Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis
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PROVIDER: PRJNA985789 | ENA |
REPOSITORIES: ENA
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Project description:Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398 ).
| S-EPMC10709271 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-07 | GSE235398 | GEO
Project description:In summary, we discovered (1) that glucose dose-dependently inhibits cardiac maturation in vitro and in vivo, (2) that the maturation-inhibitory effect is dependent on nucleotide biosynthesis via the PPP, (3) that the developing heart accomplishes glucose deprivation condition by limiting the glucose uptake at late gestational stages during normal embryogenesis, and (4) that perturbation of the glucose deprivation in gestational diabetes affects natural cardiomyocyte maturation and potentially contributes to congenital heart disease.
2017-12-01 | GSE84814 | GEO
Project description:Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity
| PRJNA962479 | ENA
Project description:Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in murine hepatocytes. These findings identify SLC13A3 as a key itaconate importer in murine hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.
2024-07-08 | GSE230735 | GEO
Project description:Metabolic dysfunction of skeletal muscle is often prevalent at an early stage in the development of several non-communicable diseases. Here, we investigated the effect of a myokine, secreted protein acidic and rich in cysteine (SPARC), on glucose tolerance in human and mouse skeletal muscles. SPARC knockout mice showed marked decreases in parameters for whole-body glucose metabolism, along with reduced phosphorylation of AMPK and Akt in skeletal muscle tissues compared with wild-type mice. Furthermore, mice injected with SPARC showed improved glucose tolerance concomitant with AMPK activation. Exogenous SPARC treatment accelerated glucose uptake in muscle tissues isolated from wild-type mice but not from AMPKγ3 knockout mice. In muscle cells, SPARC increased glucose uptake concomitant with AMPK activation, mediated by a calcium-dependent signal. Chronic treatment of SPARC restored metabolic functions in diet-induced obese mice. These findings suggest that SPARC improves glucose metabolism via AMPK activation in skeletal muscle, providing mechanistic insights on exercise-induced metabolic benefits and physical inactivity-induced glucose intolerance.
2019-06-03 | GSE93546 | GEO
Project description:Saccharomyces cerevisiae developed elegant mechanisms to monitor nutrient availability and trigger adaptative responses to nutrient deficiency. Nutrient sensing requires close coordination of cell surface sensors with intracellular mechanisms. This yeast senses the presence of glucose by two modified hexose transporters, Rgt2 and Snf3 (regulating expression of genes encoding hexose transporters) and the G-protein coupled receptor Gpr1 (modulating Protein Kinase A (PKA) activity).. It has been difficult to differentiate between cellular responses mediated by cell surface and intracellular sensors, respectively. Using a strain that is devoid of glucose uptake, we show that the mere presence of glucose does not elicit any glucose-dependent transcriptional responses. This indicates that signals generated by surface sensors are not sufficient to mediate glucose-dependent transcriptional responses. Instead, intracellular glucose or metabolites derived from it are required for transcriptional changes associated with glucose exposure. We used microarrays from biological triplicate samples to measure the global transcriptional response to sudden addition of glucose to yeast cells growing at steady state on ethanol. The experiment was conducted using a strain that is devoid of glucose uptake and compared with an isogenic strain.
2010-03-02 | GSE20566 | GEO
Project description:Listeria monocytogenes (Lm) strains expressing high levels of the virulence regulator PrfA (mutant PrfA* or wild-type PrfA) show strong growth inhibition in minimal media when supplemented with glucose but not when supplemented with glucose-6-phosphate compared to the isogenic strains expressing low levels of PrfA. A significantly reduced rate of glucose uptake is observed in the PrfA* over-expressing strain growing in LB supplemented with glucose. Comparative transcriptome analyses were performed with RNA isolated from a prfA mutant and the isogenic strain carrying multiple prfA or prfA* copies on a plasmid. The analysis reveals in addition to high transcriptional up-regulation of the known PrfA-regulated virulence genes (group I), less pronounced up-regulation in the expression of several phage- and metabolic genes (group II) and strong down-regulation of several genes involved mainly in carbon- and nitrogen- metabolism in the PrfA* over-expressing strain (group III). Among the latter genes are in particular the nrgAB-, gltAB-, glnRA- (involved in nitrogen metabolism), ilvB- operons (involved in biosynthesis of the branched chain amino acids) and genes for some ABC transporters. Most of the down-regulated genes have been shown previously in Bacillus subtilis to belong to a class of genes whose expression is negatively affected by impaired glucose uptake. The results lead to the conclusion that excess PrfA(*) interferes with component(s) essential for PTS-mediated glucose transport. Keywords: Metabolism and Virulence gene expression
2006-05-01 | GSE4414 | GEO
Project description:Saccharomyces cerevisiae developed elegant mechanisms to monitor nutrient availability and trigger adaptative responses to nutrient deficiency. Nutrient sensing requires close coordination of cell surface sensors with intracellular mechanisms. This yeast senses the presence of glucose by two modified hexose transporters, Rgt2 and Snf3 (regulating expression of genes encoding hexose transporters) and the G-protein coupled receptor Gpr1 (modulating Protein Kinase A (PKA) activity).. It has been difficult to differentiate between cellular responses mediated by cell surface and intracellular sensors, respectively. Using a strain that is devoid of glucose uptake, we show that the mere presence of glucose does not elicit any glucose-dependent transcriptional responses. This indicates that signals generated by surface sensors are not sufficient to mediate glucose-dependent transcriptional responses. Instead, intracellular glucose or metabolites derived from it are required for transcriptional changes associated with glucose exposure. We used microarrays from biological triplicate samples to measure the global transcriptional response to sudden addition of glucose to yeast cells growing at steady state on ethanol. The experiment was conducted using a strain that is devoid of glucose uptake and compared with an isogenic strain. The CEN.PK strain was used in this research. A strain with all known hexose transporters deleted (Null strain) was compared with an isogenic reference. The two strains were grown in a chemostat (D = 0.1 h-1) using ethanol as the carbon source. Transcriptional responses between the strains were measured in biological triplicates at steady state and then pulsed with glucose at time t = 0. Transcriptional response was measured again after t = 20 min to determine changes in gene expression changes only in response to the presence of glucose.
2010-03-06 | E-GEOD-20566 | biostudies-arrayexpress
Project description:Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed ‘committed pre-adipocytes’ from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.
2023-12-13 | GSE250078 | GEO