ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse α-cells

Jesper Gromada, Xiaosong Ma, Marianne Høy, Krister Bokvist, Albert Salehi, Per Olof Berggren, Patrik Rorsmam

Research output: Contribution to journalArticle

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Abstract

NanPatch-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 [Ca 2+]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.

Original languageEnglish
JournalDiabetes
Volume53
Issue numberSUPPL. 3
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

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Glucagon
Adenosine Triphosphate
Glucose
Tolbutamide
KATP Channels
Action Potentials
Membrane Potentials
Cell Membrane
Insulin
Glyburide
Tetrodotoxin
Ion Channels
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse α-cells. / Gromada, Jesper; Ma, Xiaosong; Høy, Marianne; Bokvist, Krister; Salehi, Albert; Berggren, Per Olof; Rorsmam, Patrik.

In: Diabetes, Vol. 53, No. SUPPL. 3, 01.12.2004.

Research output: Contribution to journalArticle

Gromada, Jesper ; Ma, Xiaosong ; Høy, Marianne ; Bokvist, Krister ; Salehi, Albert ; Berggren, Per Olof ; Rorsmam, Patrik. / ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1-/- mouse α-cells. In: Diabetes. 2004 ; Vol. 53, No. SUPPL. 3.
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N2 - NanPatch-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 [Ca 2+]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.

AB - NanPatch-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 [Ca 2+]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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