bluuebunny/crossref_metadata_2025_split huggingface dataset:
333-OR: What Motivates People to Enroll in the National Diabetes Prevention Program Lifestyle Change Program
Authors: PAPALII MICHELLE , ELY ELIZABETH 
Published: June 2023

In 2021, the Centers for Disease Control and Prevention (CDC) began collecting data on what motivates people to enroll in the National Diabetes Prevention Program (National DPP) lifestyle change program (LCP). Upon enrolling in the LCP, participants are asked, “Who/what motivated you the most to sign up for this program?” Participants may choose health care professional, blood test results, prediabetes risk test, someone at a community-based organization (CBO), family/friends, current/past participant in the LCP, employer/employer’s wellness plan, health insurance plan, and media advertisements. By October 2022, these data had been collected on 128,116 eligible participants, of whom 25% reported that the prediabetes risk test motivated them the most, followed by their employer/employer’s wellness plan (23%), and health care professional (14%). Motivators were similar in men and women, with the prediabetes risk test and employer/employer’s wellness plan being the top 2 motivators. Across age groups, the prediabetes risk test and employer/employer’s wellness plan motivated adults aged 18-64 years the most, while health care professionals motivated individuals aged 65 years and over the most. Motivators varied across racial/ethnic groups, with family/friends, current/past participants, and someone at a CBO motivating some groups more than others. Though more participants were motivated by the prediabetes risk test, they did not stay in the program as long as those who were motivated by their employer/employer’s wellness plan, family/friends, or someone at a CBO (180 mean days vs. 278, 264, and 261 days, respectively). What might motivate participants to enroll in the LCP may not be what helps them stay in the program longer and may influence their risk reduction outcomes, including weight loss and engagement in physical activity. Understanding motivators can help organizations focus recruitment and enrollment efforts and support participants in achieving their goals.

Disclosure
M.Papalii: None. E.Ely: None.
337-OR: Hyperglycemia Lowers Lactate Clearance during Exercise in Type 1 Diabetes
Authors: ROMERES DAVIDE , YADAV YOGESH , RUCHI FNU , CARTER RICKEY , COBELLI CLAUDIO , BASU RITA , BASU ANANDA 
Published: June 2023

To determine the role of hyperglycemia on lactate metabolism during exercise in type 1 diabetes (T1D), we studied 7 T1D participants during two visits (EuLoI; euglycemia, low insulin; HyLoI: hyperglycemia, low insulin) in random order. 7 nondiabetic (ND) subjects were studied on one occasion (EuLoI). Lactate turnover was measured using [1-13C] lactate before, during and after 60 min of exercise at 65% VO2 max. While lactate clearance was lower (p=0.031) during exercise at HyLoI than EuLoI in T1D, it was not different between T1D and ND subjects at EuLoI (p=0.707). In contrast, rate of lactate appearance during exercise was not different between EuLoI vs. HyLoI in T1D (p=0.129), demonstrating that higher plasma lactate concentration during exercise in HyLoI (p&lt;0.001) was due to reduced lactate clearance in T1D. The results from this pilot study indicates that hyperglycemia modulates lactate metabolism during exercise by lowering lactate clearance in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner, in type 1 diabetes.

Disclosure
D.Romeres: None. Y.Yadav: None. F.Ruchi: None. R.Carter: None. C.Cobelli: None. R.Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A.Basu: None.

Funding
National Institutes of Health (DK29953 to R.B.), (DK85516 to A.B.)
34-LB: Effectiveness of Combination Use of a Lifestyle Improvement Support App and a Wearable Device on Glycemic Control in Japanese People with T2DM—STEP-DM
Authors: TAKAHASHI AKIKO , ISHII MANABU , KINO YURIKA , SASAKI KAZUYO , HASHIMOTO TAKAFUMI , MATSUI TAKAHIRO , ARAKAWA KENJI , KUNISAKI MAKOTO 
Published: June 2023

