bluuebunny/crossref_metadata_2025_split huggingface dataset:
Both Elafibranor and Liraglutide Improve NAFLD / NASH but Affect Differentially the Hepatic Lipidome and Metabolome in a Diet-Induced Obese and Biopsy-Confirmed Mouse Model of NASH
Authors: Perakakis Nikolaos , Stefanakis Konstantinos , Feigh Michael , Veidal Sanne S , Mantzoros Christos S 
Published: May 2021

Abstract
Treatment of Nonalcoholic fatty liver disease (NAFLD) constitutes an unmet clinical need owing to the relatively limited efficacy of both novel and readily available metabolic medications, thus warranting pathobiological investigations on the mechanisms of single or combination regimens. In this context, our study aimed to assess and compare whether and how liraglutide, a glucagon-like peptide-1 receptor agonist, and elafibranor, a dual peroxisome proliferator-activated receptor alpha-delta agonist, may affect hepatic histology and metabolipidomic fingerprints in a model of advanced NAFLD. Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by AMLN diet (40% fat with 20% trans-fat, 2% cholesterol and 22% fructose) were randomized to receive for 12 weeks: a) Liraglutide (0.4 mg/kg/d s.c.), b) Elafibranor (30 mg/kg/d p.o.), c) vehicle. Metabolic indices, liver function markers, liver pathology, and metabolomics/lipidomics were assessed at study completion. Both drugs markedly reduced body weight and fat percentage (p-value &lt;0.001), and improved glucose tolerance and insulin sensitivity, as indicated by oral glucose and intraperitoneal insulin tolerance tests. Hepatic lipid content was downregulated under both treatments (p-value &lt;0.001), especially under elafibranor, which also elevated liver weight in contrast with liraglutide (p-value vs liraglutide &lt;0.001). NAFLD activity score (pre-to-post) and its histological components were substantially improved (mean difference ± standard error of mean: -1.4 ± 0.3 for liraglutide; -2.0 ± 0.2 for elafibranor), with elafibranor demonstrating a more robust anti-steatotic effect vs liralgutide (p-value &lt;0.01) as well as anti-fibrotic effects (-0.5 ± 0.1). Liraglutide also limited the immunohistochemical expression of pro-inflammatory markers of Kupffer and hepatic stellate cell function (Galectin-3, Collagen type I alpha 1, and alpha-smooth muscle actin). In the omics analysis, elafibranor profoundly ameliorated the hepatic lipidome by diminishing the concentrations of glyceride species, increasing phospholipids and carnitine metabolites, and modifying key regulators of fatty acid oxidation, inflammation, and oxidative stress, including metabolites of methionine, glutathione, and pantothenate. Liraglutide significantly affected bile acid and carbohydrate metabolism by restoring the concentrations of metabolically beneficial primary and secondary bile acids, glycogen metabolism by-products, and pentoses, thus probably driving glycogen utilization-turnover and nucleic acid synthesis. Thus, liraglutide and elafibranor diverge in their mechanistic treatment of advanced NAFLD pathology, indicated by their robust but differential regulation of the hepatic metabolipidome. These findings support their combinatory therapeutic evaluation in future studies.
Analysis of Novel Histone Methylase MLL Function for Glucose Metabolism in Mouse Pancreas
Authors: Yoshino Satoshi , Ishida Emi , Horiguchi Kazuhiko , Matsumoto Shunichi , Nakajima Yasuyo , Yamada Eijiro , Okada Shuichi , Yamada Masanobu 
Published: May 2021

