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<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>

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Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Rui Gao,
  • Samuel Acreman,
  • Haiqiang Dou,
  • Jinfang Ma,
  • Caroline Miranda,
  • Ruiling Zhao,
  • Matthew T. Dickerson,
  • Andrei Tarasov,
  • Qi Zou,
  • Marta Gironella-Torrent,
  • Johan Tolö,
  • Anne Clark,
  • Rui Gao,
  • Yang De Marinis,
  • David A. Jacobson,
  • Joan Camunas-Soler,
  • Tao Yang,
  • Patrik Rorsman,
  • Quan Zhang

摘要

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.