Despite the availability of various therapeutic agents for T2DM, about half of patients do not achieve their glycemic control targets in Japan. In recent years, apps and wearable devices supporting diabetes treatment have rapidly spread. However, evidence of their impact, especially in combination, is limited. This is the first study to explore the effectiveness of combination use of a lifestyle improvement support app (TOMOCOTM Mitsubishi Tanabe Pharma Co.) and a wearable device (Fitbit) in Japanese people with T2DM under insufficient glycemic control (jRCT1070220007).
Of 61 patients enrolled, 59 completed (HbA1c: 7.57 ± 0.42%, Body weight: 69.12 ± 13.36 kg; at baseline). The participants used TOMOCOTM and Fitbit in addition to conventional diet/exercise and antidiabetic drug therapy for 12 weeks, and were provided feedback/advice based on TOMOCOTM and Fitbit records from health care providers (Fig). At the end of the observation period, HbA1c was significantly decreased (-0.41 ± 0.41%; range -1.9 to 0.7, p&lt;0.001) and body weight was also reduced (-0.88 ± 1.58 kg; range -5.7 to 2.1, p&lt;0.001), and the trend was consistent across the pre-specified patient background.
In conclusion, combination use of a lifestyle improvement support app and a wearable device with conventional therapy may be effective for glycemic control in people with T2DM.

Disclosure
A. Takahashi: Employee; Mitsubishi Tanabe Pharma Corporation. M. Ishii: Employee; Mitsubishi Tanabe Pharma Corporation. Y. Kino: Employee; Mitsubishi Tanabe Pharma Corporation. K. Sasaki: Employee; Mitsubishi Tanabe Pharma Corporation. T. Hashimoto: Employee; Mitsubishi Tanabe Pharma Corporation. T. Matsui: Employee; Mitsubishi Tanabe Pharma Corporation. K. Arakawa: Employee; Mitsubishi Tanabe Pharma Corporation. M. Kunisaki: Research Support; Mitsubishi Tanabe Pharma Corporation, Novo Nordisk.
340-OR: ADA Presidents' Select Abstract: Structural Neuroimaging and Cognitive Function in Long-Duration Type 1 Diabetes
Authors: SHAH HETAL , DESALVO MATTHEW , HAIDAR ANASTASIA , VISHVA TEJA JANGOLLA SURYA , GREGORY YU MARC , GAUTHIER JOHN , ZIEMNIAK NOLAN A. , WU I-HSIEN , BILLAH TASHRIF , NING LIPENG , ADAM ATIF , RATHI YOGESH , KING GEORGE L. 
Published: June 2023

Cognitive decline is an increasingly important complication in people with type 1 diabetes (T1D) as they age. We previously reported that compared with nondiabetic people, those with long-duration T1D have impaired cognitive function, similar to people with type 2 diabetes. To characterize factors associated with cognitive decline in people with T1D, 52 participants of the Joslin Medalist Study (“Medalists”) with T1D≥50 years, and 20 age-matched nondiabetic controls, underwent clinical evaluation, cognitive assessments, and neuroimaging (Alzheimer Disease Neuroimaging Initiative-3 protocol). Compared to controls, Medalists had 49.4 (±21.9) cm3 (p=0.03) lower total brain volume, and 2.7 (±0.8) cm3, 3.0 (±1.5) cm3 and 3.1 (±1.5) cm3 lower volumes (p&lt;0.05), respectively, in the deep gray matter region (thalamus, putamen, caudate and globus pallidus), the Alzheimer disease signature region (hippocampus, parahippocampus, entorhinal cortex, inferior parietal lobule, precuneus and cuneus), and the occipital lobe. No significant differences were observed in frontal, temporal, or parietal lobe volumes. In assessing small vessel disease, the number of white matter hyperintensities (WMHs) or microvascular hemorrhages did not differ between Medalists and controls, nor did regional cerebral blood flow measures (via arterial spin labeling). Among Medalists, reduced total and all regional brain volumes were associated (p&lt;0.05) with worse motor skills, female sex, lower education status, increased age, and longer diabetes duration. Increased WMHs were associated with worse renal function and higher coronary artery calcification scores. Volumes did not associate with other cognitive domains (recall, working memory, or executive function). These findings suggest that cognitive decline in people with long-duration T1D is related mainly to abnormalities in parenchymal CNS rather than neurovascular changes. Definitive confirmation of this finding by brain histopathology is underway.

Disclosure
H. Shah: None. M. Desalvo: None. A. Haidar: None. S. Jangolla: None. M. Yu: None. J. Gauthier: None. N.A. Ziemniak: None. I. Wu: None. T. Billah: None. L. Ning: None. A. Adam: None. Y. Rathi: None. G.L. King: Research Support; Janssen Research & Development, LLC.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (3P30DK036836-34S1); Thomas J. Beatson, Jr. Foundation
344-OR: Post-translational Modification of SHDA Regulating Macrophage Polarization and Inflammation in Obesity
Authors: WU RUI , JIANG HAOWEN 
Published: June 2023

