bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-LB: Flash Glucose Monitoring in the Reduction of Hypoglycemia in Diabetic Kidney Disease: A Randomised Controlled Trial
Authors: LING JAMES , NG JACK K. , MA RONALD C. , KONG ALICE P. , LUK ANDREA , SZETO CHEUK CHUN , CHAN JULIANA C. , CHOW ELAINE 
Published: June 2021

Patients with moderate-to-advanced diabetic kidney disease (DKD) are at high risk of hypoglycemia. There are few studies evaluating personal continuous glucose monitoring (CGM) use in this group. We investigated whether flash glucose monitoring (FGM) was effective in reducing hypoglycemia compared with standard self-monitoring of blood glucose (SMBG) in individuals with chronic kidney disease (CKD) stages 3b-5 (non-dialysis). This was a single-centre, parallel-group randomised clinical trial of 94 adults with diabetes and CKD [G3b (n=36), G4 (n=44) and G5 (n=14)] and a history of hypoglycemia. Patients were randomly assigned 1:1 to FGM or SMBG for 16 weeks. Both groups received structured education on hypoglycemia and monthly reviews by healthcare professionals. Blinded CGM was performed at baseline and end of study in both groups. Patients were aged (mean±SD) 65.4±9.0 years with estimated glomerular filtration rate (eGFR) 26.1±9.6 ml/min/1.73m2, HbA1c 7.4±0.8% and median duration of diabetes for 20 years. 93 patients had type 2 diabetes and 99% were on insulin. After 16 weeks, percentage time &lt;70mg/dL (3.9 mmol/L) decreased significantly from 4.0% to 2.5% in FGM group (- 1.7%; 95% CI -3.4 to -0.01%) but not in SMBG group (-1.1%; 95% CI -2.6 to 0.4%; between-group difference, p=0.73). Mean HbA1c improved significantly in both FGM (-0.33%, 95% CI -0.52 to -0.1) and SMBG groups (-0.36%, 95% CI -0.52 to -0.21; between-group difference p=0.08). One severe hypoglycemic event occurred in the FGM and none in SMBG group. The acceptability of FGM was high with overall 87% mean sensor use and average 8 scans per day. FGM was effective in reducing hypoglycemia and improving HbA1c in moderate-to-advanced DKD, but not significantly different from SMBG. Future studies are needed to assess whether real-time CGM with alerts would further reduce hypoglycemic episodes in this high-risk group.

Disclosure
J. Ling: None. J. K. Ng: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. C. Szeto: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis.

Funding
Hong Kong College of Physicians; University Grants Committee Research Matching Grant Scheme
203-OR: Measurement of Intact Insulin by Mass Spectrometry Identifies Nonalcoholic Fatty Liver Disease (NAFLD)
Authors: BRIL FERNANDO , MCPHAUL MICHAEL J. , KALAVALAPALLI SRILAXMI , LOMONACO ROMINA , BARB DIANA , GODINEZ EDDISON , CUSI KENNETH 
Published: June 2021

Patients with NAFLD are characterized by insulin resistance (IR) and hyperinsulinism. However, prior studies have been unable to predict NAFLD based on IR measurements. The aim of this study was to explore the application of a newly validated measurement of intact insulin by mass spectrometry to predict NAFLD in patients without diabetes. Ninety-eight patients were recruited and underwent: a 2-hour OGTT with measurements of insulin every 30 min, and a liver magnetic resonance spectroscopy (1H-MRS) to measure liver fat and diagnose NAFLD. A mass spectrometry method was used to measure intact molecules of insulin. A total of 62 patients had NAFLD (48±11 yr, 66% male, BMI: 34.4±4.6kg/m2, A1c: 5.8±0.4%); and 36 did not have NAFLD (52±12 yr, 56% male, BMI: 30.5±6.8kg/m2, A1c: 5.5±0.4%). Fasting insulin levels were higher in NAFLD patients (17±10 vs. 7±3 μU/ml, p&lt;0.001), but showed similar excursions during the OGTT (120 min incremental AUC: 7.4 [4.4-14.5] vs. 5.7 [4.2-8.9], p=0.22). Fasting intact insulin measurements had an AUROC of 0.90 (0.84-0.96) to predict NAFLD. This was significantly better than measuring insulin by radioimmunoassay (RIA) (AUC 0.80 [0.71-0.89], p=0.007). Using a cut-off of 10.5 μU/ml, we observed a sensitivity, specificity, PPV, and NPV of 92% (87-98%), 71% (62-80%), 79% (71-87%), and 89% (83-95%), respectively. Intact fasting insulin was better than other clinical variables (e.g., ALT, AST, triglycerides, HDL, glucose, A1c, and BMI) to predict NAFLD. When combined with ALT (intact insulin x ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and PPV and NPV of 93 and 88%, respectively. This newly described approach was significantly better than previously validated non-invasive scores such as NAFLD-LFS (p=0.009), HIS (p&lt;0.001) and TyG index (p=0.039).
Conclusions: In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and non-invasive strategy to predict presence of NAFLD.

