clinical benefits of the nomogram in both datasets.
Conclusions: Our simple nomogram could assist in predicting MS remission in Chinese patients with obesity 1 year after SG.

Disclosure
Y.Pan: None. X.Han: None. Y.Tu: None. P.Zhang: None. H.Yu: None. Y.Bao: None.

Funding
Clinical Research Plan of SHDC (2020CR1017B)
1724-P: Caspase 3/7 Activation and RIPK3 Are Dispensable for Synthetic hIAPP-Induced ß-Cell Death
Authors: MUKHERJEE NOYONIKA , CONTRERAS CHRISTOPHER J. , LIN LI , CAI ERICA P. , KAHN STEVEN E. , TEMPLIN ANDREW T. 
Published: June 2023

Islet amyloid is a hallmark of type 2 diabetes that is associated with β-cell loss. Aggregation of the β-cell secretory product human islet amyloid polypeptide (hIAPP) to form islet amyloid promotes β-cell death 1) via direct effects on the β cell and 2) by stimulating islet immune cell cytokine production. We recently showed that β cells are susceptible to TNFα-induced necroptosis, a form of caspase-independent, receptor interacting protein kinase 3 (RIPK3)-mediated cell death. We hypothesized that RIPK3 also promotes β-cell death in response to islet amyloid formation. To test this hypothesis, we evaluated INS-1, NIT-1 and isolated mouse islet cells treated with synthetic hIAPP (20 μM) +/− the pan-caspase inhibitor zVAD (40 μM). We found synthetic hIAPP increased cell death and caspase activity in INS-1, NIT-1 and mouse islet cells over 48 h. Remarkably, inhibition of caspases with zVAD (as measured by caspase 3/7 activity) failed to reduce synthetic hIAPP-mediated cell death in INS-1 (n=3, p=0.99), NIT-1 (n=3, p=0.99) or mouse islet cells (n=4, p=0.98). To evaluate RIPK3 in hIAPP-induced β-cell death, we examined a small molecule RIPK3 inhibitor (GSK’872, 5 μM), gene-edited NIT-1 Ripk3Δ cells (gRNA targeting exon 6), and intact isolated Ripk3−/− mouse islets. We found GSK’872 failed to protect INS-1 (n=3, p=0.32) or NIT-1 (n=3, p=0.30) cells from hIAPP-induced cell death over 48 h. Similarly, neither NIT-1 Ripk3Δ cells (n=2, hIAPP: p=0.82, hIAPP+zVAD: p=0.97) nor Ripk3−/− islets (n=4, hIAPP: p=0.63, hIAPP+zVAD: p=0.86) were protected from synthetic hIAPP-induced cell death either when caspases were active or inhibited. Our data indicate that caspase 3/7 activity and RIPK3 are dispensable for synthetic hIAPP-induced β-cell death in vitro. However, we found that RIPK3 is upregulated in response to endogenous islet amyloid formation in vitro. Future studies will determine whether RIPK3 promotes β-cell loss in part via effects on endogenous amyloid-induced cytokine signaling.

Disclosure
N.Mukherjee: None. C.J.Contreras: None. L.Lin: None. E.P.Cai: None. S.E.Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Other Relationship; Novo Nordisk. A.T.Templin: None.

Funding
U.S. Department of Veterans Affairs (IK2BX004659 to A.T.T.); National Institutes of Health (T32DK064466 to C.J.C.); Indiana University School of Medicine (to N.M.)
1727-P: Mitochondrial-Encoded Peptide MOTS-c Prevents Senescence-Induced Diabetes
Authors: KONG BYUNGSOO , HONG SERIN , MIN CHO YOUNG 
Published: June 2023

