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ATP-Sensitive K⁺ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1^–/– Mouse -Cells

¹ From the Lilly Research Laboratories, Hamburg, Germany
² Department of Physiological Sciences, Lund, Sweden
³ Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
⁴ Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, Stockholm, Sweden
⁵ Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, The Churchill Hospital, Oxford, England

Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K⁺ channels (K_ATP channels) in the control of glucagon secretion from mouse pancreatic -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 K_ATP 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 -cells generate action potentials in the absence of glucose. Addition of glucose depolarized the -cell by 7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the -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 -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^–/– -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 -cells, the sugar was far less effective on [Ca²⁺]_i in SUR1^–/– -cells. We conclude that the K_ATP channel is involved in the control of glucagon secretion by regulating the membrane potential in the -cell in a way reminiscent of that previously documented in insulin-releasing ß-cells. However, because -cells possess a different complement of voltage-gated ion channels involved in action potential generation than the ß-cell, moderate membrane depolarization in -cells is associated with reduced rather than increased electrical activity and secretion.

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