In vivo drug discovery for β-cell proliferation in diabetes

In vivo drug discovery for β-cell proliferation in diabetes

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In a examine printed in Nature Metabolism, researchers on the division of Cell and Molecular Biology developed a novel method to establish small molecules that may make insulin-producing β-cells divide.

Olov Andersson and Jeremie Charbord explains: “Diabetes is characterised by the progressive lack of practical β-cells. One attainable strategy to curing diabetes is to generate new β-cells in situ to replenish the pool of β-cells. β-cell proliferation expands the β-cell mass principally throughout growth but additionally underneath sure hyperglycemic circumstances in maturity, a course of that would doubtlessly be used for β-cell regeneration in diabetes.

“To display screen for chemical compounds that may induce β-cell proliferation, we developed a novel assay in zebrafish primarily based on the fluorescence ubiquitination cell-cycle indicator (FUCCI) technique, during which the S/G2/M marker geminin is fused to a fluorescent protein. As a substitute of fusing geminin to a fluorescent protein, we fused it to a luciferase protein and expressed it underneath the management of the insulin promoter to particularly report β-cell proliferation in vivo in a high-throughput method. We named this assay LUCCI (for Luminescence Ubiquitination-based Cell Cycle Indicator) and used it to arrange a high-throughput chemical display screen in transgenic zebrafish. On this manner, we recognized a kinase inhibitor that potently stimulates β-cell proliferation, and confirmed this impact in mouse and human β-cells to ensure the impact is conserved throughout species.

“Utilizing single-cell transcriptomic analyses of β-cells, we discovered that the kinase inhibitor induced an unfolded-protein response previous to cell-cycle entry, that’s, a light and transient wave of unfolded protein response that was mandatory for proliferation to happen. Importantly, this wave was not related to a rise in insulin expression, which in diabetes might be related to robust and protracted activation of a maladaptive unfolded protein response. Our findings counsel a novel idea during which a small molecule can transiently activate the unfolded-protein response to induce β-cell proliferation—a mechanism that may be leveraged to develop the variety of β-cells in diabetes.”

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Extra info:
Jérémie Charbord et al, In vivo display screen identifies a SIK inhibitor that induces β cell proliferation by means of a transient UPR, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00391-x

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Karolinska Institutet

In vivo drug discovery for β-cell proliferation in diabetes (2021, Could 26)
retrieved 31 Could 2021

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