Disclosure
F. Bril: None. M. J. Mcphaul: Employee; Self; Quest Diagnostics. S. Kalavalapalli: None. R. Lomonaco: None. D. Barb: None. E. Godinez: None. K. Cusi: None.

Funding
The Obesity Society; University of Florida
205-LB: HGFAC Is a ChREBP-Regulated Hepatokine That Enhances Glucose and Lipid Homeostasis
Authors: SARGSYAN ASHOT , DORIDOT LUDIVINE , HANNOU SARAH A. , TONG WENXIN , SRINIVASAN HARINI , IVISON RACHAEL , MONN RUBY , KOU HENRY H. , HALDEMAN JONATHAN , ASTAPOVA INNA , TSAI LINUS T. , HERMAN MARK A. 
Published: June 2021

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates metabolic gene programs. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating triglycerides (TG). The transcriptional targets that mediate its pleiotropic physiological effects are poorly understood. To identify novel ChREBP-regulated hepatokines that contribute to its effects on metabolism, we integrated ChIP-seq for ChREBP in mouse liver with human GWAS data for TGs and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising candidate. HGFAC is a circulating zymogen that activates Hepatocyte Growth Factor (HGF), a multifunction cytokine involved in cellular growth, motility, and morphogenesis. High fructose feeding increased circulating HGFAC by 1.8-fold (p&lt;0.001) and this was abrogated in liver specific ChREBP KO mice. Similar increases were seen in mice fed high sucrose/high fat diet and in obese Zucker rats (2.6-fold, p&lt;0.001). In humans, expression of hepatic ChREBP transcriptional targets associated with HGFAC expression (Pearson r= 0.66, p &lt;0.0001), and its expression was elevated in patients with obesity and T2D (2.7-fold, p&lt;0.001). Putative loss of function variants in HGFAC associated with hypertriglyceridemia in humans, and deletion of HGFAC in mice increased circulating TGs (1.4-fold, p&lt;0.005), and caused glycerol and glucose intolerance despite a 40% reduction in hepatic TG content (p&lt;0.001). RNA-seq indicated that HGFAC regulates hepatic metabolism through modulation of hepatic PPARG expression. Reciprocal effects on PPARG expression and metabolic phenotypes were observed following adenovirus HGFAC overexpression in mice. Moreover, HGF induces PPARG express 1.3-fold in HepG2 cells (p&lt;0.0001). In conclusion, ChREBP responds to carbohydrate overnutrition and regulates systemic glucose and lipid metabolism via an HGFAC-HGF-PPARG signaling axis.

Disclosure
A. Sargsyan: None. I. Astapova: None. L. T. Tsai: None. M. A. Herman: Research Support; Self; Eli Lilly and Company. L. Doridot: Employee; Spouse/Partner; Eli Lilly and Company. S. A. Hannou: None. W. Tong: None. H. Srinivasan: None. R. Ivison: None. R. Monn: None. H. H. Kou: None. J. Haldeman: None.

