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Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line
Author(s) -
Sturgess N.C.,
Kozlowski R.Z.,
Carrington C.A.,
Hales C.N.,
Ashford M.L.J.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb16551.x
Subject(s) - tolbutamide , diazoxide , glibenclamide , endocrinology , medicine , insulin , chemistry , sulfonylurea receptor , potassium channel , intracellular , biology , diabetes mellitus , biochemistry
1 The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch‐clamp methods in an insulinsecreting cell line derived from a rat islet cell tumour. 2 Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2–5 fold. The concentrations of tolbutamide and glibenclamide giving half‐maximum effects on insulin secretion were approximately 40 μ M and 0.2 μ M , respectively. 3 Diazoxide (0.6‐1.0 mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20 mM), it produced inhibition. Tolbutamide‐induced release was also inhibited by diazoxide. 4 Tolbutamide, glibenclamide, HB699 and HB985 reduced the open‐state probability of the ATP‐K + channel in a dose‐dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5 In whole cell recording, in which the total ATP‐sensitive K + conductance of the cell could be measured, dose‐inhibition curves for tolbutamide and glibenclamide were constructed, resulting in K i values of 17 μ M and 27 nM, respectively. The value of K i for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6 Diazoxide (0.6 mM) activated the ATP‐K + channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3–30 μ M ). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7 Neither tolbutamide (1.0 mM) nor glibenclamide (10 μ M ) altered the open‐state probability of the Ca 2+ ‐activated K + channel or the Ca 2+ ‐activated non‐selective cation channel which are present in this cell line. 8 It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP‐K + channel or a protein closely associated with this channel.