bluuebunny/crossref_metadata_2025_split huggingface dataset:
256-OR: Hypoglycemia Effect on Relationship of Renal and/or Retinal Disease with CVD and Vice Versa
Authors: FAHRMANN ELKE R. , DRISCOLL HENRY 
Published: June 2023

Baseline microvascular complications have been reported to affect the relationship of severe hypoglycemia (SH: needing assistance) with cardiovascular disease (CVD) in DCCT/EDIC type 1 diabetes (T1D) cohort followed for ~ 30 years. We investigated if this finding holds true considering any presence/absence of renal/retinal disease (any RR: sustained AER &gt;30 mg/24 h and/or eGFR &lt;60 mL/min/1.73 m2, and/or PDR and/or CSME) and whether it is bidirectional during longer follow up of &gt;35 DCCT/EDIC years. DCCT/EDIC data provided by NIDDK CR were evaluated applying time dependent Cox models. Outcome was composite of CV death, myocardial infarct (MI), silent MI, revascularization, congestive heart failure, and angina. Subset SH (sSH) is SH with seizures and or loss of consciousness. Interaction between RR and SH (sSH) was evaluated and probed. During follow up, of 1441 patients (mean baseline age 27 ± 7 years, 47% women) 975 (660) had a SH (sSH) event, 741 experienced RR, and 222 had a CV event. All unadjusted (u) / adjusted (a) interactions (I) were significant: I(SH, RR) with p&lt;0.05 (u) and p~0.01 (a), and I(sSH, RR) with p&lt;0.01 (u) and &lt;0.001 (a). Probing interactions showed: 1) In absence of SH or sSH, hazard ratio (HR) for RR was nonsignificant (ns): p&gt;0.5, p&gt;0.6, respectively. 2) In presence of SH or sSH, HR for RR was 1.74 [1.19, 2.53] p&lt;0.01, 2.40 [1.46, 3.96] p&lt;0.001, respectively. 3) In absence of RR, HR for SH and sSH was ns: p&gt;0.4, p~0.08, respectively. 4) In presence of RR, HR for SH and sSH was 1.78 [1.22, 2.60] p&lt;0.01 and 1.81 [1.28, 2.56] p&lt;0.001, respectively. Subanalyses (stratification by SH (sSH) or RR absence / presence) were consistent. Our analyses provide additional evidence for multifactorial nature of relationship between SH and CVD. We demonstrate that SH increases strengths of association between any RR and CVD during &gt; 35 years of follow up, and vice versa. This bidirectionality in a young cohort should be realized and considered in T1D management to identify individuals at higher CVD risk.

Disclosure
E.R.Fahrmann: None. H.Driscoll: None.
258-LB: Iridoid Glycoside Modulates Gut Microbiota and Ameliorates Nonalcoholic Fatty Liver Disease–Related Metabolic Disorders
Authors: XIE CEN , LIU YAMENG 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease closely associated with glucose and lipid metabolism disturbance. The development of herbal medicine interventions for NAFLD is presently a popular topic in pharmaceutical research. However, although many active natural ingredients have been reported as promising agents for NAFLD, their potential benefits are contrasted by their poor oral absorption. GG-01, an effective iridoid glycoside discovered from a clinical prescription of traditional Chinese medicine (TCM), is exposed first in the intestinal tract, and gut microbes may quickly react to GG-01. Therefore, it is intriguing to explore the role of gut microbiota and microbial metabolites in the beneficial effects of GG-01 on NAFLD-related disorders. Our research intends to commence with the intestinal nutritional characteristics of GG-01. Firstly, the crucial role of intestinal microbiota in the pharmacological effects of GG-01 is confirmed using different animal models. Subsequently, we identify the key microbes by combining high-throughput sequencing and an in vitro culture system of intestinal microbiota. We then focus on one of the key microbes, Akkermansia muciniphila, and elucidate how GG-01 can treat NAFLD-related metabolic disorders by stimulating the bile acid biotransformation of Akkermansia muciniphila based on “TCM-microbiome-host” interaction. Finally, we present a novel therapeutic strategy of the synergistic effect of Akkermansia muciniphila and GG-01 via TGR5 to activate epithelial regeneration, promote GLP-1 production, and further treat NAFLD-related metabolic disorders. We also propose GG-01 as a new type of probiotic for the treatment of NAFLD.

