Ontology highlight
ABSTRACT:
PROVIDER: PRJNA578926 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10326062.fastq.gz | Fastqsanger.gz | |||
| SRR10326063.fastq.gz | Fastqsanger.gz | |||
| SRR10326064.fastq.gz | Fastqsanger.gz | |||
| SRR10326065.fastq.gz | Fastqsanger.gz | |||
| SRR10326066.fastq.gz | Fastqsanger.gz |
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Project description:Adult pancreatic β cells are refractory to proliferation, a roadblock for the treatment of insulin-deficient diabetes. Consumption of energy-dense Western or high-fat diet (HFD) triggers mild adaptive β cell mass expansion to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. Here we show that Toll-like receptors (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged islet mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and CDK4 in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
2019-03-21 | GSE101392 | GEO
Project description:The progression towards type 2 diabetes depends on the success of the allostatic response of the pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physio and pathological states such as pregnancy, obesity or ageing. The mechanisms, mediating beta cell mass expansion in these scenarios are not well defined. We have recently showed that beta cell mass failed to expand in ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Here we investigate PPAR gamma dependent transcriptional responses occurring during early stages of the adaptation of beta cells to insulin resistance. As it could be expected we have identified genes known to regulate proliferation and survival signals of the beta cells. Moreover we have also identified new pathways induced in ob/ob islets that fail to do so in POKO islets. Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with activation of immune response and is missing in POKO islets. Other PPARγ dependent differentially regulated pathways include cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation. In this study, we used gene expression arrays to investigate differences between four experimental classes by pairs
2012-01-16 | E-GEOD-33647 | biostudies-arrayexpress
Project description:The inability of the beta-cell to meet the demand for insulin brought about by insulin resistance leads to type 2 diabetes. In adults, beta-cell replication is one of the mechanisms thought to cause the expansion of beta-cell mass. Efforts to treat diabetes require knowledge of the pathways that drive facultative beta-cell proliferation in vivo. A robust physiological stimulus of beta-cell expansion is pregnancy, and identifying the mechanisms underlying this stimulus may provide therapeutic leads for the treatment of type 2 diabetes. The peak in beta-cell proliferation during pregnancy occurs on day 14.5 of gestation in mice. Using advanced genomic approaches, we globally characterize the gene expression signature of pancreatic islets on day 14.5 of gestation during pregnancy. We identify a total of 1,907 genes as differentially expressed in the islet during pregnancy. We demonstrate that the islet's ability to compensate for relative insulin deficiency during metabolic stress is associated with the induction of both proliferative and survival pathways. A comparison of the genes induced in three different models of islet expansion suggests that diverse mechanisms can be recruited to expand islet mass. The identification of many novel genes involved in islet expansion during pregnancy provides an important resource for diabetes researchers to further investigate how these factors contribute to the maintenance of not only islet mass, but ultimately beta-cell mass.
2010-06-26 | E-MTAB-120 | biostudies-arrayexpress
Project description:The progression towards type 2 diabetes depends on the success of the allostatic response of the pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physio and pathological states such as pregnancy, obesity or ageing. The mechanisms, mediating beta cell mass expansion in these scenarios are not well defined. We have recently showed that beta cell mass failed to expand in ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Here we investigate PPAR gamma dependent transcriptional responses occurring during early stages of the adaptation of beta cells to insulin resistance. As it could be expected we have identified genes known to regulate proliferation and survival signals of the beta cells. Moreover we have also identified new pathways induced in ob/ob islets that fail to do so in POKO islets. Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with activation of immune response and is missing in POKO islets. Other PPARγ dependent differentially regulated pathways include cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.
2012-01-16 | GSE33647 | GEO
Project description:We found that in rodents, b-cell mass expansion during pregnancy and obesity is associated with changes in the expression of a group of islet microRNAs. We were able to reproduce in isolated pancreatic islets the decrease of miR-338-3p level observed in gestation and obesity by activating the G-protein coupled estrogen receptor GPR30 and the GLP1 receptor. Blockade of miR-338-3p in b-cells using specific anti-miR molecules mimicked gene expression changes occurring during b-cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory b-cell mass expansion occurring under different insulin resistance states.
2012-11-20 | GSE36067 | GEO
Project description:Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.
2023-12-19 | GSE242718 | GEO
Project description:Toll-like receptors 2 and 4 control adaptive β-cell expansion in diet-induced obesity
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Project description:We found that β-arrestin 1 -/- mice were more sensitive to hypoxia-induced pulmonary arterial hypertension with increased right ventricle hypertrophy and higher right ventricle systolic pressure, while β-arrestin 2 -/- mice developed right ventricle hypertrophy comparable to wild type mice. Moreover, β-arrestin 1 -/- mice had worse right ventricle function than wild type mice in response to chronic hypoxia, whereas β-arrestin 2 -/- mice relatively preserved right ventricle function compared to wild type mice. To investigate the molecular mechanisms responsible for the worse PAH in β-arrestin 1 -/- mice, we performed lung transcriptome analysis of wild type, β-arrestin 1 -/-, and β-arrestin 2 -/- mice using high-throughput RNA-seq.
2018-11-19 | GSE110131 | GEO
Project description:During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta-cells. However, the exact mechanisms by which the lactogenic hormones drive beta-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive beta-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in beta-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes. Analysis of poly(A)+ RNA from 3 biological replicates of pancreatic islets isolated from normal female and pregnant female mice
2010-07-01 | E-GEOD-21860 | biostudies-arrayexpress
Project description:Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.
2020-11-02 | GSE150281 | GEO