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Sequential global gene expression analysis of glucose stimulated human islets

ABSTRACT: Islet transplantation has the potential to benefit patients with type I diabetes, but this cellular therapy is limited by a shortage of islets, which necessitates the collection or production of islets from alternative sources. If islets produced from stem cells are to be used for transplant therapy they should precisely replicate beta-cell function. Characterization of the unique molecular mechanisms underlying the beta-cell’s response to glucose stimulation will allow a better understanding of critical elements that the alternative cells must possess. Human islets from five donors were stimulated with glucose for various durations of time to discover the glucose-responsive pathways operating at a molecular level in islets. Compared with human hepatocytes, fibroblasts and peripheral blood mononuclear cells, human islets displayed distinct gene expression signatures. Seven hundred and forty genes were differentially expressed in islets during short-term glucose stimulation and 42 of these genes were exclusively expressed in terms of tissue specificity and exposure duration. One thousand six hundred and thirty five genes were differentially expressed in islets during long-term glucose stimulation and 148 of these genes were exclusively expressed. The expression of two important glucose-responsive genes TSC2 and ARF1 were measured by real-time PCR in mouse MIN6 beta-cell line. Insulin secretion from ARF1 knockdown MIN6 cells decreased by 1-fold compared with controls, and TSC2-knockdown MIN6 cells decreased by 2-fold. These findings may allow for better direction of the differentiation of other types of cells such as embryonic and induced pluripotent stem cell into insulin-producing cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24555 | GEO | 2016/12/26

SECONDARY ACCESSION(S): PRJNA132647

REPOSITORIES: GEO

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Adrenergic Receptor Stimulation Suppresses Metabolism in the Pancreatic β Cell

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2019-11-08 | PXD006330 | Pride

BHLHE40 is key hypoxia-induced transcriptional repressor in beta cells

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Monitoring Autophagic Flux in vivo Revealed its Physiological Response and Significance of Heterogeneity in Pancreatic Beta Cells

Project description:Autophagy plays an important role in preserving cellular homeostasis in pancreatic beta cells. However, the extent of autophagic flux induced in various physiological settings in vivo is unclear. In this study, we generated transgenic mice expressing pHluorin-LC3-mCherry reporter for monitoring systemic autophagic flux. Our findings revealed that autophagic flux in pancreatic islets enhanced after starvation, although suppression of the flux after short-term refeeding needs more prolonged restarvation in islets than in liver and skeletal muscle. Furthermore, heterogeneity of autophagic flux in beta cells manifested after increasing insulin resistance and intracellular calcium influx by glucose stimulation increased more in high- than low-flux beta cells, with differential gene expression based on the flux. Thus, our monitor mouse enables us to reveal physiological response and biological insight of heterogeneity in autophagic flux in pancreatic beta cells.

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Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion

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2023-12-03 | PXD047140 | Pride

miR-7a is regulated in beta-cell dysfunction and couples early and late stages of pancreatic beta-cell differentiation to insulin secretion

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2015-06-30 | E-GEOD-48195 | biostudies-arrayexpress

Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion

Project description:Pancreatic beta-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair beta-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on beta-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during beta-cell glucose toxicity that impairs expression of proteins with critical roles in beta-cell function.

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Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation

Project description:SC-β cells and native β cells from cadaveric islets have different transcriptome profiles. In this study, we demonstrate that SC-β cells can acquire mature gene signatures via transplantation in mice for 6 months. MAFA, a marker for mature β cells, is expressed and resulted in significant improvements in insulin release and glucose regulation in diabetic mice.

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