Disclosure
C. Xie: None. Y. Liu: None.
26-OR: A Novel Drug That Normalizes Hyperglycemia in Type 1 Diabetes
Authors: ASADI FARZAD , GUNAWARDANA SUBHADRA C. , PISTON DAVID W. 
Published: June 2023

Treatment of hyperglycemia in patients with type 1 diabetes (T1D) depends on insulin injections, which risk hypoglycemia and represent an unfavorable route of administration. Inhibition of EphA4 signaling in α-cells reduces glucagon hypersecretion, which suggests an alternative approach for the treatment of hyperglycemia in T1D. We have designed and synthesized a novel EphA4 agonist (Ki = 0.1 µM), termed WCDD301, that dose-dependently suppresses glucagon secretion (p&lt;0.001) from mouse islets and dispersed α-cells at high glucose levels. Co-treatment of the EphA4 competitive inhibitor, Rhyncophylline (2.5µM) and WCDD301 (2.5µM or 5µM) substantially or partially, respectively, abolishes WCDD301 effects. Further, WCDD301 reduces glucagon secretion from nondiabetic human donor islet cells following 1h (p&lt;0.05), 3h (p&lt;0.01) and 6h (p&lt;0.001) exposure. WCDD301 suppresses glucagon secretion (p&lt;0.001) from isolated islets and dispersed islet cells from T1D subjects, comparable to the natural EphA4 ligand ephrinA5. Similar to ephrinA5 treatment, WCDD301 increases F-actin density in both human and mouse α-cells. WCDD301 exhibits good plasma (&gt;289 and 105 min) and microsomal (&gt;145 and 93.6 min) stability in human and mouse, respectively. In STZ-induced diabetic mice (initial blood glucose &lt;300mg/dL, n=6), oral administration of WCDD301 (daily 10 mg/kg) substantially reduces blood glucose levels (140±31 mg/dL after four weeks). In diabetic NOD mice (initial blood glucose 249.6±13.1 mg/dL; n=7), oral administration of WCDD301 (daily 10 mg/kg) normalizes glucose (105±2.6 mg/dL after 3 weeks), which remains constant for &gt;3 months (experiments on-going) accompanied by reduced plasma glucagon (16.6±7.9 pg/mL) compared to diabetic control (328.5±18.7 pg/ml). The data support our hypothesis that oral administration of WCDD301 suppresses glucagon secretion by an EphA4-dependent pathway. The recovery of euglycemia in T1D mouse models is promising for further evaluation towards potential treatment of T1D.

Disclosure
F. Asadi: None. S.C. Gunawardana: None. D.W. Piston: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (2305-06050); National Institutes of Health (R01DK123301, P30DK020579)
260-LB: The Effect of LXR Activation on Liver Metabolism and Diet-Induced Steatohepatitis in Mice
Authors: BEDNARSKI TOMASZ , RAHIM MOHSIN , WHITTENBARGER NOAH , OLICHWIER ADAM J. , YOUNG JAMEY 
Published: June 2023

