bluuebunny/crossref_metadata_2025_split huggingface dataset:
1101-P: Association between Insulin Utilization and Average Out-of-Pocket Cost in Commercially Insured Patients with Diabetes
Authors: RUIZ-NEGRON NATALIA , SULLIVAN JANE , TUCKER JAMIE , MCADAM-MARX CARRIE 
Published: June 2021

Introduction: Concerns over cost-related non-adherence and high patient out-of-pocket (OOP) costs for insulin has prompted policies limiting insulin copays. This study examines the associations of insulin OOP cost by policy-relevant groupings, with gaps in therapy and insulin dose, expanding on current cost-related non-adherence data.
Methods: This retrospective cohort study included patients from the OptumLabs® Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data, with commercial insurance, type 1 (T1D) or 2 diabetes (T2D), and insulin claims between 2006 and 2018. Index date was January 1 following two insulin claims at least 30 days apart in the prior year. Patients were grouped by average insulin OOP cost per 30-day supply over 1-year of follow-up: $0, &gt;$0-$20, &gt;$20-$35, &gt;$35-$50, and &gt;$50. Descriptive statistics were used to assess the proportion of patients with a &gt;/=90 continuous-day gap in insulin therapy and insulin daily average consumption (DACON) by OOP group.
Results: A total of 21,085 and 72,512 patients with T1D and T2D, respectively, were included. Mean age was 40.6 and 53.9 years. More patients with T2D in OOP groups $35-$50 (29.7%) and &gt;$50 (34.2%) experienced a 90-day gap in therapy vs. &gt;$0-$20 (28.3%, p ≤0.02 for both). These groups also had a significantly lower mean (SD) DACON at 67.2 (136.1) and 63.9 (159.3) units/day vs. &gt;$0-$20 at 72.8 (133.7) units/day, p &lt;0.001 for both. In the T1D OOP groups, DACON did not differ by OOP group, and only the &gt;$50 OOP group had significantly more patients with a gap in therapy vs. &gt;$0-$20 (22.7% vs. 19.6%, p =0.003).
Conclusions: In commercial patients, insulin OOP costs &gt;$35 were associated with gaps in therapy, and a decrease in average daily insulin dose in those with T2D. However, those with T1D may exhibit an inelastic demand to insulin in this patient population, as it is life-saving medication.

Disclosure
N. Ruiz-negron: Research Support; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation. J. Sullivan: None. J. Tucker: None. C. Mcadam-marx: None.

Funding
Robert Wood Johnson Foundation; Health Data for Action Research Program (ID77105)
1104-P: Normative Fasting C-Peptide Values in Adolescents in the National Health and Nutrition Examination Surveys (NHANES)
Authors: SONI PRIYA Y. , WANG YUMIN , ECKERT GEORGE J. , ISMAIL HEBA M. 
Published: June 2021

Background: C-peptide values are used for evaluation of residual β-cell function as well as endpoints in clinical trials. Therefore, it is crucial to have normative standards as a reference. This study aims to report normative fasting C-peptide values and variations across demographics in healthy adolescents included in the NHANES dataset.
Materials and Methods: In this analysis, we used fasting C-peptide data (n=2063) from the 1999-2004 NHANES dataset for participants ages 12 to &lt; 18 yrs old.
Results: The mean ± SE age of participants was 14.99 ± 0.06; 992 were females and 1071 were males. The majority (&gt;80%) of females and males had a BMI percentile (%ile) &lt;85%. Among males, geometric mean C-peptide levels increased from 0.52 nmol/L at age 12, to 0.66 nmol/L at age 15 yrs. Mean values decreased slightly at age 16 and increased back to 0.66 nmol/L at age 17 yrs. Among females, C-peptide levels fluctuated around a geometric mean of 0.67 nmol/L and age did not have a significant effect on C-peptide (p=0.15). Females had significantly higher mean log-transformed C-peptide concentrations than males (p&lt;0.0001) after adjusting for age, race, and BMI %ile category. After adjusting for age and BMI %ile category, we found that in males, non-Hispanic blacks had significantly lower C-peptide levels than non-Hispanic whites (p=0.0026), Mexican Americans (p&lt;0.0001) and other races including multiracial (p=0.0186). Similarly, in females, non-Hispanic blacks had significantly lower concentrations than non-Hispanic whites (p=0.0093), Mexican Americans (p&lt;0.0001), and other Hispanics (p=0.0187). BMI %ile category was positively correlated with C-peptide levels in both males and females after adjusting for age and race.
Conclusions: Here we describe normative fasting C-peptide in a healthy adolescent population. These data will provide novel information which can be used in assessing residual β-cell function and response to intervention therapy.

