ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 10.14 | DOI: 10.1530/ey.18.10.14

Nature Metabolism. 2020;2(2):192–209. doi: 10.1038/s42255-020-0171-3.

This experimental mouse study examined whether or not dedifferentiated β cells could be reversed or targeted by pharmacological intervention for diabetes remission. They identified evidence for β-cell dedifferentiation and dysfunction which could be reversed by single and combined pharmacological approaches.

Dedifferentiation is a process whereby mature differentiated cells transition back to a less mature state to allow potential for regeneration, but with the loss of some cell functions. Dedifferentiation of insulin-secreting β cells in pancreatic islets has been proposed to be a major mechanism of β-cell dysfunction. In this study, mice with streptozotocin-induced diabetes were used as a model to study β-cell dedifferentiation. Single-cell RNA sequencing (scRNA-seq) of islet cells identified markers and pathways associated with β-cell dedifferentiation and dysfunction.

Administration of insulin triggered insulin receptor pathway activation in β cells and restored cell maturation and function, leading to islet differentiation and diabetes remission. Additionally, β-cell selective delivery of oestrogen combined with Glucagon-like peptide-1 (GLP-1-oestrogen) decreased insulin requirements by 60%, triggered oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increased β-cell survival and even regeneration. The GLP-1-oestrogen combination also protected human β cells against cytokine-induced dysfunction.

This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals potential pharmacological entry points to target dedifferentiated β cells for diabetes remission and cure.

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