The succinate dehydrogenase enzyme (SDH) catalyzes the oxidation of succinate into fumarate in the tricarboxylic acid cycle. Among the four subunits, SDHA and SDHB carry the catalytic activity. Mounting evidence implicates the link between the catalytic subunit SDHA expression and mitochondrial energy metabolism. However, the molecular mechanisms regulating SDH subunits stabilization in macrophages remain largely unknown. Here, we showed that AMPK, an energy sensor, could be a key regulator of SDHA ubiquitination through directly binding to sentrin-specific protease in adipose tissue macrophages, thus contributing to obesity-induced inflammation. Our study identified that SDHA expression was significantly downregulated in AMPKα siRNA RAW264.7 cells. Moreover, MG132 could significantly rescue AMPKα knockdown-induced SDHA degradation in cells, indicating that AMPK regulates SDHA stabilization via proteasomal degradation. However, AMPK protein interaction analyses by yeast two-hybrid showed that SDHA is not AMPK downstream target. Instead sentrin-specific protease was identified as a novel, putative AMPK substrate. To further clarify the potential interaction between AMPK, SDHA, and sentrin-specific protease, Co-IP experiment was included, and results indicated that AMPK directly binds with sentrin-specific protease instead of SDHA. As a desumoylating enzyme, SENP catalyzes hydrolysis peptide bond of SUMO. How the SUMOylation of SDHA impacts its ubiquitination still needs more investigations. In our scenario, we identified a new regulatory mechanism of SDHA stabilization, AMPKα-induced SUMOylation, that partially impacts the ubiquitination level of SDHA in activated macrophages. AMPKα-induced SUMOylation level change of SDHA is directly involved in the regulation of macrophage polarization, which may contribute to adipose inflammation.

Disclosure
R.Wu: None. H.Jiang: None.
347-OR: Methionine Restriction Differentially Protects against High-Fat Diet-Induced Neuroinflammation and Central Insulin Resistance in Male and Female Mice
Authors: LAIL HANNAH L. , LAWRENCE ROWAN , WANDERS DESIREE 
Published: June 2023

High-fat diets (HFD) promote central inflammation and insulin resistance (IR). Methionine restriction (MR) improves peripheral insulin sensitivity, lipid metabolism, and cognitive function, at least in part by increasing fibroblast growth factor 21 (FGF21). However, the ability of MR to protect against neuroinflammation and central IR during adolescence has not been examined. Moreover, whether MR depends on FGF21 to protect against HFD-induced changes in central insulin signaling or neuroinflammation is unknown. We sought to determine whether MR protects against HFD-induced neuroinflammation and central IR during adolescence in males and females and whether MR’s effects are dependent on FGF21. Male and female wild-type (WT) and FGF21 knockout (KO) mice, aged 5 to 6 wk, were fed normal (18.9% fat-derived kcal) or high-fat (60% fat-derived kcal) versions of control (0.86% methionine) or MR (0.17% methionine) diets for 5 wk. To investigate insulin action, ITTs were performed after 4 wk on the diet, and saline or insulin (0.6U/kg body weight) was administered 15 min prior to sacrifice.
MR significantly decreased weight gain of HFD-fed mice regardless of sex or genotype (p &lt; 0.05). MR increased serum FGF21 of all males and HFD-fed females (p &lt; 0.05), and strongly tended to increase FGF21 in female mice on the normal-fat diet. HFD feeding tended to promote inflammatory gene expression in the hippocampus of WT males, while MR trended to mitigate inflammation independent of FGF21. MR also significantly reduced fasting blood glucose and improved peripheral insulin response in an FGF21-dependent fashion (p &lt; 0.05). Though, neither HFD nor MR had a notable impact on markers of IR in the hypothalamus or hippocampus. Our findings indicate that short-term MR improves metabolic parameters of adolescent mice fed normal or high-fat diets. In addition, MR acts in an FGF21-independent and sex-dependent manner to improve neuroinflammation.