A polymorphism MOTS-c, a mitochondrial-derived miniprotein, was reported to be associated with longevity in humans. Previous reports showed that MOTS-c regulates senescence in cells, enhances physical capacity in old mice and in humans. However, it is still unknown how MOTS-c is able to intervene the cellular senescence, what tissue or cell-type MOTS-c targets, and whether the regulation of aging by MOTS-c can lead to the prevention of aging- or senescence-induced disorders. Here, using S961 (or senescence)-induced mouse model, we show that MOTS-c is capable of targeting pancreas and is able to prevent senescence-induced diabetes. To test how MOTS-c is associated with β cell senescence, we firstly assess whether β cell senescence is associated with MOTS-c expression using pancreatic β cells isolated from 12-week-old mice. After isolation, pancreatic β cells were treated with H2O2 in concentration-dependent manner. Treatment of H2O2 lowered MOTS-c expression in concentration-dependent manner, but increased other senescence-related markers such as β-gal expression. Furthermore, MOTS-c treatment decreased H2O2-induced senescence-associated β-gal expression and SASPs (i.e., IL-1). To understand the inhibitory effect of MOTS-c against β cell senescence in vivo, we have transplanted S961-osmotic pump in 28-week-old mice with or without MOTS-c for 2 weeks. Mice treated with MOTS-c showed lowered random glucose level (310 mg/dL versus 180 mg/dL) and decreased level of pancreatic β-gal expression compared to S961-treated mice. Also, an i.p. glucose tolerance test (IPGTT) in 30-week-old mice revealed that MOTS-c treatment significantly improved glucose clearance. As a result, we showed that senescence/S961-induced diabetes were inhibited by MOTS-c treatment.

Disclosure
B.Kong: None. S.Hong: None. Y.Cho: Consultant; LG Chem.

Funding
Ministry of Health & Welfare, Republic of Korea (HI14C1277)
1733-P: Evaluating the Role of Chd3 Helicase Subunit on ß-Cell Function
Authors: KANOJIA SUKRATI , OSMULSKI MEREDITH E. , DAVIDSON REBECCA K. , SPAETH JASON 
Published: June 2023

Evaluating the role of Chd3 helicase subunit on β-cell function
Pancreatic β-cells play a crucial role in maintaining whole-body glucose homeostasis by secreting insulin upon increased blood glucose levels. To develop effective therapies to combat hyperglycemia, it is of vital importance to understand how β-cells function normally and the mechanisms driving their dysfunction in settings of diabetes. Pdx1, an essential transcription factor involved in β-cell development and function, dynamically recruits coregulators to drive gene expression programs. Recently, Pdx1 was shown to interact with Chd4, a helicase of Nucleosome Remodeling and Deacetylase (NuRD) complex within pancreatic β-cells. Chd4 was found to regulate insulin secretion, modulate expression of β-cell functional genes by modifying chromatin accessibility. We discovered that Chd4 removal from mature β-cells (Chd4Δβ) increased Chd3 levels, an alternate Chd subunit of the NuRD complex. This led us to evaluate whether Chd3 alone plays a role in β-cell function and/or does it compensate in absence of Chd4. To investigate this possibility, we generated tamoxifen inducible, β-cell-specific Chd3 (Chd3Δβ) and Chd3/Chd4 double knockout (Chd3/4Δβ) mouse models. Whereas 4-weeks following Chd3 removal, Chd3Δβ mice did not display glucose intolerance, the Chd3/4Δβ mutants were profoundly glucose intolerant with elevated ad libitum fed blood glucose levels and near complete loss of insulin secretion in response to glucose, a phenotype much more severe than Chd4Δβ mutants previously characterized. This data suggests Chd3 plays a pertinent role in the absence of Chd4 within the β-cell. Current efforts are focused on determining the insulin secretion capacity of Chd3/4Δβ islets and evaluating gene expression and chromatin accessibility of Chd3/Chd4Δβ β-cells.

Disclosure
S.Kanojia: None. M.E.Osmulski: None. R.K.Davidson: Employee; Eli Lilly and Company. J.Spaeth: None.