Funding
American Diabetes Association (1-19-PDF-088 to A.S.)
207-LB: Simultaneous 2H/13C Assessment of Liver and Kidney Metabolic Fluxes Reveals Reciprocal Upregulation of Renal Gluconeogenesis in Hepatic PEPCK-C Knockout Mice
Authors: RAHIM MOHSIN , HASENOUR CLINTON M. , BEDNARSKI TOMASZ , HUGHEY CURTIS C. , WASSERMAN DAVID , YOUNG JAMEY 
Published: June 2021

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a novel stable isotope approach to simultaneously quantify hepatic and renal gluconeogenic and oxidative metabolic fluxes. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic PEPCK (KO). Experiments were performed in fasted (~18hr) KO and wild-type (WT) littermate mice (n≥4, per group) fitted with jugular vein and carotid artery catheters. A multi-compartment metabolic model was used to assess fluxes using the isotopic enrichment of plasma and tissue metabolites from mice infused with 2H/13C isotopes. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis of 17 and 30-fold, respectively. This was consistent with a ~2-fold rise in PEPCK-C and mitochondrial PEPCK protein expression in the kidneys. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by regulating gluconeogenic flux through PEPCK-C. This reciprocity creates a layer of redundancy that protects glucose homeostasis in the event that hepatic glucose production is impaired. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multi-tissue metabolism in various genetic, (patho)physiological, and pharmacological settings.

Disclosure
M. Rahim: None. C. M. Hasenour: Employee; Self; Eli Lilly and Company. T. Bednarski: None. C. C. Hughey: None. D. Wasserman: None. J. Young: Consultant; Self; Pfizer Inc., Stock/Shareholder; Self; Metalytics.

Funding
National Institutes of Health (R01DK106348, U01CA235508, T32DK101003, U24DK059637)
208-LB: Peripheral CB1 Inverse Agonism Improves Metabolism in DIO Mice Independent of Hepatic FGF21
Authors: LIU JIE 
Published: June 2021

Obesity is associated with an overactive endocannabinoid system, and selective blockade of CB1R in peripheral tissues, including the liver, reverses HFD-induced metabolic abnormalities by restoring normal lipid and glucose homeostasis and avoid unwanted adverse neuropsychiatric effects. The CB1R inverse agonist JD5037 has been shown equal effective with its brain-penetrant compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance. Fibroblast growth factor-21 (FGF21) has emerged as a major endocrine regulator derived from the liver that reduces adiposity and hepatic steatosis and improves glucose tolerance and insulin sensitivity, with changes similar to those induced by CB1R blockade. Here we investigated whether FGF21 mediate the metabolic effects of CB1R blockade by JD5037 in DIO mice. In C57BL/6J wild-type mice, HFD caused a robust increase in hepatic Fgf21 mRNA and serum FGF21 levels, which were reversed by chronic peripheral CB1R antagonist JD5037 treatment to levels observed in STD or vehicle-treated hepatocyte-specific CB1R-/- (hCB1-/-) mice, indicating activation of CB1R in the liver is largely involved in HFD-induced “FGF21-resistant” state. In contrast, the expression of the FGF21 receptor Fgfr1 and co-receptor β-klotho (Klb) were dramatically reduced by HFD in both epididymal fat and brain tissue in wild-type mice, and these effects were reversed by JD5037 treatment. To address whether FGF21 mediated the metabolic effects of CB1R blockade, we repeated JD5037 treatment in liver-specific FGF21-/- (hFGF21-/-) mice. Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in hFGF21-/- mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB1R blockade by inverse agonist in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21.

Disclosure
J. Liu: None.

Funding
National Institutes of Health
209-LB: RNA-Seq Analysis of Liver from Diabetic and NASH Model Mouse Treated with Streptozotocin, High-Fat Diet
Authors: BUI LINH P. , SAKAKIBARA YUKI , TANAKA RYUTO , PIGNEY ELIZABETH H. , HASHIGUCHI TAISHI 
Published: June 2021