Disclosure
P. Y. Soni: None. Y. Wang: None. G. J. Eckert: None. H. M. Ismail: None.
111-LB: Preadmission Insulin Treatment Was Associated with Increased In-Hospital Mortality among Critically Ill Patients with Type 2 Diabetes
Authors: FAN RONGPING 
Published: June 2021

Introduction: Insulin treatment was associated with enhanced systemic inflammation that may lead to adverse clinical outcomes of critical illness, but clinical data are limited. We examined the impact of pre-admission insulin use on in-hospital mortality among critically ill patients with type 2 diabetes (T2D). Methods: This retrospective study investigated 372 critically ill patients with T2D from 3500 cases admitted to an ICU between March 2011 and April 2020 at Tongji Hospital (Wuhan). Clinical characteristics and outcomes were compared among those treated with or without insulin before admission.
Results: Among the 372 critically ill patients with T2D, 249(59%) had pre-admission insulin prescriptions for &gt; 3 months. A total of 246 patients were 1:1 matched by age and diabetic complications, among whom the median age was 62 (IQR, 54.0-70.0) years, and 155(63.0% ) were male and 91(37.0%) were female. Compared with critically ill patients with T2D treated without insulin before admission, patients with pre-admission insulin treatment had increased in-hospital mortality(22.8%(28/123)vs.(12.2%(15/123); P=0.029) and longer length of ICU stay(6(4~10)vs. 5(3~8); P=0.025). Logistic regression analysis showed that pre-admission insulin treatment was associated with a 2.122-fold higher risk for mortality in critically ill patients with T2D (OR=2.122, 95% CI (1.07-4.21) P=0.031), and the risk was higher after adjustment for age, gender, chronic kidney disease, hemoglobin, creatinine, eGFR, CRRT (OR=2.487, 95% CI (1.190-5.197) P=0.015).
Conclusions: Pre-admission insulin treatment might be associated with increased in-hospital mortality and longer length of ICU stay among critically ill patients with T2D. This association warrants further investigation.

Disclosure
R. Fan: None.
1132-P: Genetic Relationships between Birth Weight and Type 2 Diabetes
Authors: WEDEKIND LAUREN E. , HSUEH WEN-CHI , OLAIYA MUIDEEN , KOBES SAYUKO , BAIER LESLIE , KNOWLER WILLIAM C. , MAHAJAN ANUBHA , MCCARTHY MARK , HANSON ROBERT L. 
Published: June 2021

There is considerable evidence that birth weight is associated with increased risk of type 2 diabetes (T2D) in adulthood. However, evidence from populations with high prevalence of T2D on the genetic relationships between birth weight and T2D is limited.
Data were obtained from a genome-wide association study (GWAS) in an Indigenous population from the Southwest US with high prevalence of T2D in which the relationship of T2D with birth weight is “U-shaped." Weighted polygenic scores (PSs) were constructed using imputed genotypes for genome-wide significant single-nucleotide polymorphisms (SNPs) from GWAS meta-analyses for birth weight (EGG Consortium, 126 SNPs) and T2D (DIAGRAM Consortium, 293 SNPs). Associations of birth weight PS and T2D PS with T2D and birth weight were calculated, accounting for participants’ pairwise relationships, using linear mixed models. Birth weight data (n=3700) were normalized separately by sex and analyzed for associations, adjusted for birth year, gestational age and the first 5 genetic principal components (PCs). T2D (n=7659) data were analyzed for associations, adjusted for age, sex, birth year and the first 5 genetic PCs.
Birth weight PS had a significant, positive association with birth weight (β=0.134 SD birth weight per SD PS (95% CI 0.101, 0.168); p=4.1×10-15). The T2D PS was likewise significantly, positively associated with T2D (OR=1.48 per SD (1.38, 1.58); p=8.1×10-31). The birth weight PS was significantly, inversely associated with T2D (OR=0.91 (0.85, 0.97); p=0.0043); we found no evidence for a non-linear relationship between birth weight PS and T2D (p=0.80). The T2D PS was not significantly associated with birth weight (β=-0.005 (-0.040, 0.030); p=0.80).
Results indicate that genetic variants that associate with birth weight and T2D from larger European GWAS largely also influence these traits in this Indigenous population. Current findings also support the notion that many variants conferring susceptibility to low birth weight also confer susceptibility to T2D.