While nonalcoholic fatty liver disease (NAFLD) affects approx. 30% of the US population, there is currently no approved pharmaceutical treatment to inhibit the progression of NAFLD to its more severe stage of nonalcoholic steatohepatitis (NASH). The liver X receptors (LXRs) are key regulators of cholesterol and fatty acid homeostasis in liver. However, the effects of LXR activation on liver metabolism in NASH pathogenesis are not well understood. We hypothesize that LXR activation might reduce NAFLD progression by augmenting lipid composition and metabolism in hepatocytes. To test this hypothesis, 8-week-old male wild type (WT) or obese, melanocortin-4 receptor knockout (Mc4r-/-) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were given WD supplemented with GW3965 (100mg/kg), a selective, orally active agonist for the LXRs. Animals fed GW3965-supplemented diet had increased gene expression of Abca1 and Lpcat3, both transcriptional targets of LXR action. LXR activation significantly decreased body mass of both WT and Mc4r-/- mice, which was correlated with reduction of subcutaneous fat. GW3965 supplementation greatly improved glucose homeostasis of Mc4r-/-. LXR activation significantly decreased hepatic triglycerides, cholesterol esters and ceramides content which was accompanied by decreased expression of lipogenic factors (Fasn, Dgat1 and 2, Fatp5, Elovl1 and 6) in Mc4r-/-. Contrary expression of genes involved in fatty acid β-oxidation together with pyruvate cycling fluxes (VPC, VPK+ME, VPEPCK) were elevated in Mc4r-/- fed diet supplemented with GW3965. These metabolic changes were related to decrease in hepatic fibrosis, expression of NF-κB pathway genes as well as inflammatory (Itgam, Cd274), oxidative (Sod2), and endoplasmic reticulum stress markers (Chop, Atf4 and 6). Taken together, these data suggest that LXR activation improves phenotype of genetically obese WD-fed animals and inhibits progression from NAFLD to NASH.

Disclosure
T. Bednarski: None. M. Rahim: None. N. Whittenbarger: None. A. J. Olichwier: None. J. Young: Consultant; Pfizer Inc. Stock/Shareholder; Metalytics, Inc. Consultant; Metalytics, Inc. Research Support; Merck Sharp & Dohme Corp.

Funding
National Institutes of Health (R01DK106348); Vanderbilt University; University of Nebraska-Lincoln Nutrition and Health Sciences Fund
261-LB: Hepatocyte Gdf15 Protects against CCL4-Induced Liver Injury Independent of Changes in Feeding and Inflammation
Authors: KASTROLL JAKE , JURCZAK MICHAEL J. , BELLO FIONA , VANDEVENDER AMBER , SIPULA IAN J. , ALDER JONATHAN 
Published: June 2023

Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels increase in obesity and fibrotic liver disease, like NAFLD. GDF15 KO mice develop more severe fibrosis after carbon tetrachloride (CCL4) treatment, suggesting a protective effect of GDF15. Despite this, the tissue specific sites of GDF15 production during liver injury are unknown and the potential for local action is understudied. To determine the hepatocyte specific contribution of Gdf15 to changes in circulating GDF15 and effects on fibrosis, we utilized a Gdf15 KO-first mouse strain where endogenous expression of Gdf15 can be restored in a tissue specific fashion via Flp recombinase (FLP). Gdf15 KO-first mice received AAV8-TBG-Gfp (KO+GFP) or AAV8-TBG-Flp (liver specific Gdf15 expression; KO+FLP) and were treated with CCL4 3X per week for 3 weeks alongside wild type (WT) controls. CCL4 increased circulating GDF15 7X in WT and 3.5X in KO+FLP compared with WT vehicle (VEH), and levels were undetected in KO+GFP mice. CCL4 caused significant BW loss in WT and KO+FLP mice and had no effect on KO+GFP mice. CCL4 reduced feeding similarly in all groups despite marked differences in circulating GDF15. Liver gene expression markers of fibrosis were upregulated in KO+GFP mice compared with WT and KO+FLP mice. Interestingly, despite differences in fibrosis, circulating cytokines and liver expression of inflammatory markers were reduced in KO+GFP and KO+FLP compared with WT mice. These data demonstrate that hepatocyte Gdf15 protects against CCL4-induced fibrotic liver injury independent of feeding and inflammation. They also suggest that GDF15 may have local, GFRAL-independent effects within liver to remodel the extracellular matrix that require further study.

