Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells
Open accessAbstract
Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na(+)/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications.
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A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level.
“A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level (12–21).”
From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [16]
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- Authors
- Pedersen, M. G., Ahlstedt, I., El Hachmane, M. F., & Göpel, S. O.
- Affiliations
- University of Padua (IT)
- AstraZeneca (Sweden) (SE)
- Corresponding author
- Pedersen, Morten Gram
- Göpel, Sven O.
- Venue
- Scientific Reports
- Published
- 2016-08-18
- Volume
- 6
- Issue
- 1
- Pages
- 31214-31214
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4989223
- OpenAlex
- W2516573111
- Cited by
- 64
- References
- 48
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 7 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 16 · 2019: 10 · 2018: 5 · 2017: 4 · 2016: 1
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- European Foundation for the Study of Diabetes
- Università degli Studi di Padova
- 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 Transport and Channel Regulation
- Keywords
- dapagliflozin, SGLT2 inhibitors, glucagon secretion, pancreatic A cells, glucose detection, islets, action potential, membrane depolarization, voltage-gated ion channels, diabetes mellitus
- MeSH terms
- Animals, Benzhydryl Compounds, Cells, Cultured, Electric Stimulation, Glucagon, Glucose, Glucosides, Humans, Models, Theoretical, Glucagon-Secreting Cells, Sodium-Glucose Transporter 2, Mice
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