Abstract
Background) Myeloid / Lymphoid or Mixed-lineage leukemia gene (MLL) is translocated to chromosome 11 long arm q23 region (11q23) and the MLL fusion gene expressed as a result of translocation reconstruction plays an important role in MLL-related leukemia development. It has also been reported that MLL and MLL protein play an important role in tumor development as a Menin-binding protein in Multiple Endocrine Neoplasia Type I (MEN1). More recently, normal MLL protein has been shown to have histone H3 lysine 4-methylation (H3K4-HMT) activity and to be an epigenetic transcriptional regulator. In addition, the function of MLL protein as a histone methylase has been reported in the gene region involved in metabolism regions. Here, we analyzed the involvement of MLL in glucose metabolism in the pancreas using MLL knockout mice. Methods:) Glucose metabolism in MLL knockout mice and the function of MLL in cultured cells were analyzed. Result) Since the homozygotes of MLL knockout mice are embryonic lethal, we analyzed them using Heterozygous mice. MLL heterozygous mice showed significantly weight loss compared to the wild type mice. MLL heterozygous mice showed no difference in food intake compared to wild type mice. IPGTT showed impaired glucose tolerance in MLL heterozygous mice. However, ITT showed no insulin resistance and decreased insulin secretion during glucose loading. In GSIS tests, Islets isolated from heterozygous mice pancreas have been observed to decrease insulin secretion in the response to glucose stimulation. In comprehensive gene analysis using Microarray analysis of mRNA extracted from mice islet, the gene expression changes related insulin secretion and apoptosis have been revealed in MLL heterozygous mice. Histological search showed no decrease in β-cell number, and immunohistological search showed no difference in insulin, glucagon, and TUNEL staining between heterozygous and wild type mice. And also, MLL knockdown was performed in a cultured cell line. Insulin secretion was decreased to glucose stimulation in MLL knockdown cell line same as in MLL knockout mice. In addition, RNA microarrays were performed to these cell lines, several same genes that have confirmed in MLL mouse islets were observed in MLL knockdown cell. In conclusion, MLL knockout mice showed decreased insulin secretion. It was suggested that MLL may be involved in insulin secretion in islets.
BLNK/BTK: Novel Components in the NF-kappa B Pathways of Endothelial Cells in Diabetic Condition
Authors: Singh Madhu V , Wong Thomas , Dokun Ayotunde O 
Published: May 2021

Abstract
Peripheral artery disease (PAD) is atherosclerotic occlusion of vessel outside the heart that most commonly affects the lower extremities. The effects of PAD-related ischemia are exacerbated under diabetic hyperglycemic conditions. Under ischemic conditions, an adaptive induction of the NFkB pathways is in vascular endothelial cells is required for recovery. We have recently shown that prolonged exposure of cells to high glucose before ischemia resulted in impairment of the canonical NFkB pathway through decrease in IkBa degradation. However, the signaling pathways involved in hyperglycemia and ischemia mediated effects on the NFkB pathways are not well understood. Since the NFkB signaling pathways propagate through a cascade of phosphorylation events, we used arrays of antibodies to approximately 100 proteins known to participate in the NFkB pathway to identify the changes in their phosphorylation states in human umbilical vein endothelial cells (HUVEC). Cells grown for three days either in culture medium with normal glucose (LG) or high glucose (HG) were subjected to ischemia for 24 hours (LGI and HGI, respectively). Cell lysates were then incubated with the array of antibodies printed on glass slides (Full Moon Biosystems, Sunnyvale, CA) and fluorescent signals were digitally recorded and normalized. The change in protein phosphorylation was calculated by dividing the intensity of the phosphorylated spot by the signal intensity of the corresponding non-phosphorylated spot for each protein. Differential expression between LG and LGI samples, and HG and HGI were calculated by dividing the phosphorylation ratio of the LGI and HGI with that of the LG and HG controls, respectively. A threshold of 1.5-fold increase or decrease was used to determine changes. Compared to the LG, LGI samples had 26 protein sites with increased phosphorylation whereas 36 sites had decreased phosphorylation. Similarly, compared to HG, HGI samples increased phosphorylation of 25 protein sites and decreased phosphorylation of 40 sites. A Venn-diagram analysis of LGI and HGI sites revealed 8 sites with an increase and 12 sites with a decrease in phosphorylation were specific to HGI. Pathway analyses using bioinformatics tools on 65 modulated phosphorylation sites in HGI (represented by 35 genes) suggested involvement of B cell linker/adapter protein (BLNK)/Bruton’s tyrosine kinase (BTK) that are critical for B cell antigen receptor (BCR)-coupled signaling. BTK expression in EC was confirmed by immunoblotting. Inhibition of BTK by a specific inhibitor terreic acid restored IkBa degradation in EC grown in high glucose suggesting a critical role of BLNK/BTK in diabetic ischemia. Thus, we have identified BLNK/BTK as potentially new components of the NFkB pathway in endothelial cells that contributes to the poor recovery during hyperglycemic ischemia.
Definition of Norma / Prediabetes Cut-off Point for Fasting Glycaemia on the Basis of Glucose Tolerance Test and HbA1c Interrelationships
Authors: Ismayilova Sevil , Sultanova Sadaqat , Huseynova Aygun , Mirzazade Valeh 
Published: May 2021

