The insulinotropic mechanism of the novel hypoglycaemic agent JTT‐608: direct enhancement of Ca 2+ efficacy and increase of Ca 2+ influx by phosphodiesterase inhibition

We examined the effects of the novel hypoglycaemic agent JTT‐608 [trans‐4‐(4‐methylcyclohexyl)‐4‐oxobutyric acid] on insulin secretion using rat pancreatic islets, and analysed the mechanism of its effect. JTT‐608 augmented 8.3 m M glucose‐induced insulin secretion dose‐dependently, and there was a stimulatory effect of 100 μ M JTT‐608 at both moderate and high concentrations (8.3, 11.1 and 16.7 m M ) of glucose, but not at low concentrations (3.3 and 5.5 m M ). In perifusion experiments, both phases of insulin release were enhanced, and the effect was eliminated 10 min after withdrawal of the agent. In the presence of 200 μ M diazoxide and a depolarizing concentration (30 m M ) of K + , there was an augmentation of insulin secretion by 100 μ M JTT‐608, not only under high levels of glucose but also under low levels, and the effects were abolished by 10 μ M nitrendipine. JTT‐608 augmented insulin secretion from electrically permeabilized islets in the presence of stimulatory concentrations (0.3 and 1.0 μ M ) of Ca 2+ , and the intracellular Ca 2+ concentration ([Ca 2+ ] i ) response under 16.7 m M glucose, 200 μ M diazoxide, and 30 m M K + was also increased. The cyclic AMP content in the islets was increased by 100 μ M JTT‐608, and an additive effect to 1 μ M forskolin was observed, but not to 50 μ M 3‐isobutyl‐1‐methylxanthine (IBMX). JTT‐608 inhibited phosphodiesterase (PDE) activity dose‐dependently. We conclude that JTT‐608 augments insulin secretion by enhancing Ca 2+ efficacy and by increasing Ca 2+ influx. This appears to be a result of the increased intracellular cyclic AMP concentration due to PDE inhibition.British Journal of Pharmacology (2000) 129 , 901–908; doi: 10.1038/sj.bjp.0703133