Inceptor counteracts insulin signalling in β-cells to control glycaemia
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PROVIDER: PRJNA603905 | ENA |
REPOSITORIES: ENA
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Project description:Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose 6-phosphate domain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir-/-) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir-/- mice showed an increase in the activation of INSR–IGF1R in Iir-/- pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific Iir-/- knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulinproducing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
2021-01-27 | GSE144519 | GEO
Project description:Insulin and insulin-like growth factor signalling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. Such responses can be tailored so that changes in insulin signalling result in distinct physiological responses to different stimuli. For example, the inhibition of insulin-like signalling is key in the responses of the nematode C. elegans to both osmotic stress and starvation, but these two stresses result in responses that are both physiologically and molecularly distinct. How does reduced insulin-like signalling elicit different responses to different environmental stimuli? We report that neurohormonal signalling involving the C. elegans cytosolic sulfotransferase SSU-1 controls developmental arrest in response to osmotic stress but does not control the distinct developmental arrest that occurs in response to starvation. SSU-1 functions in a single pair of sensory neurons to control intercellular signalling -- likely by catalyzing the synthesis of a steroid hormone -- via the nuclear hormone receptor NHR-1. SSU-1-controlled signalling antagonizes insulin-like signalling and hence modulates insulin sensitivity. In short, we describe a previously unknown neurohormonal signalling pathway that is required specifically for some but not all consequences of reduced insulin-like signalling. In mammals, the nervous system plays a similarly important yet poorly understood role in modulating insulin sensitivity. Our results suggest that the mammalian nervous system might regulate insulin sensitivity via sulfotransferase-controlled neurohormonal signalling.
2018-10-14 | GSE111074 | GEO
Project description:We report the transcritional targets of transcription factor downstream of insulin signalling. We knocked down transcription factors under reduced insulin signalling in Caenorhabditis elegans and did transcriptom analysis. This study identified target genes interaction complexity in analogous genetic and experimental conditions. It aid in gaining insight into the new molecular mechanisms downstream of rIIS
2021-12-01 | GSE184415 | GEO
Project description:G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.
2021-03-20 | GSE151826 | GEO
Project description:Transcriptome of insulin signalling associated transcription factor targets
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Project description:Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion
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Project description:Insulin signalling activity is well known to mediate transcriptional changes in response to nutrients and it is changed in the spargel mutant. We performed a genome-wide microarray study to investigate the role of Spargel as a transcriptional coregulator downstream of insulin receptor signalling.
2009-02-13 | GSE14779 | GEO
Project description:Background: Despite the prevalence and biological relevance of both signalling pathways and alternative pre-mRNA splicing, our knowledge of how intracellular signalling impacts on alternative splicing regulation remains fragmentary. We report a genome-wide analysis of changes in alternative splicing using splicing-sensitive microarrays, induced by activation of two distinct signalling pathways, insulin and wingless, in Drosophila cells in culture. Results: Alternative splicing changes induced by insulin affect more than 150 genes and more than 50 genes are regulated by wingless activation. About 40% of the genes showing changes in alternative splicing also show regulation of mRNA levels, suggesting distinct but also significantly overlapping programs of transcriptional and posttranscriptional regulation. Distinct functional sets of genes are regulated by each pathway and, remarkably, a significant overlap is observed between functional categories of genes regulated transcriptionally and at the level of alternative splicing. Functions related with carbohydrate metabolism and cellular signalling are enriched among genes regulated by insulin and wingless, respectively. Computational searches identify pathway-specific sequence motifs enriched near regulated 5â splice sites. Conclusion: Taken together, our data indicate that signalling cascades trigger pathway-specific and biologically coherent regulatory programs of alternative splicing regulation. They also reveal that alternative splicing can provide a novel molecular mechanism for cross-talk between different signalling pathways. To monitor transcriptional and alternative splicing changes induced by activation of the insulin and wingless pathways, a custom-designed microarray platform was employed featuring probes for all Drosophila genes for which different mRNA isoforms generated by alternative splicing have been described (see Blanchette M, Green RE, Brenner SE, Rio DC: Global analysis of positive and negative pre-mRNA splicing regulators in Drosophila. Genes Dev 2005, 19(11):1306-1314.). Three biological replicates of total RNA isolated after pathway activation or controls (untreated cells for insulin, control dsRNA for wingless) were purified, reverse transcribed into cDNA and labelled with Cy5 or Cy3 fluorochromes and the cDNA was hybridized to the microarray,
2010-05-06 | E-GEOD-14085 | biostudies-arrayexpress
Project description:In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain poorly defined. Here, through a systems biology approach, we identify the transcription factor Klf6 as a regulator of β-cell adaptation to metabolic stress. We show that inactivation of Klf6 in mouse β-cells blunts their proliferation induced by the insulin resistance of pregnancy, high-fat high-sucrose feeding, and insulin receptor antagonism. Transcriptomic analysis showed that Klf6 controls the expression of β-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature β-cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of β-cells into alpha cells. Our study identifies a new transcription factor that protects β-cells against dedifferentiation and which may be targeted to prevent diabetes development.
2020-03-01 | GSE137187 | GEO
Project description:Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in the skeletal muscle of five genetically distinct inbred mouse strains exposed to two controlled dietary environments, with and without acute insulin treatment. Almost half of the insulin-regulated phosphoproteome was altered by genetic background independently of diet, and high-fat high-sugar feeding also affected insulin signalling in a strain-dependent manner. Our data illuminated signalling network organisation principles, including the uncoupling of phosphosites targeted by the same kinase. Associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key glycolytic enzyme.
2023-12-21 | PXD041229 | Pride