Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells
Abstract
In isolated rat pancreatic α-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker ω-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. ω-Conotoxin suppressed glucagon release to 15 mm K+, whereas a combination of ω-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mm K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat α-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated α-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.
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In isolated rat alpha cells with high KATP channel density, the direct effect of glucose seems to be stimulation of secretion and the inhibitory action may require release of paracrine islet factors.
“In isolated rat alpha cells with high K ATP channel density [43] the direct effect of glucose seems to be stimulation of secretion and the inhibitory action may require release of paracrine islet factors [46].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [46]
Glucose stimulates glucagon release from purified rat alpha cells.
“and glucose was recently found to stimulate glucagon release from purified rat alpha cells [46].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [46]
Depolarization by tolbutamide-induced closure of KATP channels increases electrical activity, [Ca2+]i, exocytosis, and secretion in rat alpha-cells.
“Depolarization by tolbutamideinduced closure of the K ATP channels thus increases the electrical activity (24), [Ca 2ϩ ] i (8), exocytosis (28), and secretion (8) in rat ␣-cells”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [8]
The U-shaped dose-response patterns are different from those obtained with perfused rat pancreas and batch-incubated rat islets, which only show glucose inhibition of glucagon secretion.
“The U-shaped dose-response patterns are different from those obtained with perfused rat pancreas (7) and batch-incubated rat islets (8), which only show glucose inhibition of glucagon secretion.”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [8]
Glucagon secretion occurs in response to hypoglycemia and is inhibited already when the glucose concentration reaches 4-6 mmol/l.
“Secretion occurs in response to hypoglycemia and is inhibited already when the glucose concentration reaches 4 -6 mmol/l (7,8).”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [8]
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References 52 · Cited by 156
- Authors
- Olsen, H. L., Theander, S., Bokvist, K., Buschard, K., Wollheim, C. B., & Gromada, J.
- Affiliations
- Rigshospitalet (DK)
- Corresponding author
- Gromada, Jesper
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-11-01
- Volume
- 146
- Issue
- 11
- Pages
- 4861-4870
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2035095846
- Cited by
- 156
- References
- 52
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 8 · 2015: 7 · 2014: 10 · 2013: 9 · 2012: 8
- FWCI
- 10.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › 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 › Cell Biology › Cellular transport and secretion
- Keywords
- glucagon secretion, alpha cells, glucose, ATP-sensitive potassium channels, diazoxide, N-type calcium channels, omega-conotoxin, exocytosis, adenine nucleotides, ADP, ATP, potassium, stimulus-secretion coupling, tolbutamide, L-arginine, islets
- MeSH terms
- Adenine Nucleotides, Adenosine Triphosphate, Animals, Calcium, Calcium Channel Blockers, Diazoxide, Electric Stimulation, Enzyme Inhibitors, Exocytosis, Glucagon, Glucose, Intracellular Membranes, Male, Osmolar Concentration, Potassium, Potassium Channels, Rats, Sprague-Dawley, Patch-Clamp Techniques, Thapsigargin, Sodium Azide, Potassium Channel Blockers, Sodium Channel Blockers, Glucagon-Secreting Cells, Rats, In Vitro Techniques
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