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OBJECTIVE: These studies were designed to investigate the mechanism through which enterostatin inhibits insulin secretion from pancreatic islets. DESIGN: 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 μM), 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. CONCLUSION: Enterostatin may suppress insulin secretion through the reduction of cAMP, but other mechanisms may also be possible. [ABSTRACT FROM AUTHOR]

Leptin is a hormone secreted by adipocytes as a peripheral metabolic signal for the central regulation of energy homeostasis or the reproductive system. Recent studies demonstrated that leptin receptor mRNA is expressed in pancreatic islets of rodents and that leptin at relatively high doses inhibits glucose-induced insulin secretion from rat islets. However, the physiological mechanism of leptin on insulin secretion has not been identified. In this study, we report that leptin inhibits glucose-induced insulin secretion at lower concentrations ranging from 25 to 50 ng/ml using a static incubation method. A perifusion study revealed that leptin (50 ng/ml) affected the second phase of insulin secretion but not the first phase. Leptin did not affect insulin secretion stimulated by glibenclamide (1 and 5 micromol/l) or forskolin (1 micromol/l). Leptin (50 ng/ml) significantly inhibited insulin secretion induced by the phorbol ester phorbol 12-myristate 13-acetate (TPA) in the presence of Ca2+ but not in the absence of Ca2+. Because TPA is known to activate protein kinase C (PKC), these present results suggest that leptin, at a physiological concentration, suppresses the second phase of insulin secretion by reducing activity of the Ca2+-dependent PKC isoform. [ABSTRACT FROM AUTHOR]