Abstract
Unification of the approach to the diagnosis of prediabetes (PD) is hardly in doubt. The borderline between PD and diabetes is recognized by all, as well as the upper and lower bounds of PD according to the results of glycemia 120 minutes after 75 g glucose loading (GL120). There are still ambiguities regarding glycohemoglobin (HbA1c) and fasting glycemia (FG). For determination of the Norma/PD cut-off point for FG, we analyzed 85 nondiabetic glucose tolerance test results (75.0 glucose; Samples of fasting blood, and 30, 60, 90, 120 minutes after glucose loading) by using correlation and regression analysis. Glycemic values were measured in mg/dl, HbA1c values were measured in %. The fact of identifying the relationship between FG and Gl120 (r=+0.52 [95%CI +0.346, +0.659]; p&lt;0.001), as well as between FG and HbA1c (r=+0.59 [95%CI +0.432, +0.713]; p&lt;0.001) were the basis of this study. As a result of using regression analysis, multiple regression equations were obtained. GL0 =-4.2439 + 0.1927 * GL120 + 15.462 * HbA1c If GL120 is equal to 139 mg/dl (in accordance with all recommendations), and HbA1c is equal to 5.9% (in accordance with the recommendations of NICE, Canadian Diabetes Association, Australian Diabetes Association, et al.), the maximal normal value for FG should be equal to 114 mg/dl. If GL120 is 139 mg/dl and HbA1c is 5.6% (as recommended by the American Diabetes Association), the maximum normal value of FG should be 109 mg/dl. The optimal upper limit of normal carbohydrate metabolism is levels of GL120 equal to 139 mg/dl, HbA1c - equal to 5.6%, and FG - equal to 109 mg/dl. Values above these and below diabetic levels (200 mg/dl, 6.5%, and 126 mg/dl, respectively) can be considered as prediabetes.
LGR4 and Its Extracellular Domain as Novel Regulators of ß-Cell Survival and Proliferation
Authors: Filipowska Joanna K , Kondegowda Nagesha G , Vasavada Rupangi C 
Published: May 2021

Abstract
Our lab has shown that RANK (Receptor activator of the NF-κB) by interacting with its ligand, RANKL, inhibits ß-cell proliferation and survival; which can be reversed by Osteoprotegerin (OPG). Recently, the G protein-coupled receptor LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4), which binds R-spondin (RSPO), was identified as a novel receptor for RANKL in osteoclast precursor cells. Thus, RANKL can bind two distinct receptors, RANK and LGR4 in osteoclasts, leading to opposite effects on osteoclastogenesis. LGR4 is expressed in rodent and human ß-cells, but the role of this receptor in ß-cells remains unknown. We postulated that LGR4 through its interaction with RANKL is involved in regulating ß-cell survival and proliferation. Our data indicate expression of specific LGR4 family members, Lgr4, Rank, Rankl, is modulated by stressors, such as cytokines, ER stress, diabetes and aging, in INS1 cells, rodent and human islets. Knocking down Lgr4 in INS1 cells or rodent islets has no significant effect on ß-cell proliferation but is detrimental for ß-cell survival in basal and cytokine-stimulated conditions. We also propose that the soluble extracellular domain of LGR4 (LGR4-ECD), which binds to its ligands (RSPO/RANKL), holds therapeutic potential like OPG, by inhibiting the interaction between RANKL/RANK. At 200ng/ml LGR4-ECD significantly enhances young adult (8-12-week-old) and aged (1.y.o.) rodent ß-cell proliferation, as well as human ß-cell proliferation, in islets from not only control subjects (45±17 y.o.), but also with Type 2 diabetes (48±7 y.o.). Additionally, LGR4-ECD significantly promotes mouse and human ß-cell survival against cytokine-induced cell death. Future studies will determine the physiological role of LGR4 and the therapeutic potential of LGR4-ECD on the beta cell in vivo in basal conditions and in the setting of diabetes.
Acknowledgements: Funding: JDRF postdoctoral fellowship # 3-PDF-2020-936-A-N to JF; Human Islets: IIDP
Racial Disparities Among Clinical Trials for Inherited Forms of Lipodystrophy
Authors: Abel Brent S , Cochran Elaine K , Startzell Megan S , Brown Rebecca J 
Published: May 2021

