TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion – published online 26/03/2025

Xiong Liu, Theodore dos Santos, Aliya F. Spigelman, Shawn Duckett, Nancy Smith, Kunimasa Suzuki, Patrick E. MacDonald

The hallmark of diabetes is hyperglycaemia resulting from disrupted insulin signalling or secretion. Glucagon is also altered in diabetes, and this may contribute to blood glucose volatility; however, we know relatively little about the glucagon-secreting pancreatic alpha cell. In this issue, Liu et al (https://doi.org/10.1007/s00125-025-06411-9) investigated a protein called TMEM55A (encoded by the gene PIP4P2), a lipid phosphatase. Using RNA interference and patch-clamp electrophysiology, the authors found that TMEM55A acts as a positive regulator for glucagon exocytosis in human and mouse alpha cells, but does not affect beta cell insulin exocytosis. The detailed molecular mechanism was explored in human islets, mouse islets and cell lines. Altogether, the authors describe a novel pathway by which TMEM55A regulates glucagon exocytosis in alpha cells by controlling the cellular actin cytoskeleton downstream of intracellular lipid signalling.

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