bluuebunny/crossref_metadata_2025_split huggingface dataset:
308-OR: Hippo-YAP/TAZ Signaling Coordinates Adipose Plasticity and Energy Balance by Uncoupling Leptin Expression from Fat Mass
Authors: CHOI SUNGWOO , PARK KUN-YOUNG , SHIN HYEMI , MYOUNG SUH JAE 
Published: June 2023

Adipose tissue regulates systemic energy homeostasis by acting as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the underlying mechanisms are unknown. Here we show that the transcriptional coregulators YAP and TAZ mediate the crosstalk between adipose tissue mass and leptin levels to maintain systemic energy balance. The activation of adipocyte-specific YAP/TAZ via genetic ablation of the upstream regulators LATS1 and LATS2 resulted in a profound reduction in fat mass due to the conversion of mature adipocytes into delipidated cells with progenitor-like features. Rosiglitazone treatment normalized fat mass, indicating that PPARG inhibition is a major contributor to YAP/TAZ-induced lipoatrophy. Surprisingly, LATS1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction. This phenotype was attributed to a paradoxical increase in circulating leptin levels, which was found to offset the energy storage deficit by increasing fat oxidation and energy expenditure. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by direct binding to an upstream enhancer site of the leptin gene. Finally, we show that YAP/TAZ activity is associated with leptin regulation during fasting and refeeding, indicating that YAP/TAZ links nutrient status in adipose tissue to systemic energy homeostasis. Taken together, we reveal that adipocyte Hippo-YAP/TAZ functions as a nexus for coordinating nutrient storage capacity and systemic energy balance by regulating adipocyte plasticity and leptin gene transcription.

Disclosure
S.Choi: None. K.Park: None. H.Shin: None. J.Suh: None.
309-OR: Adipose RNA N6-Methyladenosine (m6A) Modification Promotes Obesity and Insulin Resistance through Suppressing Lipolysis
Authors: KANG QIANQIAN , RUI LIANGYOU , REN DECHENG 
Published: June 2023

Excessive white adipose tissue (WAT) promotes insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obesity; however, the WAT expansion mechanism remains poorly understood. We reported that WAT lipolysis is suppressed in obesity, likely contributing to WAT growth. Adipose triglyceride lipase (Atgl) catalyzes the lipolysis reaction, and its lipolytic activity is increased by phosphorylation and binding to cofactor Cgi58. The sympathetic nervous system activates adipocyte β adrenergic receptor (Adrb)/cAMP/PKA pathway to stimulate lipolysis via Atgl and Cgi58. In this study, we have identified a novel m6A modification of Adrb, Atgl, and Cgi58 transcripts that promotes obesity and metabolic disorders. We found that obesity was associated with increased expression of adipose Mettl3 and Mettl14 and elevated m6A levels in WAT. Mettl14 directly binds to Mettl3 to form a methyltransferase complex that catalyzes m6A on RNA. Insulin also increased Mettl14 expression and m6A levels in adipocytes. We generated adipocyte-specific Mettl14 knockout mice (Mettl14 Δfat) and placed mice on a high fat diet (HFD). Remarkably, Mettl14 Δfat mice, both males and females, were resistant to HFD-induced obesity, insulin resistance, and NAFLD. Adipose Adrb2/3, Atgl, and Cgi58 protein levels were significantly upregulated in Mettl14 Δfat mice and consequently, adipose β adrenergic signaling and lipolysis were significantly higher in Mettl14 Δfat than in Mettl14f/f mice. Mettl14 deficiency dramatically decreased the m6A content of Adrb2/3, Atgl, and Cgi58 transcripts in WAT; strikingly, m6A inhibition markedly increased translational rates of these transcripts in adipocytes. Collectively, these results unravel a previously unrecognized adipose Mettl14/m6A/translation axis that promotes obesity, insulin resistance, and NAFLD by suppressing adipose β adrenergic signaling, lipolysis, and fatty acid oxidation.

Disclosure
Q.Kang: None. L.Rui: None. D.Ren: None.

