@article{93c77bec-4312-4923-9f79-96988d7ae6b6,
  abstract     = {{<p>Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet’s ‘metabolic memory’, which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes.</p>}},
  author       = {{Gao, Rui and Acreman, Samuel and Dou, Haiqiang and Ma, Jinfang and Miranda, Caroline and Zhao, Ruiling and Dickerson, Matthew T. and Tarasov, Andrei and Zou, Qi and Gironella-Torrent, Marta and Tolö, Johan and Clark, Anne and Gao, Rui and De Marinis, Yang and Jacobson, David A. and Camunas-Soler, Joan and Yang, Tao and Rorsman, Patrik and Zhang, Quan}},
  issn         = {{2522-5812}},
  language     = {{eng}},
  publisher    = {{Springer Nature}},
  series       = {{Nature Metabolism}},
  title        = {{Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control}},
  url          = {{http://dx.doi.org/10.1038/s42255-025-01422-7}},
  doi          = {{10.1038/s42255-025-01422-7}},
  year         = {{2026}},
}