Defective regulation of insulin release and transmembrane Ca2+ fluxes by human islet cell tumours.
Regulation of insulin release and transmembrane Ca2+ fluxes was examined using pieces of 3 benign medullary-type insulinomas removed from the pancreas of female patients at surgery. Immunocytochemical staining confirmed the presence of insulin-containing cells with no demonstrable glucagon, somatostatin or pancreatic polypeptide. After 3 days of culture in RPMI-1640, tumour pieces released 11-158 mg insulin kg-1 dry wt during acute 60 min incubations with the concomitant uptake of 2-47 mmol 45Ca kg-1 into the intracellular lanthanum-nondisplaceable pool. At 2.56 mM Ca2+, glucose alone or in combination with glyceraldehyde, mannoheptulose or diazoxide did not modify insulin release or 45Ca uptake. Theophylline significantly increased insulin release from 2 tumours with a small stimulatory effect on the third. A depolarising concentration of K+ enhanced insulin release from one tumour but this was not associated with an increase of 45Ca uptake. Calcium antagonists, (verapamil, D-600 and trifluoroperazine) and calcium ionophores (A23187 and Br-X537A) failed to modify insulin release or 45Ca uptake by each of the two tumours tested. Evaluation of 45Ca efflux from one tumour confirmed the unresponsiveness to glucose, K+, verapamil and A23187. Prolonged culture of 2 tumours for up to 16 days was associated with the gradual decline of insulin release to a steady output of 2-15 ng 24 h-1. Addition of verapamil to the cultures inhibited insulin output from one tumour, but mannoheptulose or diazoxide were without effect. The results indicate that inappropriate insulin release from these 3 benign medullary-type insulinomas is associated with disturbances in the regulation of transmembrane Ca2+ fluxes.
Flatt
P R
PR
Department of Biochemistry, University of Surrey, Guildford, UK.
Swanston-Flatt
S K
SK
Powell
C J
CJ
Marks
V
V
D007516:Adenoma, Islet Cell / Q000378:metabolism*; D000293:Adolescent; D002118:Calcium / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D012636:Secretory Rate / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D007328:Insulin; D007476:Ionophores; D013806:Theophylline; D011188:Potassium; D002118:Calcium