A nutrient sensing transition at birth triggers glucose-stimulated insulin secretion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA613929 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11365000_1.fastq.gz | Fastqsanger.gz | |||
| SRR11365000_2.fastq.gz | Fastqsanger.gz | |||
| SRR11365001_1.fastq.gz | Fastqsanger.gz | |||
| SRR11365001_2.fastq.gz | Fastqsanger.gz | |||
| SRR11365002_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2020-05-07 | GSE147321 | GEO
Project description:A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system of the neonate. Despite their central role in metabolic homeostasis, little is known about how pancreatic β cells adjust to the new nutritional challenge. Here, we find that after birth β cell function shifts from amino acid- to glucose-stimulated insulin secretion in correlation with the change in the nutritional environment. This adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 activity. Disrupting nutrient sensitivity of mTORC1 in mature β cells reverts insulin secretion to a functionally immature state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived β cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrients regulate β cell function, thereby enabling a metabolic adaptation for the newborn.
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Project description:Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient cues adapt insulin secretion by modulating chromatin state and transcription of genes regulating β-cell nutrient sensing and metabolism. Feeding stimulates histone acetylation at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation, features we also observed in the db/db model of chronically increased insulin demand. Moreover, genetic variants associated with fasting glucose levels and type 2 diabetes risk are enriched at LSD1-bound sites in human islets, suggesting interindividual variation in β-cell functional adaptation in humans. These findings reveal nutrient state-dependent modulation of the islet epigenome and identify Lsd1 as a regulator of feeding-stimulated chromatin modification and adaptive insulin secretion.
2023-02-24 | GSE134901 | GEO
Project description:Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in this tissue contributes to hyperglycemia in type 1 and type 2 diabetes. While glucose is known to stimulate insulin secretion by pancreatic b cells, whether it directly engages nutrient-sensing pathways in skeletal muscle to regulate glucose metabolism remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improves postprandial glucose disposal in mice, whereas the muscle-specific ablation impaired insulin action and led to glucose intolerance. Mechanistically, glucose triggers a rapid calcium response in myocytes that acts on the class IIa histone deacetylase HDAC5, leading to Baf60c induction and insulin-independent AKT activation. The pathway is engaged by the anti-diabetic drugs sulfonylureas, suggesting that its therapeutic activation may have beneficial effects on glycemic control in diabetes. We used microarrays to elucidate the role of of Baf60c in transcriptional regulation by glucose in skeletal myocytes.
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Project description:Nutrient regulation of the islet epigenome controls adaptive insulin secretion
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Project description:Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and in fact, characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about the molecular mechanisms underlying how these signals are integrated and transduced into biological effects. Galectins are proteins that bind glycans and are secreted by a poorly characterized non-classical secretory mechanism. Once outside the cell, galectins bind to terminal galactose residues of cell surface glycans and modulate numerous extracellular functions like clathrin independent endocytosis (CIE). Originating in the cytoplasm, galectins are predicted substrates for O-GlcNAc addition and removal; and, as we have shown, galectin 3 is a substrate for OGT. This study also shows that galectin 3 secretion is sensitive to changes in O-GlcNAc levels. We determined that there is a significant difference in O-GlcNAcylation status between cytoplasmic and secreted galectin 3. We observed dramatic alterations in galectin 3 secretion in response to nutrient conditions and these changes were dependent on dynamic O-GlcNAcylation. Importantly, we showed that these O-GlcNAc driven alterations in galectin 3 secretion drove changes in CIE. These results indicate that dynamic O-GlcNAcylation of galectin 3 plays a role in modulating its secretion and can tune its function of transducing nutrient sensing information coded in cell surface glycosylation into biological effects.
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Project description:Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health.
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Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.
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