Summary
The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 μmol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 μmol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.
Article PDF
Similar content being viewed by others
References
Ashcroft FM (1988) Adenosine-5′-triphosphate-sensitive K+ channels. Ann Rev Neurosci 11: 97–118
Petersen OH, Findlay I (1987) Electrophysiology of the pancreas. Physiol Rev 67: 1054–1116
Sturgess NC, Ashford MLJ, Cook DL, Hales CN (1985) The sulphonylurea receptor may be an ATP-sensitive potassium channel. Lancet 8453: 474–475
Sturgess NC, Kozlowski RZ, Carrington CA, Hales CN, Ashford MLJ (1988) Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide-sensitive channels in an insulin-secreting cell line. Br J Pharmacol 95: 83–94
Trube G, Rorsman P, Ohno-shoskau T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic B-cells. Pflugers Arch 407: 493–499
Dunne MJ, Ilott MC, Petersen OH (1987) Interactions of diazoxide, tolbutamide and ATP4− on nucleotide-dependent K+ channels in an insulin-secreting cell-line. J Memb Biol 99: 215–224
Zunckler BJ, Lenzen S, Manner K, Panten U, Trube G (1988) Concentration-dependent effects of tolbutamide, meglitinide, glipizide, glibenclamide and diazoxide on ATP-regulated K currents in pancreatic B-cells. Naunyn-Schmiedbergs Arch Pharmacol 337: 225–230
Henquin JC, Meissner HP (1982) Opposite effects of tolbutamide and diazoxide on 86Rb fluxes and membrane potential in pancreatic B-cells. Biochem Pharmacol 31: 1047–1415
Ashcroft FM, Kakei M, Kelly RP, Sutton R (1987) ATP-sensitive K-channels in isolated human pancreatic β-cells. FEBS Letts 215: 9–12
Sturgess NC, Carrington CA, Hales CN, Ashford MLJ (1987) Nucleotide-sensitive ion channels in human insulin producing tumor cells. Pflugers Arch 410: 169–172
Gray DWR, McShane P, Grant A, Morris PJ (1984) A method for isolation of islets of Langerhans from the human pancreas. Diabetes 33: 1055–1061
Grant AM, Christie MR, Ashcroft SJH (1980) Insulin release from human pancreatic islets in vitro. Diabetologia 19: 114–117
Harrison DE, Christie MR, Gray DWR (1985) Properties of isolated human islets of Langerhans: insulin secretion, glucose oxidation and protein phosphorylation. Diabetologia 28: 99–103
Malaisse-Lagae F, Stefan Y, Cox J, Perrelet A, Orci L (1979) Identification of a lobe in the adult human pancreas rich in pancreatic polypeptide. Diabetologia 17: 361–365
Ashcroft FM, Ashcroft SJH, Harrison DE (1987) Effects of 2-ketoisocaproate on insulin release and single potassium channel activity in dispersed rat pancreatic β-cells. J Physiol 385: 517–529
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch clamp techniques for high resolution current recordings from cells and cell-free membrane patches. Pflugers Arch 391: 85–100
Findlay I, Dunne MJ (1986) ATP maintains ATP-inhibited K+ channels in an operational state. Pflugers Arch 407: 238–240
Misler S, Falke LC, Gillis K, McDaniel ML (1986) A metabolite regulated potassium channel in rat pancreatic B cells. Proc Natl Acad Sci USA 83: 7119–7123
Ohno-shosaku T, Zunckler BJ, Trube G (1987) Dual effects of ATP on K+ currents of mouse pancreatic β-cells. Pflugers Arch 408: 133–138
Zunckler BJ, Lins S, Ohno-shosaku T, Trube G, Panten U (1988) Cytpsolic ADP enhances the sensitivity to tolbutamide of ATP-dependent K+ channels from pancreatic β-cells. FEBS Letts 239: 241–244
Kakei M, Ashcroft FM (1986) A microflow superfusion system for use with excised membrane patches. Pflugers Arch 409: 337–341
Rorsman P, Trabe G (1986) Calcium and delayed potassium currents in mouse pancreatic β-cells under voltage clamp conditions. J Physiol 374: 531–550
Findlay I, Dunne MJ, Petersen OH (1985) High conductance K+ channel in pancreatic islet cells can be activated and inactivated by internal calcium. J Memb Biol 83: 169–175
Balant L (1981) Clinical pharmokinetics of sulphonylurea hypoglycaemic drugs. Clin Pharmocokinet 6: 215–241
Hermans MP, Schmeer W, Henquin JC (1977) The permissive effect of glucose, tolbutamide and high K+ on arginine stimulation of insulin release in isolated mouse islets. Diabetologia 30: 659–665
Kakei M, Kelly RP, Ashcroft SJH, Ashcroft FM (1986) The ATP-sensitivity of K+ channels in rat pancreatic B-cells is modulated by ADP. FEBS Letts 208: 63–66
Dunne MJ, Petersen OH (1986) Intracellular ADP activates K+ channels that are inhibited by ADP in an insulin-secreting cell line. FEBS Letts 208: 59–63
Ashcroft FM, Kakei M, Kelly RP (1989) Rubidium and sodium permeability of the ATP-sensitive K+ channels in single rat pancreatic β-cells. J Physiol 408: 413–430
Kakei M, Noma A, Shibasaki T (1985) Properties of adenosine triphosphate regulated potassium channels in guinea-pig ventricular cells. J Physiol 363: 441–462
Noma A, Shibasaki T (1985) Membrane current through adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol 363: 463–481
Vague P, Moulin JP (1982) the defective glucose sensitivity of the B cell in non-insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 31: 139–144
Efendic S, Wajngot A, Vranie M (1985) Increased activity of the glucose cycle in liver. Early characteristic of type 2 diabetes. Proc Natl Acad Sci USA 82: 2965–2969
Rorsman P, Berggren PO, Bokvist K, Efendic S, Khan A, Low H, Welsh M (1988) Does type II diabetes result from defective regulation of glucose- and ATP-sensitive K-channels? Biosci Abstr 1: 149
Rorsman P, Bokvist K, Arkhammar P, Berggren PO, Hellerström C, Nilsson T, Welsh M, Welsh N (1988) Defective regulation of glucose- and ATP-regulafed K channels results in disturbed glucose sensitivity in fetal B cells. Diabetolegia 31: 537 A
Misler S, Gee WM, Gillis KD, Scharp DW, Falke LC (1989) Metabolite-regulated ATP-sensitive K+ channel in human pancreatic islet cells. Diabetes 38: 422–427
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ashcroft, F.M., Kakei, M., Gibson, J.S. et al. The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells. Diabetologia 32, 591–598 (1989). https://doi.org/10.1007/BF00285333
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00285333