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Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia – published online 28/11/2023

Castillo‑Armengol graphical abstract

Judit Castillo‑Armengol, Flavia Marzetta, Ana Rodriguez Sanchez‑Archidona, Christian Fledelius, Mark Evans, Alison McNeilly, Rory J. McCrimmon, Mark Ibberson, Bernard Thorens

Repeated insulin-induced hypoglycaemia in individuals with diabetes progressively leads to defective counterregulation to restore normoglycaemia, particularly resulting in a decrease in glucagon secretion. This defect is thought to be caused by impaired hypoglycaemia sensing by hypothalamic neurons, although the precise mechanisms are mostly unknown. In this issue, Castillo-Armengol et al (https://doi.org/10.1007/s00125-023-06043-x) report findings from a study in which they developed a mouse model of type 2 diabetes with defective glucagon secretion caused by repeated hypoglycaemic episodes. Using this mouse model, they analysed hypothalamic gene expression via single-nuclei RNA sequencing and performed proteomic analysis of hypothalamic synaptosomal fractions. The authors show that repeated exposure to hypoglycaemia induces changes in neurons, oligodendrocytes and astrocytes that point to reduced sensing of hypoglycaemia, decreased activity of tripartite synapses, and impaired myelination. They also demonstrate increased signs of neurodegeneration with a high propensity for amyloid beta production in these cells. In summary, the authors state that the findings from this study help to define the hypothalamic causes of defective counterregulation and may lead to measures aimed at preventing hypoglycaemic episodes in insulin-treated individuals with diabetes.

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