Abstract
Background: There has been renewed interest in understanding how medical research serves minority communities disproportionally affected by disease. A recent study in a predominantly white population identified 12 subjects with partial lipodystrophy by genetics without clinical diagnosis of lipodystrophy (Gonzaga-Jauregui et al., 2020). Partial lipodystrophies are rare monogenic disorders leading to diabetes that can be challenging to diagnosis due to their similarity with common obesity-associated metabolic syndrome. We hypothesize minority populations may be underdiagnosed with lipodystrophy, and thus underrepresented in clinical trials.
Methods: We compared racial demographics of lipodystrophic subjects participating in clinical trials to subjects with predicted loss-of-function (pLOF) mutations in 4 genes associated with lipodystrophy in the GnomAD dataset (&gt;140K exome sequences): LMNA & PPARG (causing dominantly inherited partial lipodystrophy), and AGPAT2 & BSCL2 (causing recessively inherited generalized lipodystrophy, which is more phenotypically apparent, as an internal control for the study design). We also compared rates of synonymous mutations in these 4 genes among races to test if subjects of different ethnicities may be more genetically predisposed to developing inherited forms of lipodystrophy. Comparisons were done using chi-square analysis.
Results: We identified 322 subjects with pLOF mutations in genes associated with lipodystrophy in the GnomAD dataset. The racial composition of GnomAD subjects with pLOF mutations in each gene was different than GnomAD subjects without pLOF mutations (p&lt;0.001). 144 lipodystrophic subjects with known pathogenic variants in these genes participated in clinical trials. The racial composition of GnomAD and clinical trial subjects with LMNA mutations were significantly different (p=0.024) with the clinical trial cohort being more enriched for white patients (78 vs 21%) and less enriched for Latino patients (7 vs. 21%). There were no differences for other genes. The rates of synonymous mutations were different among patients of different ethnicities, p&lt;0.001 for all genes.
Discussion: Partial lipodystrophy due to LMNA mutations may be underdiagnosed in Latinos, leading to reduced participation in clinical trials. The lack of differences in other genes suggests there is no overall cohort bias. Different rates of synonymous mutations suggest there may be evolutionary drivers to racial differences in inherited forms of lipodystrophy, such as founder mutations or heterozygote advantage. Future work will determine prevalence of pLOF variants in lipodystrophy-associated genes in other genetic data sets enriched for minority subjects.
The Role of Inositol Phosphate Multikinase (IPMK) in Time Restricted Feeding in Animal Model
Authors: Jung Ik-Rak , Tu-Sekine Becky , Anokye-Danso Frederick , Ahima Rexford S , Kim Sangwon 
Published: May 2021

Abstract
Obesity is a major public health problem of the U.S. and is associated with diabetes, cardiovascular diseases and other diseases. Most research studies focus on excessive food consumption as the main cause of obesity. However, emerging data indicate that the timing of feeding can have significant effects on body weight and metabolism. Numerous studies in animals and small clinical studies in humans have shown that eating erratically over the 24 hour period or out of phase with the circadian rhythm predisposes toward weight gain, steatosis, dyslipidemia, insulin resistance and diabetes. Furthermore, studies indicate that restricting food intake to the active period synchronizes the circadian rhythm and metabolism, enhances weight loss and improves metabolic outcomes. Time restricted feeding (TRF) increases the amplitudes of clock gene expression and pathways mediating nutrient sensing and hepatic metabolism. However, the mechanisms mediating the effects of TRF are not fully understood. Here we characterized mice (10 week-old) fed a high-fat diet ad libitum (ALF) or from 7 pm to 7 am (TRF) for 2 weeks. The basal glucose production rate was similar between the two groups. Under hyperinsulinemic-euglycemic clamp, the glucose infusion rate (GIR) was significantly greater in TRF group compared to ALF group indicating an increase in insulin sensitivity. Using radioisotopic tracers, we demonstrated that the hepatic glucose production (HGP) was significantly reduced and the glucose disappearance rate was increased in TRF group compared to ALF group. Moreover, a biochemical analyses of liver tissues revealed that Inositol phosphate multikinase (IPMK) act as a key enzyme for inositol polyphosphate biosynthesis and play a role in insulin-, nutrient-, and energy-mediated metabolic signaling, was increased during TRF. Moreover, deletion of IPMK in hepatocytes decreased insulin stimulated AKT phosphorylation while increased lipid accumulation and gluconeogenesis. Importantly, hepatic deletion of IPMK attenuated the beneficial effects of TRF suggesting that IPMK in the liver may contributes to beneficial effects of TRF. Our findings provide the potential mechanism by which TRF confers the beneficial effects and may provide a novel therapeutic strategy for treating diabetes.
Clinical Trials Evaluating Turmeric Dietary Supplement Treatment of Obesity-Associated Disorders of Glucose Metabolism or Bone
Authors: Panknin Timothy M , Bucchireddigari Bhanu , Howe Carol , Hauer Megan , Rossi Anthony M , Funk Janet L 
Published: May 2021