Funding
National Institutes of Health (DK129287)
174-OR: Identification of Gestational Diabetes (GDM) Subtypes via Machine Learning and Associations with Perinatal Complications
Authors: ZHU YEYI , HARVILL RACHEL , GREENBERG MARA , NGO AMANDA , LIAO LAUREN D. , CHEHAB RANA F. , FERRARA ASSIAMIRA 
Published: June 2023

There has been increasing recognition of GDM heterogeneity. We aimed to identify GDM subtypes using 45 variables from the electronic health records via Uniform Manifold Approximation and Projection and Density-Based Spatial Clustering of Applications with Noise, and assess associations with risk of perinatal complications via logistic regression. Since risk factors for GDM and complications were used to identify subtypes, association between subtypes and complications were not adjusted. In a cohort study of 37,561 racially and ethnically diverse individuals with GDM in 2011-2021, we split the sample into training/validation (70%/30%) sets. In the training set, 4 clusters (C) were identified. C1 (14.4%) and C2 (7.8%) were more likely to have early GDM diagnosed by Carpenter-Coustan criteria, pre-existing conditions (hypertension, prediabetes, polycystic ovary syndrome, and obesity), and to be older and multiparous, compared to C3 (65.7%) and C4 (12.1%; Table). Compared to C3 as the mildest and most common subtype, C2 and C4 had higher risk of preeclampsia/eclampsia, C2 had higher risk of placental abruption, and C1, C2, and C4 had higher risk of preterm birth, large for gestational age, and neonatal intensive care unit admission. Findings were confirmed in the validation set. Subtyping GDM may inform personalized risk assessment and management to improve perinatal outcomes.

Disclosure
Y.Zhu: None. R.Harvill: None. M.Greenberg: None. A.Ngo: None. L.D.Liao: None. R.F.Chehab: None. A.Ferrara: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK120807); National Heart, Lung, and Blood Institute (R01HL157666)
1741-P: Placental Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Regulate Offspring Glucose Homeostasis and Insulin Sensitivity
Authors: BEETCH MEGAN , ALEJANDRO EMILYN 
Published: June 2023

Maternal hyperinsulinemia, often underlying pregnancies complicated by obesity and gestational diabetes, is associated with impaired placental insulin signaling, yet the consequences of altered placental insulin action on the metabolic health trajectory of the offspring remains unclear. Insulin binds to the insulin receptor (IR) and to the insulin-like growth factor receptor 1 (IGF1R). We reported that IR ablation in placental trophoblast cells mildly improved glucose homeostasis in adult male offspring when metabolically challenged by a high-fat diet. The current study examines metabolic phenotypes of offspring that experienced placental IGF1R knockout (IGF1RKO) or double IGF1R/IR knockout (DKO) in utero. We report that male IGF1RKO offspring have a decrease in body weight at embryonic day 17.5 but no differences in placenta weight. After weaning and throughout adulthood, no body weight differences were observed in male or female offspring. At 16 weeks of normal chow diet (NCD), random blood glucose was decreased in female IGF1RKO offspring but increased in male IGF1RKO offspring compared to respective littermate controls. Interestingly, these opposite changes in glycemia corresponded with reciprocal pancreas weights, prompting our investigation of beta-cell and alpha-cell mass and function. Glucose tolerance tests revealed improved glucose tolerance in IGF1RKO male offspring at 20 weeks NCD. Insulin tolerance tests have demonstrated comparable insulin sensitivity in IGF1RKO offspring of both sexes. In contrast, DKO offspring display reduced body weights at post-natal days 7 and 21. At 12 weeks of NCD, DKO females were significantly more insulin sensitive than littermate controls but had comparable glucose tolerance and body weights across adulthood. DKO males did not display glucose or insulin intolerance. Together, findings from these models suggest a need for further investigation of insulin action during pregnancy.

Disclosure
M.Beetch: None. E.Alejandro: None.

Funding
National Institutes of Health (T32DK007203, T32DK083250)
1745-P: Voltage-Gated K+ Channel Kv7.1 Is an Important Regulator of Insulin Secretion in Normal and Hyperinsulinemic Islets
Authors: JULIANA CHRISTINE , DE LEON DIVA 
Published: June 2023