Disclosure
J. Kastroll: None. M. J. Jurczak: None. F. Bello: None. A. Vandevender: None. I. J. Sipula: None. J. Alder: None.
264-LB: Aerobic Exercise Training Reorganizes Skeletal Muscle Mitochondrial and Lipid Droplet Architecture
Authors: PARRY HAILEY A. , AXELROD CHRISTOPHER L. , BAENA VALENTINA , DANTAS WAGNER S. , KIRWAN JOHN P. , GLANCY BRIAN 
Published: June 2023

Exercise is a known intervention to alleviate insulin resistance. This study investigated how a 12-week endurance exercise intervention changes skeletal muscle mitochondrial and lipid droplet architecture in patients with type 2 diabetes. Participants completed 12 weeks of endurance exercise at 70% of their VO2 max five days a week at one hour a day. Muscle biopsies were taken before and 72 hours after the last exercise session. A subset of these muscle biopsies from two participants (58±0 years, 42.3±3.3 BMI, 2.5±0.7 medications, 8.2±0.1% HbA1c) was imaged using focused ion-beam scanning electron microscopy. Due to these results being preliminary, general trends are discussed. A deep-learning model segmented 14,197 mitochondria and 4,400 lipid droplets to assess individual mitochondrial and lipid droplet 3D structures, and mitochondria-to-lipid interactions. Surprisingly, exercise did not change individual mitochondrial and lipid droplet volume, surface area to volume ratio, or sphericity. There was an increase in mitochondria-to-mitochondria and mitochondria-to-lipid droplet interactions after endurance training. These preliminary data suggest that exercise may relieve insulin-resistant skeletal muscle by increasing the connectivity among mitochondria and lipid droplets prior to changing individual organelle morphology. Further analyses are ongoing to confirm these findings.

Disclosure
H. A. Parry: None. C. L. Axelrod: None. V. Baena: None. W. S. Dantas: None. J. P. Kirwan: None. B. Glancy: None.
268-LB: Dietary Resistant Starch Supplementation Upregulates Deoxycholic Acid Production in Mice
Authors: REUTER MELANIE , TUCKER MADELYNN , MARFORI ZARA , SHISHANI RAHAF , BUSTAMANTE JESSICA M. , MORENO ROSALINDA , CUMMINGS BETHANY 
Published: June 2023

The gut microbiome plays an important role in the regulation of metabolic health, largely through the metabolites it produces, making it an important target for management and prevention of diabetes. Some of the most abundant metabolites produced by the gut microbiome are bile acids. Primary bile acids produced in the liver are converted into secondary bile acids by bacteria in the gut via 7-ɑ-dehydroxylation. These secondary bile acids are strong ligands for bile acid receptors known to improve glycemic regulation. However, the bacteria and enzymatic pathways involved in 7-ɑ-dehydroxylation have not been fully defined. Therefore, we are developing tools with which to study the dynamic regulation of gut bacterial 7-ɑ-dehydroxylation. In this study, we hypothesized that feeding mice a diet rich in resistant starch (RS) would alter the gut microbiome to favor bacteria capable of executing 7-ɑ-dehydroxylation. To test this, mice were fed a diet supplemented with RS or an isocaloric (IC) control diet. Profiling of gut luminal bile acids shows that RS supplementation proportionally increases the production of the secondary bile acid, deoxycholic acid (DCA) (DCA as a proportion of total bile acids in gut luminal contents: IC = 0.16 ± 0.03 RS = 0.55 ± 0.08, P = 0.001). RS tended to decrease unconjugated cholic acid (CA) concentrations, the substrate for 7-ɑ-dehydroxylation in DCA production, compared to IC-fed controls. Hepatic expression of the enzyme required for production of CA, Cyp8b1, did not differ between groups. Therefore, these data suggest that RS-induced increases in DCA are due to increased gut bacterial conversion of CA to DCA. Determining which bacteria can carry out 7-ɑ-dehydroxylation is critical to targeting gut bacterial bile acid metabolism. This study demonstrates that RS supplementation upregulates DCA production, identifying RS supplementation as a tool with which to define the dynamic regulation of 7-ɑ-dehydroxylation by gut bacteria.