Abstract
Curcumin-enriched turmeric dietary supplements (DS) are one of the top selling botanicals in the United States. Recent observational studies by our research group have documented turmeric DS use by almost a quarter of breast cancer survivors concurrent with anti-estrogen therapy and a third of those with rheumatoid arthritis. However, some recent reviews have suggested that there is no evidence of any biological effect of curcumin in humans, albeit without rigorous review of published reports. A scoping review of the literature was therefore undertaken to identify clinical trials testing oral curcumin-containing turmeric dietary supplements in humans. Using a defined search strategy, eight databases were reviewed (thru 05/29/2019), identifying 4767 potential English language reports for inclusion, from which all but n = 315 were excluded after review by three independent observers. The majority of studies reported significant effects of turmeric DS on clinical endpoints. Obesity-associated disorders of glucose and lipid metabolism (n =69, including type 2 diabetes mellitus [T2DM], metabolic syndrome and/or hyperlipidemia) or musculoskeletal disorders (n = 46), of which half related to osteoarthritis, were among the most commonly studied diseases in turmeric DS clinical trials, with reported benefits related to inhibition of inflammation, amelioration of hyperlipidemia, increases in adiponectin, and improved glucose control. As is common for botanical clinical trials, the quality of the studies were variable due to lack of clarity about product content as well as study design (e.g. only 60% of T2DM trials and 74% of osteoarthritis trials were randomized, placebo-controlled and double-blinded). However, particularly with respect to treatment of osteoarthritis and metabolic consequences of insulin resistance, the preponderance of the data were suggestive of beneficial physiologic effects. Given the current widespread use of turmeric DS by Americans and existing evidence of possible clinical benefits, further evaluation of turmeric DS efficacy and safety may be warranted.
Comparison Between Glycemic Variability Values Calculated From Professional-CGM and Glycemic Variability Values Calculated From Personal-CGM
Authors: Takeishi Soichi , Inoue Tatsuo 
Published: May 2021

Abstract
It is important whether the differences between glycemic variability (GV) values calculated from professional CGM and GV values calculated from personal CGM are acceptable when using professional CGM data and personal CGM data together in studies. This is a prospective study. 41 inpatients with type 2 diabetes wore professional CGM (iPro2) and personal CGM (GUARDIAN CONNECT) in parallel for 6 days (CGM attachment: day 1). Each CGM were calibrated 22 times from day 2 to day 5, on the same timing in all patients (n of calibration = 902). Four 24 h GV from day 2 to day 5 per patient were evaluated (n of 24 h GV = 164) on each CGM. There were no significant differences between the standard deviation on professional CGM and that on personal CGM (32.2 mg/dL vs 32.8 mg/dL, p = 0.21). For time in range (70–180 mg/dL) [TIR 70–180], mean glucose levels and coefficient of variation (CV), the values were numerically almost equal between GV on professional CGM and that on personal CGM. However, for TIR 70–180 and CV, the GV on professional CGM was statistically significantly lower than that on personal CGM (70.8 % vs 72.5 %, p = 0.002, 20.6 % vs 21.3 %, p = 0.04); and for mean glucose levels, the GV on professional CGM was statistically significantly higher than that on personal CGM (157.7 mg/dL vs 155.2 mg/dL, p &lt; 0.001). For mean absolute glucose (MAG) and glycemic variability percentage (GVP), the GV on professional CGM was significantly lower than that on personal CGM (25.3 mg/dL/h vs 41.0 mg/dL/h, p &lt; 0.001, 14.4 % vs 31.1 %, p &lt; 0.001). The calibrations, whose blood glucose levels (BG) were higher than ‘sensor glucose levels just before the BG’ (SGjb), were more than those, whose BG were lower than SGjb (482 times vs 420 times). The mean absolute relative differences on professional CGM were significantly lower than those on personal CGM (5.0 % vs 6.3 %, p &lt; 0.001). The study patients correlated to distributions of ‘ratio of CV on personal CGM to CV on professional CGM on the same day’ (correlation ratio: η 2 = 0.48, p &lt; 0.001). The results of TIR 70–180 and mean glucose levels may have been caused by the fact that the calibration BG were high dissociated from SGjb and algorithm of professional CGM is easier to allow the dissociation than that of personal CGM. The results of CV may have been caused by the individual differences in sensor accuracy between professional CGM and personal CGM. The results of MAG and GVP may have been caused by the fact that personal CGM can reveal detailed glycemic variability which cannot be revealed by professional CGM, due to real time calibration. According to purpose of studies, it should be determined whether using professional CGM data and personal CGM data together is acceptable.