Paracrine regulation of somatostatin secretion by insulin and glucagon in mouse pancreatic islets

Abstract

Aims/hypothesis

The endocrine pancreas comprises the islets of Langerhans, primarily consisting of beta cells, alpha cells and delta cells responsible for secretion of insulin, glucagon and somatostatin, respectively. A certain level of intra-islet communication is thought to exist, where the individual hormones may reach the other islet cells and regulate their secretion. Glucagon has been demonstrated to importantly regulate insulin secretion, while somatostatin powerfully inhibits both insulin and glucagon secretion. In this study we investigated how secretion of somatostatin is regulated by paracrine signalling from glucagon and insulin.

Methods

Somatostatin secretion was measured from perfused mouse pancreases isolated from wild-type as well as diphtheria toxin-induced alpha cell knockdown, and global glucagon receptor knockout (Gcgr–/–) mice. We studied the effects of varying glucose concentrations together with infusions of arginine, glucagon, insulin and somatostatin, as well as infusions of antagonists of insulin, somatostatin and glucagon-like peptide 1 (GLP-1) receptors.

Results

A tonic inhibitory role of somatostatin was demonstrated with infusion of somatostatin receptor antagonists, which significantly increased glucagon secretion at low and high glucose, whereas insulin secretion was only increased at high glucose levels. Infusion of glucagon dose-dependently increased somatostatin secretion approximately twofold in control mice. Exogenous glucagon had no effect on somatostatin secretion in Gcgr–/– mice, and a reduced effect when combined with the GLP-1 receptor antagonist exendin 9-39. Diphtheria toxin-induced knockdown of glucagon producing cells led to reduced somatostatin secretion in response to 12 mmol/l glucose and arginine infusions. In Gcgr–/– mice (where glucagon levels are dramatically increased) overall somatostatin secretion was increased. However, infusion of exendin 9-39 in Gcgr–/– mice completely abolished somatostatin secretion in response to glucose and arginine. Neither insulin nor an insulin receptor antagonist (S961) had any effect on somatostatin secretion.

Conclusions/interpretation

Our findings demonstrate that somatostatin and glucagon secretion are linked in a reciprocal feedback cycle with somatostatin inhibiting glucagon secretion at low and high glucose levels, and glucagon stimulating somatostatin secretion via the glucagon and GLP-1 receptors.

Graphical abstract

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Data availability

The datasets generated and analysed during the current study are available from the corresponding authors on reasonable request.

Abbreviations

DT:

Diphtheria toxin

DT-Gcg:

Diphtheria toxin-induced glucagon knockdown

Ex9:

Exendin 9-39

GLP-1:

Glucagon-like peptide-1

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Acknowledgements

Some of these data were presented as an abstract at the 55th EASD Annual Meeting in 2019.

Authors’ relationships and activities

JJH has served as a consultant or advisor to Novo Nordisk, Merck Sharp & Dohme, and Roche and received fees for lectures from Novo Nordisk, Merck Sharp & Dohme, and GlaxoSmithKline. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

Funding

This study was supported by grants from the Danish Council for Independent Research (6110-00660), the Lundbeck Foundation (2011-9560, 2016-2394), the European Foundation for the Study of Diabetes (EFSD–Lilly Young Investigator Research Award 2019), and the Novo Nordisk Foundation.

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Both authors contributed substantially to (1) conception and design, acquisition of data, analysis and interpretation of data as well as (2) drafting and critical revision for important intellectual content and (3) both approved of the version to be published. BS and JJH are the guarantors of this work.

Corresponding authors

Correspondence to Berit Svendsen or Jens J. Holst.

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Svendsen, B., Holst, J.J. Paracrine regulation of somatostatin secretion by insulin and glucagon in mouse pancreatic islets. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05288-0

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Keywords

  • Glucagon
  • Intra-islet communication
  • Perfused mouse pancreas
  • Somatostatin secretion