Disclosure
M. Reuter: None. M. Tucker: None. Z. Marfori: None. R. Shishani: None. J. M. Bustamante: None. R. Moreno: None. B. Cummings: None.
270-OR: Health Care Utilization and Cost Associated with Empagliflozin in Older Adults with Type 2 Diabetes—Results from the EMPRISE study
Authors: HTOO PHYO T. , TESFAYE HELEN , SCHNEEWEISS SEBASTIAN , WEXLER DEBORAH J. , GLYNN ROBERT , SCHMEDT NIKLAS , DERUAZ-LUYET ANOUK , KOENEMAN LISETTE , PAIK JULIE M. , PATORNO ELISABETTA 
Published: June 2023

Within the EMPRISE study program, we compared the cost and healthcare utilization of empagliflozin (EMPA) vs. dipeptidyl peptidase-4 inhibitors (DPP-4i) using Medicare data (2014-18). We identified 23,335 pairs of 1:1 propensity score-matched patients aged ≥65 years with type 2 diabetes (T2D) initiating EMPA or a DPP-4i, overall and stratified by baseline cardiovascular disease (CVD). We estimated ratios and differences in rates of healthcare utilization per 1,000 person-years, and costs per member per year (PMPY) for EMPA vs. DPP-4i using zero-inflated negative binomial or gamma models. Compared to DPP-4i, EMPA was associated with lower rates of hospital days [rate ratio (RR) (95% CI) 0.89 (0.82, 0.97); rate difference (RD) -557 (-587, -528)], number of hospitalizations [RR 0.86 (0.79, 0.93); RD -73 (-84, -61)], and number of emergency visits [RR 0.86 (0.82, 0.91); RD -128 (-145, -111)]. Estimates were similar when stratified by baseline CVD. Relative to DPP-4i, EMPA was associated with lower total costs in USD [RR 0.94 (0.92, 0.96); PMPY -1109 (-1478, -739)], and inpatient costs [RR 0.84 (0.81, 0.87); PMPY -713 (-847, -579)], and nearly-similar pharmacy costs [RR 1.04 (1.02, 1.06); PMPY 355 (177, 532)]. RRs in baseline CVD subgroups were similar, but absolute RDs were larger in those with CVD. Relative to DPP-4i, EMPA reduced healthcare utilization and costs in routine care.

Disclosure
P.T.Htoo: Employee; Johnson & Johnson. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration. H.Tesfaye: None. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; UCB, Inc., Boehringer Ingelheim International GmbH, Stock/Shareholder; Aetion, Inc. D.J.Wexler: Other Relationship; Novo Nordisk A/S. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis, Pfizer Inc. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Paik: None.

Funding
Boehringer Ingelheim (116283)
271-LB: Assessment of P311's Influence on Key Genetic Signatures within Brown Adipose Tissue
Authors: MORETON STEVEN L. , ALURU MANEESHA R. , BADRI KAMESWARA R. 
Published: June 2023

The dramatic ascent in global obesity levels &gt; 40% has ushered in an alarming increase in chronic metabolic illnesses such as insulin resistance, type 2 diabetes, and cardiovascular disease all for which obesity is a major risk factor. This development has created a need for a deeper understanding of the molecular underpinnings which regulate this interplay between obesity and metabolic homeostasis. Our studies show that P311 can modulate adipocyte development, plasticity and there by regulating metabolic function. Novel single cell RNA technology using the 10X platform was performed to assess key adipogenic and metabolic gene signatures. Single cells collected from brown adipose tissue of C57BL/6 control mice (WT) and P311 KO mice were used for RNA sequencing. Bioinformatic analysis using the Seurat package in R evaluated the cellular heterogeneity found in brown adipose tissue, including immune cells, preadipocytes, and beige adipocytes. Marker genes were employed to identify and characterize these distinct cell populations. Visualization using UMAP showed the significant alteration of cluster identities between WT and P311 KO tissue. Our findings showed a significant decrease (p&lt;0.01) in key brown adipocyte signatures in P311 KO brown adipocytes compared to WT brown adipocytes. We observed a tremendous decrease of browning in brown adipocytes switching them to more whitish brown adipocytes in P311KOs compared to WT that could be responsible for deranged metabolic alterations in P311KOs. We conclude that P311 regulates browning of adipocytes there by regulating metabolic homeostasis.

