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Signal transduction pathways controlling Ins2 gene activity and beta cell state transitions

ABSTRACT: Pancreatic beta cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Cells with higher Ins2 gene activity have a mature beta cell transcriptomic profile, but are also more fragile. No information is available on the spatial relationship between these beta cell states, their proteomic signatures, or the signaling mechanisms underlying state transitions. In this study, we used live 3D imaging, mass spectrometry proteomics, and 48 targeted perturbations to comprehensively investigate Ins2(GFP)HIGH and Ins2(GFP)LOW beta cell states. We found that the two Ins2 gene activity states exist in intact isolated islets, and that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure beta cells to a depth of 5555 proteins, and show that beta cells with high Ins2 gene activity had increased transcriptional and mRNA processing factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of both GFP expression and transitions from Ins2(GFP)LOW to the Ins2(GFP)HIGH states. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of beta cell states.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: James D. Johnson

PROVIDER: MSV000094689 | MassIVE | Mon May 06 09:20:00 BST 2024

SECONDARY ACCESSION(S): PXD052023

REPOSITORIES: MassIVE

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