RT Journal Article
SR Electronic
T1 Role of Thiol Groups in Insulin Release: Studies with Poorly Permeating Disulphides
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 792
OP 801
VO 9
IS 6
A1 Bo HELLMAN
A1 LARS-ÅKE IDAHL
A1 ÅKE LERNMARK
A1 JANOVE SEHLIN
A1 INGE-BERT TÄLJEDAL
YR 1973
UL http://molpharm.aspetjournals.org/content/9/6/792.abstract
AB At a concentration of 1.0 mM, 6,6'-dithiodinicotinic acid and 5,5'-dithiobis(2-nitrobenzoic acid) stimulated insulin release from microdissected pancreatic islets of hereditary obese (ob/ob) mice. Microperifusion experiments showed that the secretory responses occurred promptly upon exposure to the sulphydryl reagents. Perifusion with 6,6'-dithiodinicotinic acid induced a sustained enhancement of insulin release without any signs of multiphasic secretion. This reagent induced a similar release pattern at both 3 and 17 mM glucose, although the high glucose concentration appeared to potentiate the effect of 6,6'-dithiodinicotinic acid. The dynamics of insulin release in response to 5,5'-dithiobis(2-nitrobenzoic acid) depended markedly, however, on the accompanying glucose concentration. At 0 and 3 mM glucose an initial peak of release was followed by a steady decline towards the basal release rate, whereas at 17 mM glucose 5,5'-dithiobis(2-nitrobenzoic acid) produced a sustained enhancement of secretion. The omission of calcium significantly inhibited insulin release in response to either of the two disulphides, although clear-cut stimulation was still obtained. In marked contrast, 17 mM glucose did not elicit even an initial peak of insulin release when calcium was omitted from the perifusion medium. 6,6'-Dithiodinicotinic acid (0.01-1.0 mM) had no effect on the oxidation of [U-14C]D-glucose. Significant inhibition of glucose oxidation was obtained with 0.1 and 1.0 mM 5,5'-dithiobis(2-nitrobenzoic acid), whereas at a concentration of 0.01 mM this reagent stimulated oxidation. Since the disulphides do not readily penetrate cell membranes, the results are consistent with our hypothesis that insulin release is regulated by relatively superficial thiol groups in the β-cell plasma membrane. However, further studies are necessary to exclude the possibility that the observed effects were due to small amounts of disulphide entering the β-cells.