Funding
National Institutes of Health (R01DK130111)
31-LB: The Relationship between Improvements in Glycemic Control following a Digital Health Intervention and the Food Environment in a Medicare Advantage Population
Authors: EDWARDS CAITLYN , VOELKER LOUISE , ZIMMERMANN GRETCHEN , RAWLINGS KELLY , VENKATESAN AARATHI 
Published: June 2023

Diabetes is a complex disease that is influenced by social determinants of health (SDOH). An inadequate food environment, as a function of socioeconomic status and proximity to food retailers, has been associated with both increased prevalence of diabetes and barriers to diabetes self-management. This work examined the relationship between improvements in glycemic control as a result of a digital health intervention and the food environment in Medicare Advantage members at risk for diabetes-related complications (hemoglobin A1c [A1c] ≥ 8%). Participants enrolled in the Vida Health Diabetes Management program as part of their medical insurance benefit and utilized remote sessions with Registered Dietitians and Certified Diabetes Care and Education Specialists as well as content related to goal-setting to account for SDOH factors. The 2010 USDA Food Access Research Atlas was used to identify areas of low income and the absence of a food retailer within 0.5 or 1 urban and 10 rural miles (LILA). Participants were included if they had a laboratory A1c between -365 to -1 and 60 to 365-days of enrollment. Participants with baseline A1c ≥ 8.0 (n=430, 229 F, 68.9 y) demonstrated a decrease of -0.90 points (SD 1.71, p&lt;0.001). Thirty-five percent resided in LILA areas at the 0.5, and twenty percent at 1 mile distance. Participants who resided in LILA areas had higher baseline A1c (0.5 difference: 0.37 (p=0.02), 1 difference: 0.51 (p=0.005)). Those with baseline A1c ≥ 9.0 (n=216, 120 F, 67.8 y) demonstrated a decrease of -1.38 points (SD 1.96, p&lt;0.001). Thirty-nine percent resided in LILA areas at the 0.5, and twenty-three percent at 1 mile distance. Baseline A1c differences were not observed. Differences in improvements in A1c based on LILA were not observed (p’s &gt; 0.05). Irrespective of LILA residence, the Vida Health program demonstrated significant improvements in glycemic control within 1 year in a high-risk Medicare Advantage population.

Disclosure
C. Edwards: Employee; Vida Health. L. Voelker: Employee; Vida Health. G. Zimmermann: Employee; Vida Health. K. Rawlings: Employee; Vida Health. A. Venkatesan: Employee; Vida Health.

Funding
Vida Health
31-OR: Sex-Specific Differences in Subcutaneous Adipose Tissue in Persons with HIV May Contribute to Diabetes Risk
Authors: BAILIN SAMUEL , MASHAYEKHI MONA , GABRIEL CURTIS L. , HANNAH LATOYA , KALAMS SPYROS , MALLAL SIMON A. , KROPSKI JONATHAN A. , WANJALLA CELESTINE N. , KOETHE JOHN 
Published: June 2023

Background: Men with HIV have greater visceral adipose tissue (VAT) accumulation compared to women, which contributes to insulin resistance and derives, in part, from a failure to sequester lipids in subcutaneous adipose tissue (SAT). We assessed whether sex-specific differences in SAT composition are associated with measures of VAT volume and insulin resistance.
Methods: Adults with HIV and consistent viral suppression on antiretroviral therapy had SAT and VAT measured by CT imaging, HOMA2-IR using fasting plasma glucose and insulin, and a subset had abdominal SAT lipoaspirates for single-cell RNA-sequencing to define proportions of CD4 and CD8 T effector memory cells (TEM), perivascular (PVM) and intermediate (IM) macrophages, and fibroblasts. Adjusted ordinal regression models and partial Spearman’s assessed the interaction between sex and cell proportions.
Results: We enrolled 111 participants (24% female) with a median age of 48 years, BMI of 31.5 kg/m2, and HOMA2-IR of 3.0. VAT volume was significantly associated with HOMA2-IR. Women had lower VAT volumes and higher proportions of SAT PVMs and lower IMs, as well as fewer cytotoxic CD4 and CD8 T cells compared with men (p ≤ 0.05 for all). The proportions of SAT CD4 TEM, CD8 TEM, myofibroblasts, MYOC fibroblasts, and IMs were associated with VAT volume (p ≤ 0.05 for all), but an interaction by sex was not observed. The proportions of CD4 and CD8 TEM cells were significantly associated with HOMA2-IR and there was evidence of an interaction by sex status (interaction term p = 0.09 & p = 0.06, respectively).
Conclusions: Women with HIV have a greater adjusted proportion of PVMs and lower cytotoxic CD4 and CD8 T cells in SAT. While the relationship between immune cell proportions and HOMA-IR only appeared to differ for CD4 and CD8 TEM cells, lower ectopic fat deposition in the context of reduced SAT inflammatory cells in women suggests the sex difference in diabetes risk among persons with HIV may relate to adipose tissue cellular composition.