Disclosure
L. E. Wedekind: None. W. Hsueh: None. M. Olaiya: None. S. Kobes: None. L. Baier: None. W. C. Knowler: None. A. Mahajan: Employee; Self; Genentech, Inc. M. Mccarthy: Employee; Self; Genentech, Inc. R. L. Hanson: None.
1157-P: Brainstem Neurons Regulating Energy Homeostasis
Authors: BHAVE VARUN M. , HILL-OLIVA MICHAEL J. , KAMATKAR NACHIKET , CHOWDHURY SRIKANTA , NECTOW ALEXANDER R. 
Published: June 2021

The central nervous system (CNS) plays a key role in the sense-and-respond system which maintains proper energy stores. However, the molecular, cellular, and circuit mechanisms through which the CNS achieves this goal is poorly understood. We have recently identified the dorsal raphe nucleus (DRN) as a key node in the CNS, responsible for regulating numerous aspects of energy balance. Neurons within the DRN can potently regulate feeding, thermogenesis, and locomotor activity, and prolonged changes in their activity can ultimately drive changes in body weight. Despite playing a key role in regulating energy homeostasis, the molecular heterogeneity of the DRN had, until recently, hindered further progress in understanding it’s intricate role in the regulation of body weight. Here, we use a combination of nuclear labeling, sorting, and single-nuclear RNA-sequencing to identify the component cell types of key DRN populations, themselves known to regulate the various facets of energy balance. In particular, we identify over twenty candidate subpopulations of DRN neurons, principally defined by the neurotransmitters serotonin, glutamate, and GABA. Many of the subpopulations of these ‘principal’ cell types differentially express peptides, receptors, and signaling molecules that are directly implicated in the regulation of energy balance. We have begun to validate the expression and neuroanatomy of these molecules, including such neuropeptides as thyrotropin-releasing hormone and neuropeptide Y, and we have leveraged available recombinase-driver lines to modulate the activity of neurons expressing these genes to effectively assay their function. Together, this work represents important progress towards identifying the key cell subtypes that regulate the various aspects of energy balance.

Disclosure
V. M. Bhave: None. M. J. Hill-oliva: None. N. Kamatkar: None. S. Chowdhury: None. A. R. Nectow: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-18-ACE-49 to A.R.N.)
1166-P: Immunoproteasome Function in the Liver: A Proteomics Analysis
Authors: EDMUND AARON , YUN CHANGHO , KIM DO-HYUNG 
Published: June 2021

The liver is a key metabolic organ with functions in glucose and lipid metabolism, and whose dysfunction and inflammation are intimately linked to many metabolic disorders such as type 2 diabetes, nonalcoholic fatty liver disease, and hepatocellular carcinoma. The immunoproteasome is an inducible type of proteasome that plays crucial roles in homeostasis, immunity, and inflammation. The immunoproteasome incorporates three catalytic β subunits; LMP2, MECL1, and LMP7 which replace the proteasome subunits β1, β2, and β5, respectively, in the presence of inflammatory cytokines. We previously showed that mTORC1 promotes immunoproteasome formation, indicating that nutritional status regulates immunoproteasome abundance. Despite its strong relevance to disease, the functions of the immunoproteasome remain poorly understood. In this study we sought to illuminate the functions of the immunoproteasome in hepatocyte metabolism through multiplexed proteomics using LMP2-/- primary mouse hepatocytes. Through Reactome Pathway and GO Biological Process analysis, we found that LMP2 depletion in primary hepatocytes reduces the abundance of proteins involved in glucose metabolism and detoxification of reactive oxygen species while increasing abundance of proteins involved in mitochondrial biogenesis, TCA cycle and electron transport chain, mitochondrial and peroxisomal fatty acid oxidation, and the unfolded protein response. Under interferon γ (IFNγ)-stimulated conditions, proteins in keratinization and apoptosis were reduced suggesting reduced inflammation in LMP2-/- hepatocytes, and proteins in fatty acid and amino acid metabolism are increased. Combined, these results suggest that the immunoproteasome might play important roles in hepatic metabolism.

Disclosure
A. Edmund: None. C. Yun: None. D. Kim: None.