Introduction: NASH is a chronic liver disease often associated with type 2 diabetes. It sometimes progresses to more serious conditions such as liver fibrosis and hepatocellular carcinoma (HCC). Therapeutic agents for NASH have not yet been developed, and an animal model with high clinical correlation is required. The STAM mouse is a NASH model mouse with a background of type 2 diabetes. This mouse model shows the same pathological progression as human NASH patients, and has been used for the evaluation of many drug candidates, as well as basic research. However the gene profile, including mutations, has not been elucidated in this model. In this study, we analyzed the RNA-seq data of STAM mice at each pathological stage and examined the clinical correlation at the gene level.
Methods: NASH was induced in male mice by a single injection of streptozotocin solution 2 days after birth and feeding with high fat diet after 4 weeks of age. The mice were sacrificed and livers collected from each disease phase. RNA-Seq libraries were prepared by NEB NEXT Directional Ultra RNA Library Prep Kit (Illumina). The libraries were sequenced on Novaseq (Illumina), and the reads were aligned to mouse genome references using HISAT2. RNA-seq data analysis Sequence reads (150-bp paired read) were aligned to the mouse reference genome (GRCm38/mm10) with HISAT2 (version: 2.1.0) with default parameters.
Results: First, the gene expression of the canonical pathway in NASH progression from steatosis to hepatocellular carcinoma was analyzed. Increased expression was observed in CCL2, TLR4, HSP47, αSMA, c-Myc, and cyclin D1. Since it has been reported that genetic traits are involved in the development of NASH-HCC, we next analyzed the genetic mutations in the STAM mice. The number of individuals showing mutations in Mtor, involved in Insulin signaling, increases as the disease progresses, especially in the HCC phase.
Conclusion: These results indicated a clinical correlation of gene profiles in the STAM mouse.

Disclosure
L. P. Bui: Employee; Self; SMC Laboratories Inc. Y. Sakakibara: Employee; Self; SMC. R. Tanaka: Employee; Self; SMC Laboratories Inc. E. H. Pigney: Employee; Self; SMC Laboratories, Inc. T. Hashiguchi: Employee; Self; SMC laboratories, Inc.
213-LB: Mechanisms of Metabolic Cross Talk between Mitochondrial Pyruvate Carrier Inhibition and Branched-Chain Amino Acid Catabolism in Hepatocytes
Authors: FERGUSON DANIEL , YIEW NICOLE K.H. , MCCOMMIS KYLE S. , COLCA JERRY R. , FINCK BRIAN N. 
Published: June 2021

The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms by which MPC inhibition leads to metabolic improvements are incompletely understood. We evaluated whether MPC inhibitors might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. BCAA concentrations were assessed in plasma collected in EMMINENCE (NCT02784444), a randomized, placebo-controlled trial of the MPC inhibitor MSDC-0602K in people with NASH. MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes endpoints, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH). BCKDH activity is suppressed by phosphorylation mediated by a kinase (BDK) and activated by the phosphatase (PPM1K). In Huh7 or HepG2 cells, MPC inhibitors markedly reduced BCKDH phosphorylation, suggesting increased BCKDH activity. Chemical inhibition or siRNA-mediated silencing of BDK had no effect on suppression of BCKDH phosphorylation by MPC inhibitors. In contrast, PPM1K knockdown prevented the effects of MPC inhibition on phospho-BCKDH. Lastly, we quantified BCKDH phosphorylation in liver of wild-type and hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice after 20 weeks of high fat diet. LS-Mpc2-/- mice exhibited reduced phosphorylation of BCKDH compared to wild-type mice. Lean LS-Mpc2-/- mice also exhibited reduced plasma BCAA concentrations after an overnight fast. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K.

Disclosure
D. Ferguson: None. N. K. H. Yiew: None. K. S. Mccommis: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. B. N. Finck: Advisory Panel; Self; Cirius Therapeutics, Stock/Shareholder; Self; Cirius Therapeutics.

