Opposite, phase-dependent effects of 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester or tetracaine on islet function during three phases of glucose-stimulated insulin secretion.
The spontaneous decline of insulin secretion which occurs under a variety of secretory conditions is well documented and suggests a general desensitization of the secretory process distal to signal recognition. Accordingly, we have investigated the effects of agents thought to mobilize intracellular Ca++ on insulin secretion over 24 h, which includes periods of rising secretory activity (second phase) and desensitized secretory activity (third phase). During the first 3 h of glucose stimulation of freshly isolated rat islets, insulin secretion was strongly inhibited by 30 microM 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester (TMB) or 300 microM tetracaine hydrochloride (TC). However, when either of these agents was added for the first time to islets at h 20 when insulin secretion was at a low steady rate (third phase), insulin secretion was greatly enhanced. Both these inhibitory and stimulatory effects declined with continued administration. Removal of TMB and rechallenge with high glucose plus forskolin uncovered a residual inhibition in both chronically and acutely treated islets. Coadministration of forskolin with either TMB or TC blunted both inhibitory and stimulatory effects. Pertussis toxin pretreatment, however, did not alter subsequent response of islets to either agent. Thus TMB or TC have opposite, phase-dependent effects on glucose-stimulated insulin secretion. We postulate that potentiators of glucose-stimulated insulin secretion, which are increased during second phase, are most sensitive to inhibitory effects of TMB or TC, and that the low steady rate of third phase permits their stimulatory component(s) to become apparent.
University of California, Metabolic Research Unit, San Francisco 94143.
J L
JL
Bolaffi
G G
GG
Rodd
Y H
YH
Ma
G M
GM
Grodsky
D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D013748:Tetracaine / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007328:Insulin; D010566:Virulence Factors, Bordetella; D013748:Tetracaine; D005576:Colforsin; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D037342:Pertussis Toxin; D005947:Glucose; D003000:Clonidine