Disclosure
S.Bailin: None. M.Mashayekhi: None. C.L.Gabriel: None. L.Hannah: None. S.Kalams: None. S.A.Mallal: None. J.A.Kropski: Advisory Panel; APIE Therapeutics, Research Support; Boehringer Ingelheim Inc., Bristol-Myers Squibb Company, Genentech, Inc. C.N.Wanjalla: None. J.Koethe: Advisory Panel; Merck Sharp & Dohme Corp., Janssen Pharmaceuticals, Inc., Gilead Sciences, Inc., Theratechnologies, Research Support; Merck Sharp & Dohme Corp.

Funding
National Institutes of Health (R01DK112262, UL1RR024975, T32AI007474, P30AI110527)
312-OR: Effect of Nutritional Ketosis Trajectory on Change in Glycemia, Weight, and Atherogenic Dyslipidemia over Two Years in People with Type 2 Diabetes
Authors: MCKENZIE AMY L. , ATHINARAYANAN SHAMINIE J. , ROBERTS CAROLINE G.P. , ADAMS REBECCA N. , VOLK BRITTANIE M. , PHINNEY STEPHEN D. , VOLEK JEFF 
Published: June 2023

A very low carbohydrate diet with nutritional ketosis (NK) improves HbA1c, weight, and atherogenic dyslipidemia in people with type 2 diabetes (T2D), but effects of degree and duration of NK sustained on outcomes are unknown. Hemoglobin A1c, weight, triglycerides, and HDL-C among people with T2D who received a NK intervention via continuous telemedicine care (CC; n=262) or usual care without carbohydrate restriction (UC; n=87) over two years were assessed. Latent class trajectory modeling identified four ketosis trajectory groups within the CC. Annual change in these markers were compared among the CC groups and UC as reference using a linear mixed effects model. A dose-response relationship between the concentration of blood ketones (proxy for degree of carbohydrate restriction) and duration of NK maintenance was observed (Table 1), where the group with sustained NK of ~1mM maintained the greatest improvements. Changes in weight and HbA1c were observed with low NK (0.3-0.4mM), though continued improvements in atherogenic dyslipidemia required greater degrees of sustained NK (~0.7 followed by 0.5mM). These results inform clinical practice, showing that improvement in HbA1c and weight can occur with modest NK, though greater and broader improvements occur with moderate NK of ~0.7-0.5mM, and optimal outcomes occur with consistently sustained NK of ~1mM.

Disclosure
A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.D.Phinney: Board Member; Virta Health Corp., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. J.Volek: Stock/Shareholder; Virta Health Corp.