Disclosure
H.L.Lail: None. R.Lawrence: None. D.Wanders: None.
349-OR: Selected DYRK1A Inhibitors Simultaneously Drive Both Human Beta-Cell Proliferation and Differentiation
Authors: WANG PENG , KUMAR KUNAL , LIU HONGTAO , WOOD OLIVIA , KARAKOSE ESRA , CHOLEVA LAURYN , LAMBERTINI LUCA , GARCIA-OCANA ADOLFO , DEVITA ROBERT J. , STEWART ANDREW F. 
Published: June 2023

Small molecule DYRK1A inhibitors induce adult human beta cell proliferation and expand human beta cell mass. Harmine also enhances differentiation and function in human beta cells in vitro and in vivo, increasing expression of key beta cell genes. It is unknown whether this “pro-differentiation effect” is a feature of all DYRK1A inhibitors. We compared harmine, 2-2c, 5-Iodotubericidin (5-IT), GNF4877, INDY, CC-401 and Leucettine-41 at doses that maximally drive human beta cell proliferation. As anticipated, harmine, 2-2c and 5-IT all increased expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC30A8, and ENTPD3. These effects were observed in normal human islets as well as in islets from donors with T2D. Surprisingly, in simultaneous experiments, the DYRK1A inhibitors GNF4877, INDY, CC-401 and Leucettine failed to induce these beta cell differentiation markers. The pro-differentiation effect of harmine was independent of DYRK1A inhibition: silencing DYRK1A in human islets induced beta cell proliferation, but had no effect on differentiation; harmine treatment in DYRK1A-silenced islets restored beta cell pro-differentiation effects. The pro-differentiation effect was also independent of NFAT signaling and DREAM Complex effects, since NFAT overexpression, or p130, p107, E2F4 and E2F5 silencing had no effect on beta cell differentiation. Similarly, silencing other known harmine targets (DYRK2, 3, 4, the CLK and HIPK family) had no effect on either human beta cell differentiation nor proliferation.
In summary, harmine, 2-2c and 5-IT are unique among the DYRK1A inhibitor family in their simultaneous ability to enhance both beta cell proliferation and differentiation. While the beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor drug development.

Disclosure
P. Wang: None. K. Kumar: None. H. Liu: None. O. Wood: None. E. Karakose: None. L. Choleva: None. L. Lambertini: None. A. Garcia-Ocana: Consultant; Sun Pharmaceutical Industries Ltd. R.J. DeVita: None. A.F. Stewart: None.
352-OR: Regulation of Melanocortin Receptor 4 (MC4R) Ciliary Trafficking
Authors: NACHURY MAXENCE 
Published: June 2023

The primary cilium, a hair-like projection at the surface of nearly every cell, functions as a signaling antenna in processes as diverse as vision and body weight homeostasis. Obesity is a cardinal symptom of many ciliopathies including Bardet-Biedl Syndrome (BBS). While we are beginning to understand how cilia participate in body weight homeostasis, the molecular pathway that leads to obesity in BBS patients remains unclear.
We now know that the melanocortin receptor 4, a GPCR that regulates feeding behavior, localizes to cilia in hypothalamic neurons. Meanwhile, most BBS proteins assemble or regulate the BBSome, a protein complex that removes activated signaling receptors from cilia.
To characterize the stimuli and mechanisms that regulate MC4R trafficking in and out of cilia, we recapitulated MC4R trafficking in ciliated cell lines amenable to rapid manipulation. Surprisingly, levels of MC4R in cilia remain under the detection limit in most cells unless treated with an inverse agonist of MC4R. In addition, interference with BBSome function also increases ciliary MC4R levels in all cells. Thus, the tonic activity of MC4R promotes the constitutive clearance of MC4R from cilia via BBSome-mediated exit.
These results suggest that artificially increasing the ciliary levels of MC4R may augment its signaling activity. To selectively recognize activated GPCRs, the BBSome relies on specific ubiquitin chains linked at lysine 63 (K63Ub chains) that become attached onto activated GPCRs via β-arrestin-associated ubiquitin ligases. Depletion of β-arrestin blocked the constitutive exit of MC4R from cilia and mutation of ubiquitin acceptor lysines from MC4R and MRAP2 results in a measurable increase in the ciliary levels of MC4R. In addition, targeting a protease that specifically cleaves K63Ub chains to cilia completely blocks the exit of MC4R from cilia.
We conclude that the tonically active MC4R is ubiquitinated in cilia and actively removed by the BBSome.

Disclosure
M.Nachury: None.