Fifty percent of infants with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome caused by genetic / epigenetic abnormalities in imprinted genes on chromosome 11p15, have persistent hypoglycemia due to hyperinsulinism (BWS-HI). BWS-HI islets exhibit increased baseline and glucose-stimulated insulin secretion (GSIS) and are responsive to the KATP channel inhibitor glyburide, suggesting it is not caused by impaired KATP channels. KCNQ1 expression, encoding the pore-forming α subunit of voltage-gated K+ channel Kv7.1, is reduced in BWS-HI islets compared to normal islets (3-fold; p = 4.5×10−7) and KCNQ1 loss-of-function mutations in humans are associated with HI. We used genetic and pharmacologic methods to modify Kv7.1 activity and examined changes to insulin secretion. In response to glucose, Kcnq1−/− mice had lower plasma glucose and higher plasma insulin than wild-type controls. Perifusion of Kcnq1−/− pancreatic islets with increasing concentrations of glucose showed that GSIS in these islets was faster and greater than in wild-type islets. The perifusion GSIS responses in normal human, wild-type mouse and Sur1−/− mouse (KATP-HI mouse model) islets with two different Kv7.1 activators (hexachlorophene or ML277) were markedly slower and diminished. In contrast, wild-type mouse islet perifusion with the Kv7.1 inhibitor chromanol 293B strikingly fastened and increased the GSIS response compared to vehicle controls. Membrane potential (Vm) analysis of Kcnq1−/− islets demonstrated that depolarization occurs more quickly during the initiation of insulin secretion compared to wild-type controls. Treatment with Kv7.1 activators resulted in Vm changes in both wild-type mouse and normal human islets compared to controls. Our results reveal the capacity of Kv7.1 to regulate insulin secretion in pancreatic islets and that Kv7.1 is a viable target for development of therapeutics for HI.

Disclosure
C.Juliana: Research Support; Crinetics Pharmaceuticals, Inc., Twist Bioscience, AmideBio. D.De leon: Consultant; Zealand Pharma A/S, Crinetics Pharmaceuticals, Inc., Eiger BioPharmaceuticals, Hanmi Pharm. Co., Ltd., Research Support; Ultragenix, Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Rezolute, Inc.

Funding
National Institutes of Health (5R01DK098517-08)
1749-P: Influence of the Biomechanical Environment on Islet Function and Maturity
Authors: VAZQUEZ KELLY , BENNINGER RICHARD K. 
Published: June 2023

It is well-established that cells respond to mechanical cues via cytoskeletal remodeling. However, it is not known whether the mechanical environment influences β-cell maturity and function. To examine how mechanical cues influence the β-cell, we used biocompatible substrates with tunable mechanical properties synthesized with elastic moduli ranging from ~3kPa-33 kPa. The surface was coated with extracellular matrix and MIN6 β-like cells were seeded. To independently examine a link between β-cell function and maturity, we examined islets from mice in which β-cells express CaMPARI, a photoconvertible fluorescent protein that in the presence of high Ca2+ activity changes from green to red. For all conditions in MIN6 cells and CAMPARI-expressing islets, we imaged Ca2+ dynamics via Fluo4 at low (2mM) and high glucose (11, 20mM). qPCR was conducted on MIN6 cells (6, 22 kPa) and flow-sorted CaMPARI-expressing β-cells (green, red) to examine expression of genes linked to β-cell function and maturity. With increased substrate stiffness, MIN6 cell Ca2+ oscillations were more robust, including a significant increase in duty cycle (p&lt;0.01) and were more coordinated, consistent with increased excitability. With increasing stiffness, there was significantly decreased expression of Sur1, Kir6.2, Ins2, Pdx1, Fltp, and Ecad (p&lt;0.01). Thus, the dynamics and coordination of Ca2+ activity is mechanoresponsive and may result from altered β-cell maturity. In CaMPARI islets, Ca2+ oscillations were more robust and coordinated for photo-converted red cells which marks cells with higher Ca2+, compared to green cells. In these red cells that show higher Ca2+, qPCR showed significantly increased expression of cFos, but decreased expression of Pdx1 and Ins2, again showing more excitable cells showed altered maturity. In conclusion, our results suggest there may be an inverse relationship between β-cell maturity and function. Further, that the maturity and function of β-cells is responsive to the mechanical environment.

Disclosure
K.Vazquez: None. R.K.Benninger: None.

Funding
National Institutes of Health (R01DK102950, R01DK106412)