A distinct brain-β-cell circuit regulates insulin secretion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA780516 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR16949055.fastq.gz | Fastqsanger.gz | |||
| SRR16949056.fastq.gz | Fastqsanger.gz | |||
| SRR16949057.fastq.gz | Fastqsanger.gz | |||
| SRR16949058.fastq.gz | Fastqsanger.gz | |||
| SRR16949059.fastq.gz | Fastqsanger.gz |
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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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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 -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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Project description:The activity of pancreatic islets’ insulin-producing β-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-β-cells” (namely α-, δ- and γ-cells). Still, it is unclear whether the presence of the non-β-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of β-cells, and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. This is particularly relevant in diabetes, where non-β-cells become dysfunctional and worsen the disease’s pathophysiology. These results support efforts aimed at developing diabetes treatments by generating β-like cell clusters devoid of non-β-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-β-cells into insulin producers.
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Project description:Objective: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and -cell knockout islets. Results: HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions: HDAC3 plays an important role in regulating insulin secretion in vivo and therapeutic intervention may improve glucose homeostasis.
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Project description:Insulin secreted by pancreatic β cells is essential for maintaining the level of blood glucose. Diabetes is mainly caused by the loss of β cells or impaired β cell function. The previous study performed a whole transcriptome analysis on the islets of T2D and the control group, and the results showed that the splicing disorder of the splicing event was about 25%, breast carcinoma amplified sequence 2(BCAS2) is one of the components of the spliceosome, and its function in islet β cell is unclear. Here we report that knockdown of Bcas2 decreases in glucose and KCl-stimulated insulin secretion in the NIT-1 cell line. The pancreas weight, glucose tolerance and insulin sensitivity were detected in normal chow-fed and high-fat diet-fed Bcas2 f/f-βKO mice, and β cell mass and islet size was analyzed by immunohistochemistry. Glucose intolerance developed in Bcas2 f/f-βKO mice, but there were no significant differences in pancreas weight, insulin sensitivity, β cell mass and islet size. Further, GSIS and observation of insulin secretion granules were performed on normal chow-fed mice, and it was found that the insulin level in serum decreased and the number of insulin secretion granules decreased in Bcas2 f/f-βKO mice, which was related to the abnormal splicing of Syt7 and Tcf7l2 pre-mRNA. Taken together, these results demonstrate that BCAS2 is involved in alternative splicing during insulin synthesis and secretion. Elisa,islet isolation,insulin secretion
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