Disclosure
S. L. Moreton: None. M. R. Aluru: None. K. R. Badri: None.

Funding
National Institute of General Medical Sciences (SC1GM141937 to K.R.B.)
273-OR: Hybrid Closed-Loop Therapy vs. Other Modalities of Therapy during Ramadan Intermittent Fasting in Adults and Adolescents with Type 1 Diabetes
Authors: AL-SOFIANI MOHAMMED , ALHARTHI SAHAR , ALBUNYAN SARAH , ALZAMAN NAWEED , KLONOFF DAVID C. , ALGUWAIHES ABDULLAH M. 
Published: June 2023

Introduction: Most people with type 1 diabetes (PwT1D) are considered high risk to fast during the month of Ramadan. Yet, many of them attempt to fast and abstain from eating and drinking from dawn to dusk. Here, we evaluate the association between the sociodemographic indicators, modality of T1D treatment, and number of days when fasting is broken due to diabetes among PwT1D.
Methods: We surveyed 294 PwT1D who attempted to fast during Ramadan 2022, were seen at our Endocrine clinics during the month preceding Ramadan, and who agreed to share their health information and fasting experience. Participants were categorized into 5 groups based on their treatment modality: a) Pump + CGM [Hybrid closed loop (HCL)] (n=62); b) Pump + CGM [Conventional open loop] (n=37); c) Pump + Self-monitoring of blood glucose (SMBG) (n=8); d) Multiple daily injections (MDI) + CGM (n=155); e) MDI + SMBG (n=32). Predictors for fasting most days of Ramadan (i.e. breaking fast ≤ 2 days) were analyzed using uni- and multi-variable logistic regression.
Results: Private health insurance rates were highest among pump users (82%, 63%, and 41% for HCL, Pump + SMBG, and conventional open loop, respectively); whereas, MDI users had the lowest insurance rates (25% and 21% for MDI + SMBG and MDI + CGM, respectively). The median numbers of days when fasting was broken due to diabetes were 2, 5, 3, 3.5, and 2.5 days among the HCL, conventional open loop, MDI + CGM, Pump + SMBG, and MDI + SMBG groups, respectively (p=.047). Users of HCL therapy were two times as likely to complete fasting most days of Ramadan (i.e. breaking fast ≤2 days) compared to MDI + CGM users [odds ratio (95% CI): 2.37 (1.14, 4.90)] after adjusting for age, sex, educational level, employment status, insurance status, and diabetes duration.
Conclusion: Among the common treatment modalities of T1D, the use of HCL pump therapy is associated with the highest rates of fasting most days of Ramadan after adjusting for potential confounders.

Disclosure
M.Al-sofiani: Consultant; Eli Lilly and Company, Speaker's Bureau; Sanofi, Medtronic, Vitalair. S.Alharthi: None. S.Albunyan: Employee; ProMedEx, Medtronic. N.Alzaman: None. D.C.Klonoff: Consultant; EOFlow Co., Ltd., Fractyl Health, Inc., Integrity, Lifecare, Inc., Rockley Photonics, Thirdwayv Inc. A.M.Alguwaihes: Consultant; Eli Lilly and Company, Research Support; AstraZeneca, Novo Nordisk, Speaker's Bureau; Novo Nordisk, Sanofi.