Funding
National Institutes of Health (R01DK104735, T32DK007120)
217-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Elicits Potent and Sustained Body Weight Loss in Obese Animal Models
Authors: LIM SEYOUNG , YANG JIEUN , KIM DO-HOON , JU MI KYEONG , KIM SUKYUNG , PARK YOUNG BONG , SIM BO RA , KIM JUNHWAN , KIM JONG GYUN , OH SE-WOONG 
Published: June 2021

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an Fc fusion GDF15 variant engineered to have extended half-life and improved binding affinity to GDF15 receptors (GFRAL/RET). YH34160 exhibited superior in vitro efficacy over Fc fusion protein comprising wild-type GDF15 in GFRAL/RET overexpressing cells. Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in human. In addition, YH34160 exhibited a potent and sustained weight-lowering effect in the obese mice models. After single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight reduction. Following 8-week repeat dose study in DIO mice, YH34160-treated groups induced more potent and sustained body weight loss compared to the group of long-acting glucagon like peptide-1 receptor agonist (GLP-1RA). Significant body weight reduction and improved lipid profiles by YH34160 was also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. Furthermore, YH34160 in combination with a GLP-1RA demonstrated a complementary effect on body weight loss compared to that of each single agent treatment. These findings indicate that YH34160 would be a promising therapeutic candidate for the treatment of human obesity.

Disclosure
S. Lim: Employee; Self; Yuhan Corporation. S. Oh: Employee; Self; Yuhan Corporation, Stock/Shareholder; Self; Yuhan Corporation. J. Yang: None. D. Kim: None. M. Ju: None. S. Kim: Employee; Self; Yuhan Corporation. Y. Park: Employee; Self; Yuhan Corporation. B. Sim: Employee; Self; Yuhan Corporation. J. Kim: Employee; Self; Yuhan Corporation. J. Kim: None.
217-OR: Glycemic Outcomes by Ethnicity in Adults with Type 1 Diabetes Using Control-IQ Technology: Early Results from the CLIO Study
Authors: HABIF STEPHANIE , SINGH HARSIMRAN , MUELLER LARS , MANNING MICHELLE L. , WHITE KIRSTIN N. , LEAS SCOTT A. , SPENCER ELIAH S. ARONOFF , DOKKEN BETSY , SPENCER ELIAH ARONOFF 
Published: June 2021

Incidence of type 1 diabetes (T1D) is increasing in different ethnic groups. Given the rapid evolution of insulin delivery systems, it is important to evaluate their performance in diverse populations. The Control-IQ Observational (CLIO) Study is an IRB-approved, single-arm, longitudinal study evaluating real-world use of the Control-IQ system in people with T1D (PWT1D) who had been prescribed the Tandem t:slim X2 insulin pump with Control-IQ technology. We evaluated relationships between glycemic metrics, diabetes-specific items, and demographic variables at baseline and 3 months after study start for adult participants who had uploaded at least 21 days (21d) of Control-IQ feature usage data to Tandem’s t:connect® web application and had ≥75% CGM use during this time. Impact of baseline factors on glycemic outcomes were analyzed using generalized linear models. In all, 1094 PWT1D (963 Caucasians, 72 Hispanics, 45 African Americans, 25 Asians) were included in the analysis. African Americans had the highest HbA1c at baseline (8.1%) in contrast to the Caucasian majority (7.3%). Glucose Management Indicator (GMI) at 21d reflected significant glycemic improvement across all ethnic groups with Asians showing the lowest GMI (6.77%) followed by Caucasians (6.98%). At 21d, the sensor time in range (TIR) (median) of African Americans (62.7%, IQR=53.4-74.7) was significantly lower than for Caucasians (75.1%, IQR=70.3-81.0) while controlling for age, gender, reported exercise, annual income, and prior therapy (p=0.004). Baseline HbA1c was the key factor predicting TIR at 21d followed by exercise, annual income, and multiple daily injections (prior therapy). We identified disparities in glycemic outcomes across socioeconomic and demographic groups at baseline that remained after initiating an automated insulin delivery system. Nevertheless Control-IQ technology significantly improved glycemic outcomes for all ethnic groups.

Disclosure
S. Habif: Employee; Self; Tandem Diabetes Care. H. Singh: Employee; Self; Tandem Diabetes Care. L. Mueller: Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. M. L. Manning: Employee; Self; Tandem Diabetes Care. K. N. White: Employee; Self; Tandem Diabetes Care. S. A. Leas: Employee; Self; Tandem Diabetes Care. E. S. Aronoff spencer: None. B. Dokken: Employee; Self; Tandem Diabetes Care, Stock/Shareholder; Self; Tandem Diabetes Care. E. Aronoff spencer: None.