Funding
American Diabetes Association (1-19-IBS-071 to D-H.K.); National Institutes of Health (5T32DK007203-40)
1175-P: Inhibition of FBXO48 Improves Metabolic Changes Associated with NAFLD by Inhibiting Proteasomal Degradation of Phosphorylated AMPKa
Authors: MURALI ANJANA , EDMUNDS LIA R. , XIE BINGXIAN , CHEN BILL , LIU YUAN , JURCZAK MICHAEL J. 
Published: June 2021

Hypothesis: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries yet there are no FDA-approved therapies for the disease. AMPK is a cellular energy sensor that coordinates metabolic pathways to balance energy demand with production. Growing evidence suggests loss of AMPK activity contributes to NAFLD. We recently identified an orphan F-box protein, FBXO48, which mediates the ubiquitination and proteasomal degradation of phosphorylated AMPKα (pAMPK). We hypothesized that increasing pAMPK levels via inhibition of FBXO48 would improve glucose homeostasis and slow NAFLD progression.
Methods: Twelve-week old male wildtype (WT) mice were fed low-fat diet (LFD) or “fast food” diet (FFD) for 24 weeks and then given vehicle (VEH) or a small molecule FBXO48 inhibitor (SMI; 5 mg/kg/d) for 8 weeks. We measured changes in body weight/composition, performed glucose tolerance tests (GTT), and collected plasma and liver for analysis.
Results: SMI had no significant effect on body weight or composition, although body weight and fat mass were 2.4 and 2.1 g less in SMI FFD compared with VEH FFD mice, suggesting a modest effect on weight loss. SMI significantly improved glucose homeostasis in FFD mice and restored plasma glucose levels during GTT to those observed in LFD mice. SMI had no effect on liver triglyceride levels in LFD mice and produced a 15% non-significant reduction in FFD mice. Gene expression of inflammation markers Cd68 and Ccl2 were significantly reduced in SMI FFD compared with VEH FFD mice, as were markers of fibrosis Col1a1 and Col3a1.
Conclusions: Our data suggest that increasing pAMPK levels through inhibition of FBXO48 may be a viable treatment option for improving glucose homeostasis and reducing inflammation/fibrosis associated with NAFLD.

Disclosure
A. Murali: None. L. R. Edmunds: None. B. Xie: None. B. Chen: Board Member; Self; Generian, Employee; Self; Generian. Y. Liu: Employee; Self; Generian. M. J. Jurczak: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK007052R01, DK119627)
12-LB: Reduced Disease-Associated Microglial Phenotype Is Associated with Diabetes-Associated Alzheimer’s Disease
Authors: PENG XUEMIN 
Published: June 2021

Introduction: Type 2 diabetes mellitus (T2DM) has a significantly increased risk of developing Alzheimer’s disease (AD). Amyloid-β (Aβ) as one of the main pathological features in AD increases in the brain of T2DM. A recent study identified a protective novel subset of microglial­ in AD—disease-associated microglia (DAM), the activation of which depends on TREM2(a myeloid cell membrane receptor) to phagocytose Aβ plaques. However, as to how T2DM increases Aβ deposition and the relationship between T2DM with DAM remain elusive.
Objective: This study aims to explore the relationship between progression of T2DM with DAM and Aβ.
Methods: In vivo experiment, the deposition of Aβ, inflammation as well as the phenotype of DAM were evaluated by RT-PCR and immunofluorescence in the cortex and hippocampus of 10-,15-,20-week old db/db mice and the age-matched WT control. Additionally, the effects of high insulin-induced insulin resistance (100nM) on the DAM signature markers and the production of inflammatory cytokines in BV-2 microglial cells were investigated in vitro.
Results: We found the soluble and insoluble Aβ40, Aβ42, Aβ plaques as well as inflammation in the cortex and hippocampus increased in the progression of T2DM. Correspondingly, the DAM phenotype was reduced in the cortex and hippocampus at relatively early stage of T2DM (10 weeks and 15 weeks), while it increased reactively at the late stage (20 weeks). Likewise, high insulin-stimulated BV-2 microglial cells showed reduced Trem2 level and DAM signature markers and increase inflammation as well as Erk1/2 level. However, after the treatment of Erk1/2 inhibitor, the BV-2 cells under high insulin showed restored Trem2 level and DAM phenotype.
Conclusion: T2DM brain has decreased DAM phenotype at a relatively early stage, which may explain the increased Aβ deposition. This may involve Erk1/2 -Trem2 signaling pathway, which could be a potential candidate especially at early stages for preventing T2DM-induced AD.

Disclosure
X. Peng: None.