Funding
Virta Health
326-OR: Rod Photoreceptor Contribution to Inflammation and Angiogenesis in Diabetic Retinopathy
Authors: DE LA HUERTA IRINA , POLOWAY JACOB M. , REDDY VARUN , PENN JOHN S. 
Published: June 2023

Purpose: Rod photoreceptors (rods) are the most numerous and metabolically active retinal cells, and are susceptible to metabolic stress in response to hyperglycemia. Yet the role of rods in diabetic retinopathy (DR) is controversial. This study aims to investigate if rods exposed to high glucose can trigger inflammatory and angiogenic responses in Müller glia (MG) and retinal microvascular endothelial cells (RMEC).
Methods: The streptozocin-induced (STZ) model was used at 10 weeks of diabetes. Transcriptomic shifts in rods were analyzed by RNAseq. The mediators produced by rods were analyzed by multiplex ELISA. The effect of rod-produced mediators on RMEC permeability was assessed. Angiogenic responses of RMECs treated with rod-produced mediators were evaluated by proliferation, migration, and tube formation assays. The effect of rods on proangiogenic mediator production by RMECs and MG was evaluated by western blot.
Results: Diabetes induced upregulation of transcripts for tnf (3-fold, P=0.006) and il1a (2.2-fold, P=0.001) in rods. Primary rod cultures treated with 25 mM D-glucose (high glucose) produced increased levels of VEGF (2.5-fold, p&lt;0.05), TNF-α (2.4-fold, p&lt;0.05), and IL-6 (2-fold, p&lt;0.05) compared to rods treated with 5 mM D-glucose (normal glucose), or with 25 mM L-glucose (osmotic control). The mediators produced by rods treated with high glucose elicited increased RMEC proliferation (2.5 fold, p&lt;0.001), RMEC migration (2-fold, p&lt;0.001), and RMEC tube lengths (1.9-fold, p&lt;0.001). The rod-produced mediators induced RMEC secretion of matrix metalloproteinase 2 (MMP-2) (8-fold increase, p&lt;0.001) and of MMP-9 (5-fold increase, p&lt;0.001). MG treated with rod-produced mediators increased their production of VEGF (4-fold, p&lt;0.001) and of MMP-9 (5-fold, p&lt;0.001).
Conclusion: Rods in hyperglycemic conditions produce mediators that increase RMEC permeability, proliferation, migration, and branching and induce a proangiogenic secretory shift in RMEC and MG.

Disclosure
I.De la huerta: None. J.M.Poloway: None. V.Reddy: None. J.S.Penn: None.

Funding
National Institutes of Health (K08EY032620); International Retinal Research Foundation; Knights Templar Eye Foundation
331-OR: Fasting Metabolic Flexibility in Prediabetes
Authors: FOPPIANI ANDREA , DE AMICIS RAMONA , LEONE ALESSANDRO , BERTOLI SIMONA , BATTEZZATI ALBERTO 
Published: June 2023

Metabolic flexibility cannot be easily clinically assessed, but the respiratory exchange ratio (RER) measured via indirect calorimetry can indicate substrate utilization. When indirect calorimetry is performed to measure resting metabolic rate, a normal RER should reflect a lipolytic metabolism (close to 0.7). We aimed to describe fasting glucose metabolism in relation to RER in patients seeking a nutritional intervention. In 10175 patients (7,222 (71%) females, median (quartiles) age of 46 (36, 55) years, and BMI of 28.3 (25.0, 32.3) kg/m2) a greater RER was associated with higher fasting values of glucose, insulin and higher insulin resistance (HOMA-IR), controlling for sex, age, and BMI (differences going from a RER of 0.7 to 1 RER for glucose 1.7 (95% CI 0.66, 2.8; p=0.002), for insulin 1.9 (95% CI 1.3, 2.6; p=&lt;0.001), and for HOMA-IR 0.49 (95% CI 0.32, 0.66; p=&lt;0.001)). As an higher RER relates to an altered glucose metabolism, within the whole sample we selected patients with prediabetes with 1 year follow-up. We matched 86 patients having either a RER indicating a lipolytic metabolism (&lt;0.775) or glycolytic metabolism (&gt;0.925). Patients were matched for sex, age, BMI, waist circumference, and arm muscle area. The high RER group had a lower probability of normalizing fasting glucose level within 1 year (log(OR) -0.89 (95% CI -1.8, -0.03; p=0.046)), with higher fasting glucose levels at followup (5.4 (95% CI 0.98, 9.9; p=0.017)). Moreover, while losing similar weight than the low RER group (-0.55 (95% CI -3.7, 2.6; p=0.7)), they lost a lower amount of fat mass (1.2 (95% CI 0.02, 2.4; p=0.047)). Our results suggest than an higher RER relates to a dysfunctional glycolytic metabolism at rest. We also show that prediabetic patients with higher RER are more likely to not respond to a lifestyle intervention, warranting a more intensive treatment for this subgroup. This lower probability of success doesn’t seem related to a lower adherence to the proscription, as weight loss was similar across RER categories, but to a lower weight loss quality.

