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A TP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells
Open accessAbstract
Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (KATP channels) in the control of glucagon secretion from mouse pancreatic α-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50] = 2.5 mmol/l) reduction of glucagon release. Maximum inhibition (∼50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 μmol/l) and glibenclamide (100 nmol/l) inhibited glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional KATP channels (SUR1−/−), glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0–20 mmol/l) and the sulfonylureas failed to inhibit glucagon secretion. Membrane potential recordings revealed that α-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the α-cell by ∼7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the α-cell (∼17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K+ concentrations (threshold 25 mmol/l), glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6–15 mmol/l), and stimulation was first detectable at >25 mmol/l K+. In α-cells isolated from SUR1−/− mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1−/− α-cells. Recordings of the free cytoplasmic Ca2+ concentration ([Ca2+]i) revealed that, whereas glucose lowered [Ca2+]i to the same extent as application of tolbutamide, the Na+ channel blocker tetrodotoxin, or the Ca2+ channel blocker Co2+ in wild-type α-cells, the sugar was far less effective on [Ca2+]i in SUR1−/− α-cells. We conclude that the KATP channel is involved in the control of glucagon secretion by regulating the membrane potential in the α-cell in a way reminiscent of that previously documented in insulin-releasing β-cells. However, because α-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the β-cell, moderate membrane depolarization in α-cells is associated with reduced rather than increased electrical activity and secretion.
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“Inhibition of glucagon secretion by tolbutamide alone or K + concentrations up to 16 mmol/l has previously been observed in mouse islets [16].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [16]
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Cites
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Self-citationThapsigargin, a novel molecular probe for studying intracellular calcium release and storage
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Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels
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Self-citationIslet β-cell secretion determines glucagon release from neighbouring α-cells
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Metadata
- Authors
- Gromada, J., Ma, X., Høy, M., Bokvist, K., Salehi, A., Berggren, P.-O., & Rorsman, P.
- Affiliations
- From the Lilly Research Laboratories, Hamburg, Germany
- Lund University (SE)
- University of Copenhagen (DK)
- Karolinska Institutet (SE)
- Churchill Hospital (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-12-01
- Volume
- 53
- Issue
- suppl_3
- Pages
- S181-S189
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2050636523
- Cited by
- 164
- References
- 45
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 11 · 2020: 10 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 12
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- ATP-sensitive potassium channels, SUR1, glucagon secretion, alpha cells, glucose regulation, sulfonylureas, tolbutamide, glibenclamide, membrane potential, action potential, intracellular calcium, insulin secretion, islets, tetrodotoxin
- MeSH terms
- Adenosine Triphosphate, Animals, Glucagon, Glucose, Membrane Potentials, Mice, Inbred C57BL, Reference Values, Potassium Channels, Mice, Knockout, Mice
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