Inhibition of insulin release by enterostatin.
OBJECTIVE
These studies were designed to investigate the mechanism through which enterostatin inhibits insulin secretion from pancreatic islets.


METHODS
A static islet incubation method was used to study the effects of enterostatin on insulin secretion induced by various secretagogues and to investigate the effect of calcium ions and 8-Br-cyclic AMP on the response to enterostatin. Measurements of islet cAMP concentrations in response to enterostatin were also made.


RESULTS
Enterostatin (10(-9) to 10(-5) M) inhibited insulin secretion from islets incubated in the presence of 16.7 mM glucose in a dose-dependent manner. Enterostatin also inhibited insulin secretion stimulated by glybenclamide (5.0 and 10 microM), phorbol 12-myristate-13-acetate (TPA) (50 and 100 nM), and the kappa-opioid agonist U50,488 (100 nM). The inhibitory effect of enterostatin on TPA-induced insulin secretion was attenuated but still remained in the absence of extracellular Ca2+. The enterostatin inhibition of insulin secretion was blocked by 8-Br-cAMP (1 mM) independent of extracellular Ca2+. Enterostatin reduced the increase in intracellular cyclic AMP (cAMP) content produced by U50,488 (100 nM) and the changes in cAMP content were parallel with changes in insulin release.


CONCLUSIONS
Enterostatin may suppress insulin secretion through the reduction of cAMP, but other mechanisms may also be possible.
Ookuma
M
M
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808-4124, USA.
York
D A
DA
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003089:Colipases / Q000494:pharmacology*; D046508:Culture Techniques; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003089:Colipases; D004792:Enzyme Precursors; D007004:Hypoglycemic Agents; D007328:Insulin; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D015124:8-Bromo Cyclic Adenosine Monophosphate; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C037107:procolipase; D000242:Cyclic AMP; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D005905:Glyburide; D002118:Calcium