Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells
Open accessAbstract
Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting α-, insulin-producing β- and somatostatin-releasing δ-cells 1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion 2. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion 3. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy 4. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms 5 but their relative contributions and whether they interact remains unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na+ concentration ([Na+]i) and promoting intracellular Ca 2+-induced Ca 2+ release (CICR). This mechanism also becomes activated when [Na+]i is elevated following the inhibition of the plasmalemmal Na+-K+ pump by reductions of the extracellular K+ concentration emulating those produced by exogenous insulin in vivo 6. Islets from some donors with type-2 diabetes hypersecrete somatostatin, leading to suppression of glucagon secretion that can be alleviated by a somatostatin receptor antagonist. Our data highlight the role of Na+ as an intracellular second messenger, illustrate the significance of the intraislet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the δ-cells.
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SSTR2a CYN154806 stimulated glucagon secretion at 1 mmol/L glucose but only in islets (2 of 3) with lower glucagon secretion relative to controls.
“The SSTR2a CYN154806, stimulated glucagon secretion at 1 mmol/L glucose but only in islets (2 of 3) with lower glucagon secretion relative to controls ( Vergari et al., 2020 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
Between 1 and 20 mmol/L glucose, SST secretion increased >10-fold in mouse islets and ∼3-3.5-fold in human islets, indicating a larger magnitude response in mice.
“Between 1 and 20 mmol/L glucose, SST secretion increased >10-fold in mouse islets ( Vieira et al., 2007 ; Vergari et al., 2020 ) and ∼3–3.5-fold in human islets ( Ramracheya et al., 2010 ; Walker et al., 2011 ; Vergari et al., 2020 ) between 1 and 20 mmol/L glucose, indicating a larger magnitude response in mice.”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
In Fh1βKO mouse islets, SST secretion was increased 6-fold relative to control mouse islets at 1 mmol/L glucose, which correlated with a >75% reduction in glucagon secretion.
“As illustrated in Figure 2B , SST secretion was increased 6-fold in Fh1βKO islets relative to control mouse islets at 1 mmol/L glucose, which correlated with a >75% reduction in glucagon secretion ( Vergari et al., 2020 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
Application of SSTR2a CYN154806 in Fh1βKO islets stimulated glucagon release by 143% ± 11% compared to 13% ± 14% in control mouse islets.
“Consistent with the observation of elevated SST secretion at 1 mmol/L glucose, application of a SST receptor 2 antagonist (SSTR2a, CYN154806) in Fh1βKO islets stimulated glucagon release by 143% ± 11% compared to 13% ± 14% in control mouse islets ( Vergari et al., 2020 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
Suppression of SST secretion from islet δ-cells acts as a permissive signal for counterregulatory glucagon release.
“they support the conclusions that 1) suppression of SST secretion from islet δ-cells acts as a permissive signal for counterregulatory glucagon release, and 2) this permissive signal may be compromised in T1D and advanced T2D ( Vergari et al., 2020 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
The permissive signal from suppression of SST secretion may be compromised in T1D and advanced T2D.
“they support the conclusions that 1) suppression of SST secretion from islet δ-cells acts as a permissive signal for counterregulatory glucagon release, and 2) this permissive signal may be compromised in T1D and advanced T2D ( Vergari et al., 2020 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Vergari et al., 2020
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References 34 · Cited by 43
Research works printed but not linked: 1
- [14]Vergari E Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion Nat Commun 2019 10 139 PMC6329806 30635569
- Authors
- Vergari, E., Denwood, G., Salehi, A., Zhang, Q., Adam, J., Alrifaiy, A., Wernstedt Asterholm, I., Benrick, A., Chibalina, M. V., Eliasson, L., Guida, C., Hill, T. G., Hamilton, A., Ramracheya, R., Reimann, F., Rorsman, N. J. G., Spilliotis, I., Tarasov, A. I., Walker, J. N., Rorsman, P., & Briant, L. J. B.
- Affiliations
- Churchill Hospital (GB)
- University of Gothenburg (SE)
- University of Oxford (GB)
- University of Cambridge (GB)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Corresponding author
- Rorsman, Patrik
- Briant, Linford J. B.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2020-01-20
- Volume
- 2
- Issue
- 1
- Pages
- 32-40
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6986923
- OpenAlex
- W2996385836
- Cited by
- 43
- References
- 34
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 10 · 2020: 3
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- somatostatin secretion, pancreatic delta cells, intracellular sodium, Na+/K+-ATPase, extracellular potassium, dapagliflozin, paracrine signaling, type 2 diabetes, glucagon secretion, hypoglycemia, somatostatin receptor antagonists
- MeSH terms
- Animals, Calcium, Diabetes Mellitus, Type 2, Glucagon, Glucose, Humans, Hypoglycemia, Insulin, Sodium, Somatostatin, Somatostatin-Secreting Cells, Mice
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