Funding
National Natural Science Foundation of China (81974114)
120-OR: Dapagliflozin Increases Adiponectin and Its Receptors, and Reduces Inflammation and Ceramide Synthesis Enzymes in the Obese Prediabetic Dog
Authors: KABIR MORVARID , BERGMAN RICHARD N. , GOPAUL V. SASHI , YANG HSIUCHIUNG , KOLKA CATHRYN M. 
Published: June 2021

Sodium glucose cotransporter-2 (SGLT2) inhibitors promote urinary glucose excretion, consequently reducing blood glucose. Previously we showed that 6 weeks of Dapagliflozin (Dapa) treatment improved insulin sensitivity and prevented weight gain. In addition, Dapa promoted adipose tissue (AT) beiging, lipolysis and decreased adipocyte size primarily in the visceral (VIS) depot in a canine model of mild type 2 diabetes. Little is known about the effects of Dapa on AT inflammation and ceramide synthesis in both the subcutaneous (SC) and VIS fat depots. Twelve dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were then exposed to Dapa (n=6, 1.25mg/kg) or placebo (n=6) once per day for 6 weeks, while remaining on the high fat diet. At the end of the treatment, fasting plasma parameters were measured, and SC and VIS fat biopsies were obtained for molecular studies. Dapa increased adiponectin, adiponectin receptors 1 and 2 gene expression by 90%, 74% and 69% (&lt;0.001) in VIS depot respectively. Adiponectin gene expression was upregulated by 85% in the SC (P&lt;0.05). Inflammation markers such as TNFα and IL-6 are downregulated by 74% (P&lt;0.05) and 86% (P&lt;0.001) in the VIS depot respectively. In addition, genes involved in ceramide synthesis, toll like receptor 4 (TLR4) and serine palmitoyl-CoA transferase (SPTLC2) decreased by 77% and 73 % respectively (P&lt;0.05) in the VIS depot.
In conclusion, Dapa promoted adiponectin and its receptors, decreased inflammation and enzymes involved in ceramide synthesis mainly in the VIS depot. These changes were independent of fasting glucose and insulin. Thus, for the first time we are beginning to identify mechanisms by which Dapa enhances AT function in regulating energy homeostasis and improving AT inflammation in mild type 2 diabetes canine model.

Disclosure
M. Kabir: None. R. N. Bergman: None. V. Gopaul: None. H. Yang: Employee; Self; AstraZeneca. C. M. Kolka: Research Support; Self; AstraZeneca.

Funding
National Institutes of Health
1207-P: Tracing Telomerase Reverse Transcriptase (Tert) Expression to a Dormant Preadipogenic Origin
Authors: LYNES MATTHEW , CARLONE DIANA L. , TOWNSEND KRISTY L. , BREAULT DAVID , TSENG YU-HUA 
Published: June 2021

Adipocytes are the major cell type in adipose tissue responsible for maintaining whole body energy homeostasis, and they are continuously replaced via expansion and differentiation of undifferentiated preadipocyte cells that reside within the local niche. In these preadipocytes, the maintenance of telomere length by mouse telomerase reverse transcriptase (mTert) is critical to their function, and premature telomere shortening is associated with metabolic syndrome and insulin resistance, however the specific cell type that expresses mTert in the preadipocyte niche is unknown. In this study, we took a lineage tracing approach to follow the developmental contribution of cells that express the putative stem cell marker mTert to several tissues, including cells residing in adipose tissue stromal vasculature. Using bioluminescent imaging, we were able to localize cells belonging to the mTert lineage in 3 dimensions in live animals. By tracing the fate of cells that express mTert for up to 2 years across the life of individual animals, we identify all tissues that arise from these putative stem cells. Subcutaneous white adipose tissue, which is prone to hyperplasia, showed contribution from the mTert lineage that was increased by high fat diet feeding. Cells that express mTert isolated from adipose tissue expressed preadipocyte markers and they made up less than 2% of the total progenitor pool. The mTert-positive cells possessed the capacity to self-renewal and differentiate into adipocytes, however they required cell-cell contact with mTert-negative cells to proliferate. These data identify a new population of preadipocytes that may contribute to the depot-specific response to HFD. Since individual adipose depots have profoundly different endocrine and metabolic roles, the identification of progenitor cells with depot specific differentiation capacity may provide clues to the mechanisms that govern in whole body physiology.

Disclosure
M. Lynes: None. D. L. Carlone: None. K. L. Townsend: Other Relationship; Self; Neuright, Inc. D. Breault: None. Y. Tseng: Consultant; Self; Cellarity.

Funding
National Institutes of Health (T32DK007260, F32DK102320)