Beta-cell dependence to alpja-cell signals for proper insulin secretion in mouse pancreatic islets
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PROVIDER: PRJNA1237303 | ENA |
REPOSITORIES: ENA
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Project description:The islets of Langerhans play a central role in detecting and regulating blood glucose levels. While insulin-producing beta-cells are well-characterized, much remains to be studied about the other cell types in pancreatic islets (alpha-, delta-, PPY-, and epsilon-cells). In this context, we have developed chimeric organoids that we use to understand the interactions between the different cell populations present in pancreatic islets. We previously developed an efficient approach to purify the major cell populations present in pancreatic islets (alpha, beta, and delta) using flow cytometry. We have now developed a technique to re-aggregate these sorted cell populations, enabling the production of clusters (pseudo-islets) in which we can modulate the proportion of each cell population on demand. We generated clusters devoid of delta cells or both alpha and delta cells and confirmed this depletion at the gene and protein levels. We then evaluated the function of these pseudo-islets by measuring glucose-stimulated insulin secretion. The absence of delta-cells did not affect insulin secretion. However, the insulin secretory capacity of pseudo-islets lacking both alpha- and delta-cells was significantly reduced. Transcriptomic analysis of these pseudo-islets did not reveal a loss of beta-cell identity as the cause of the observed functional impairment but highlighted potential new signaling pathways influenced by alpha- and delta-cells. This demonstrates the importance of interactions among different endocrine cell types within the islet for the function of pancreatic beta-cells. It represents a new and effective tool for identifying signaling pathways and compounds that directly or indirectly (via other endocrine cell types) modulate the identity and function of pancreatic endocrine cells.
2025-05-01 | GSE292158 | GEO
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.
2024-07-19 | GSE226479 | GEO
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Project description:Tafazzin is a transacylase which causes the content and molecular structure of cardiolipin (CL) to be altered in the inner mitochondrial membrane. The enzymatic machinery responsible for oxidative respiration are localized to the inner mitochondrial membrane and require CL for activity. As a result, tafazzin is critical for maintaining mitochondrial function. In beta-cells, which are the insulin secreting cells in pancreatic islets, mitochondrial function is linked to insulin secretion. We previously established that tafazzin knock-down mice were lean and maintained insulin sensitivity compared to the obese insulin resistant control litter mates. However, it was unknown whether tafazzin deficiency also influenced insulin secretion in the establishment of the lean phenotype. Using X week-old mice, we ascertained that the number of beta-cells was similar between genotypes. Ex vivo insulin secretion under low glucose conditions was reduced (52%) from islets isolated from tafazzin knock-down mice. Consistent with this tafazzin knock-down mice exhibited reduced fasting insulin plasma insulin levels. Measurement of mitochondrial oxygen consumption revealed that basal oxygen consumption was reduced (58%) in islets from tafazzin-deficient animals. The addition of etomoxir, an inhibitor of mitochondrial fatty acid translocation, significantly elevated basal mitochondrial respiration (5-fold) in islets from tafazzin knockdown mice, indicating a significant fatty acid-mediated inhibitory effect. In contrast, etomoxir lacked any measurable effect on control wild-type islets. The altered mitochondrial function identified in taffazin knock-down islets was not associated with reduced CL content or elevated oxyCL species. Our experiments indicate that tafazzin plays a key role in regulating normal islet beta-cell function.
2021-07-31 | GSE136242 | GEO
Project description:Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury [Rspo3 KO]
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Project description:CMPF is elevated in diabetes and is associated with impaired insulin secretion. We used microarrays to determine the effect of CMPF on gene expression in isolated islets. Isolated islets from male CD1 mice were treated for 24h with vehicle control or 200uM CMPF.
2014-04-01 | E-GEOD-55028 | biostudies-arrayexpress
Project description:Genes encoding the virulence-promoting type III secretion system (T3SS) in phytopathogenic bacteria are induced at the start of infection, indicating that recognition of signals from the host plant initiates this response. However, the precise nature of these signals and whether their concentrations can be altered to affect the biological outcome of host-pathogen interactions remain speculative. Here we use a metabolomic comparison of resistant and susceptible genotypes to identify plant-derived metabolites that induce T3SS genes in Pseudomonas syringae pv tomato DC3000 and report that mapk phosphatase 1 (mkp1), an Arabidopsis mutant that is more resistant to bacterial infection, produces decreased levels of these bioactive compounds. Consistent with these observations, T3SS effector expression and delivery by DC3000 was impaired when infecting the mkp1 mutant. The addition of bioactive metabolites fully restored T3SS effector delivery and suppressed the enhanced resistance in the mkp1 mutant. Pretreatment of plants with pathogen-associated molecular patterns (PAMPs) to induce PAMP triggered immunity (PTI) also restricts T3SS effector delivery and enhances resistance by unknown mechanisms, and the addition of the bioactive metabolites similarly suppressed both aspects of PTI. Together, these results demonstrate that DC3000 perceives multiple signals derived from plants to initiate its T3SS and that the level of these host-derived signals impacts bacterial pathogenesis.
2014-06-24 | MTBLS95 | MetaboLights