Disclosure
A.Foppiani: None. R.De amicis: None. A.Leone: None. S.Bertoli: None. A.Battezzati: None.

Funding
Italian National Recovery and Resilience Plan Mission 4 Component 2 Investment 1.3 - Call for Proposals (341) of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU (PE00000003) Concession Decree (1550) of 11 October 2022 adopted by the Italian Ministry of University and Research (CUP D93C22000890001)
334-OR: Implementation of a Modified Diabetes Prevention Program in WIC Clinics—A Pilot Study
Authors: DORANS KIRSTEN S. , SCHULTHEIS MARY E. , BRIDGEFORTH CELIA , ALVARADO FLOR , DANDRIDGE ERIN , DOBSON TARA , HE JIANG , MARTIN COURTNEY , MILLS KATHERINE T. , SALLES MARTINA M. , SCHOONENBERG BROOKE , UWAIFO GABRIEL I. , BAZZANO ALESSANDRA N. , HARVILLE EMILY 
Published: June 2023

Background: The aim of this study was to pilot implementation of a postpartum 8-week Diabetes Prevention Program (DPP)-like intervention in Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinics.
Methods: Participants had gestational diabetes mellitus in their most recent pregnancy, delivered 6 weeks-12 months prior to recruitment, and used WIC services in the New Orleans region. The following implementation strategies were tested: partnership with and buy-in from WIC, intervention tailoring, variety of health coaches, and combining in-person and online delivery with tracking tools.
Results: We enrolled 20 women; 18 completed the study. Health coaches delivering the intervention included a community dietitian, a WIC nutritionist, and a WIC health educator. Average participant age was 31.5 years, 55% of participants were Black and 30% were Hispanic/Latina. Session attendance was high and most participants liked the idea of joining a 1-year DPP program and thought it would be feasible (Table). Average 2-month changes in clinical outcomes were -1.5 kg (95% CI: -3.9, 0.8 kg) for weight, 0.02% (95% CI: -0.10, 0.14%) for hemoglobin A1c, and -4.9 mg/dL (95% CI: -11.3, 1.4 mg/dL) for fasting glucose.
Conclusion: Based on these findings, we are conducting a cluster randomized trial to test different implementation strategies for delivering a 1-year postpartum DPP intervention in WIC clinics.

Disclosure
K.S.Dorans: None. M.M.Salles: None. B.Schoonenberg: None. G.I.Uwaifo: None. A.N.Bazzano: None. E.Harville: None. M.E.Schultheis: None. C.Bridgeforth: None. F.Alvarado: None. E.Dandridge: None. T.Dobson: None. J.He: None. C.Martin: None. K.T.Mills: None.

Funding
National Heart, Lung, and Blood Institute (OT2HL158287); National Institute of General Medical Sciences (P20GM109036)
341-OR: Association between Age at Diagnosis of Type 2 Diabetes and Subsequent Risk of Dementia and Its Major Subtypes
Authors: KIM YOUNGJOON , HEA SEO DA , KIM MINA , CHO YONGIN , HEE AHN SEONG , HONG SEONGBIN , HUN KIM SO 
Published: June 2023

