Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control
(2026) In Nature Metabolism- Abstract
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.... (More)
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.
(Less)
- author
- organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- in press
- subject
- in
- Nature Metabolism
- publisher
- Springer Nature
- external identifiers
-
- scopus:105027543679
- pmid:41530286
- ISSN
- 2522-5812
- DOI
- 10.1038/s42255-025-01422-7
- language
- English
- LU publication?
- yes
- id
- 93c77bec-4312-4923-9f79-96988d7ae6b6
- date added to LUP
- 2026-03-16 14:55:10
- date last changed
- 2026-05-27 03:29:48
@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}},
}