Funding
American Diabetes Association (1-20-VSN-03)
354-OR: Attenuation of Obesity-Induced Vascular Inflammation by microRNA-485 in Endothelial Cells
Authors: BESTEPE FURKAN , PAL-GHOSH RUMA , FRITSCHE COLETTE , LAKHOTIYA KARTIK , SMOLGOVSKY SASHA , WESTON JAMES , STEPANIAN ALEC , ALVARADO FERNANDA , CATALANO PATRICK , O'TIERNEY-GINN PERRIE F. , ALCAIDE PILAR , JAFFE IRIS Z. , ICLI BASAK 
Published: June 2023

Obesity induced endothelial dysfunction contributes to the vascular inflammation. MicroRNAs (miRNAs) are implicated in the epigenetic regulation of inflammatory pathways. However, relevant miRNAs in the microvasculature, and their relation to chronic inflammation and metabolic dysfunction are poorly understood. Using micro-RNA Seq approach to profile microRNAs from the endothelial cells (ECs) of brown adipose tissue (BAT) of mice with diet-induced obesity (DIO), we identified microRNA- 485-5p (miR-485-5p) as one of the most differentially regulated miRNA. MiR-485-5p was rapidly induced in ECs in response to TNFα, highly enriched in the BAT vascular endothelium of mice with DIO, and was increased by 1.97 fold in human plasma samples with obesity. MiR-485-5p inhibition decreased TNF-α-induced NF-kB-responsive adhesion molecules VCAM-1 (32.6%) and ICAM-1 (34.7%) and phosphorylation of IKBα in ECs in vitro. Gain and loss-of-function studies revealed that neutralization of miR-485-5p potently inhibited leukocyte adhesion to EC monolayers by 20.8% while the overexpression had the opposite effects. Mechanistically, miR-485-5p inhibited the expression of its target gene PCF11 (~40.3%), a polyadenylation factor subunit, an effect that increased VCAM-1 (2.51 fold) and ICAM-1 (1.43 fold) expression as well as leukocyte adhesion to EC monolayers by 18.6% in vitro. Systemic neutralization of miR-485-5p in mice decreased leukocyte adhesion and rolling by 55.1% and 46.7% respectively by intravital microscopy. Finally, systemic delivery of LNA-anti-miR-485-5p inhibitor resulted in improved glucose and insulin tolerance and energy expenditure in mice with DIO while decreasing Ly6Chigh proinflammatory monocytes in blood as measured by FACS. Our findings indicate that miR-485-5p plays a key regulatory role in controlling vascular inflammation in diet-induced obesity, an effect that could be exploited for therapeutic intervention in obesity-induced chronic inflammation.

Disclosure
F.Bestepe: None. P.F.O'tierney-ginn: None. P.Alcaide: None. I.Z.Jaffe: None. B.Icli: None. R.Pal-ghosh: None. C.Fritsche: None. K.Lakhotiya: None. S.Smolgovsky: None. J.Weston: None. A.Stepanian: None. F.Alvarado: None. P.Catalano: None.

Funding
American Diabetes Association (1-16-JDF-046 to B.I.); National Institutes of Health (HL149999)
359-OR: Variation in Utilization of Continuous Glucose Monitoring in Patients with Type 1 Diabetes
Authors: LACY MARY E. , FOWLKES JOHN , HEIER KORY , SOHN MIN-WOONG , KRUSE-DIEHR AARON J. , WATERS TERESA , MOGA DANIELA C. 
Published: June 2023

Background: Continuous glucose monitoring (CGM) is recommended by the American Diabetes Association for patients with type 1 diabetes (T1D) but remains underutilized. Prior studies suggest ~30% of patients with T1D use CGM with variation by race/ethnicity reported.
Methods: We used electronic health record data from an academic medical center (1/1/2018-12/31/2021) to examine variation in CGM utilization in patients with T1D and describe demographic factors associated with CGM use via multivariate logistic regression adjusted for clinical variables outlined in Table 1.
Results: Among 3,382 patients with T1D (aged 28.6 ± 17.8 y; 51% female; 83% non-Hispanic White), 52% used CGM during study period. CGM utilization was significantly lower in older (age 65+) versus younger patients (age 0-13; OR=0.15, 95% CI: 0.09, 0.26), Hispanic versus non-Hispanic White patients (OR=0.44, 95% CI: 0.21, 0.94) and patients with commercial versus government-issued insurance coverage (Medicaid, OR=0.44, 95% CI: 0.37, 0.52; Medicare, OR=0.42, 95% CI: 0.30, 0.50).
Conclusions: In this population of patients with T1D, 1 in 2 patients used CGM to manage their diabetes but there was significant variation. Identifying populations with lower-than-expected utilization is a necessary first step in developing targeted interventions to increase CGM uptake and, ultimately, improve short and long-term T1D-related outcomes.

Disclosure
M.E.Lacy: None. J.Fowlkes: None. K.Heier: None. M.Sohn: None. A.J.Kruse-diehr: None. T.Waters: None. D.C.Moga: None.

Funding
National Institutes of Health (UL1TR001998, KL2TR001996)