Calcium-binding proteins and insulin release. Differential effects of phenothiazines on first- and second-phase secretion and on islet cAMP response to glucose.
Calcium and cAMP are interdependent regulators of glucose-induced insulin release. In the present study we investigated the importance of cAMP and calcium-binding proteins for biphasic insulin secretion by assessing the effects of two phenothiazines known to block such proteins, trifluoroperazine (TFP) and promethazine (PMZ). In isolated rat islets, during 60-min incubations with 16.7 mmol/l glucose both agents inhibited the insulin response with ID50 values of 15 mumol/l for TFP and 5 mumol/l for PMZ. Both agents decreased the maximal insulin response without gross changes in the islet sensitivity to glucose. TFP (15 mumol/l), whereas inducing 50% inhibition of second-phase insulin release, totally suppressed the cAMP response to glucose and the accompanying first-phase insulin secretion (5-min incubations); these effects of TFP could be partially reversed by isobutyl methylxanthine (IBMX). In contrast, 5 mumol/l PMZ, which produced 60% inhibition of second-phase insulin release, had no effect on first-phase insulin and cAMP responses to glucose. Furthermore, IBMX did not modify the inhibitory effect of PMZ on second-phase insulin secretion. The following is concluded: 1. TFP acts preferentially on first-phase insulin release and inhibits cAMP formation; this suggests that calmodulin plays a major role in mediating the initial glucose effect on secretion via stimulation of cAMP. 2. The islet probably contains calcium-sensitive proteins other than calmodulin, since the low concentrations of PMZ shown to inhibit second-phase insulin release lack effects on calmodulin. Synexin could be such a protein.(ABSTRACT TRUNCATED AT 250 WORDS)
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D011398:Promethazine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014268:Trifluoperazine / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D007328:Insulin; D014268:Trifluoperazine; D000242:Cyclic AMP; D011398:Promethazine; D015056:1-Methyl-3-isobutylxanthine