Objectives: Type 2 diabetes mellitus (T2DM) is recognized as a major contributor to cognitive decline and dementia in older adults but its importance for its contribution according to age at diagnosis of T2DM remains uncertain. We aimed to investigate the association between dementia and its subtypes in relation to the age at diagnosis of T2DM.
Research design and methods: In a population cohort study with the Korean National Health Insurance Service data (2012-2014), a total of 612,201 patients with newly diagnosed T2DM were included. Controls were randomly selected from the general population and matched with a 1:2 ratio based on the propensity score. Participants were followed for until December, 2019. Outcomes of interest were all-cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD). The association of T2DM with dementia was stratified by baseline fasting glucose concentration in patients with T2DM. Cox regression was used to study the excess risk of outcomes.
Results: During 6.25 years follow-up, dementia developed in 66,186 patients with T2DM compared with 85,358 control subjects. Patients with T2DM diagnosed at ≤50 years had the highest excess risk for most outcomes relative to control with hazard ratio (HR) (95% CI) of 3.30 (3.11-3.50) for all-cause dementia, 4.08 (3.17-5.23) for AD, and 5.86 (3.87-8.88) for VD. All risks attenuated progressively with each increasing decade at diagnostic age but remained significant; for T2DM diagnosed at ≥80 years, the HR (95% CI) was 1.38 (1.34-1.41) for all-cause dementia, 1.36 (1.32-1.40) for AD, and 1.99 (1.71-2.31) for VD. When the analyses were stratified by fasting glucose concentration, a dose-response association was observed.
Conclusion: In this population-based cohort study, younger age at diagnosis of T2DM was associated with a higher risk of risk of both AD and VD. Physicians should closely monitor cognitive function in diabetic patients especially in those with young onset T2DM.

Disclosure
Y.Kim: None. D.Seo: None. M.Kim: None. Y.Cho: None. S.Ahn: None. S.Hong: None. S.Kim: None.
343-OR: Health Care Utilization in Older Adults with Diabetes and Dementia—Medical Expenditure Panel Survey (2000–2020)
Authors: DAWSON APRILL Z. , THORGERSON ABIGAIL , LINDE SEBASTIAN , WALKER REBEKAH J. , BHANDARI SANJAY , EGEDE LEONARD E. 
Published: June 2023

Adults with diabetes have two times the risk of developing dementia compared to adults without diabetes. The aim of this analysis was to determine the rates of healthcare utilization in older adults with diabetes and dementia.
Data representing 102,176,914 adults aged 50 and older from the Medical Expenditure Panel Survey (2000-2020) were used. Inpatient, outpatient, emergency, dental, pharmacy, home-health, and total medical visits were dependent variables. The primary independent variable had 4 categories: no diabetes or dementia, diabetes only, dementia only, comorbid diabetes and dementia (DD). Covariates included age, race/ethnicity, sex, marital status, education, region, poverty, comorbidities, and survey year. Unadjusted and fully adjusted negative binomial regression models were run. Analyses were conducted using Stata v17.0, and statistical significance was p-value&lt;0.05.
In fully adjusted models, those with diabetes only (IRR:1.48; 95%CI:1.45, 1.51), dementia only (IRR:1.58; 95%CI:1.48, 1.69), and DD (IRR:1.59; 95%CI:1.43, 1.78) had significantly greater rate of pharmacy visits compared to individuals without diabetes or dementia. In addition, those with dementia only and DD had significantly higher rate of inpatient [dementia: (IRR:2.02; 95%CI: 1.60, 2.54); DD (IRR:1.56; 95%CI:1.02, 2.38)], ED [dementia: (IRR:1.63; 95%CI:1.44, 1.84)], and home health visits [dementia: (IRR:14.90; 95%CI:7.74, 28.69); DD (IRR:7.38; 95%CI:3.55, 15.34)] compared to individuals without diabetes or dementia.
Adults aged 50 and older with comorbid diabetes and dementia have significantly higher rates of inpatient, pharmacy, and home health utilization compared to older adults with neither condition. In addition, having dementia is a key driver of healthcare utilization among adults aged 50 and older in the US.

Disclosure
A.Z.Dawson: None. A.Thorgerson: None. S.Linde: None. R.J.Walker: None. S.Bhandari: None. L.E.Egede: None.

Funding
American Diabetes Association (11-22-JDFHD-01 to A.Z.D.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118038, R01DK120861); National Institute on Minority Health and Health Disparities (R01MD013826)