Stimulus-secretion-coupling (SSC) in beta cells involves glucose uptake and metabolism, closure of ATP-sensitive K⁺ (K_ATP; KIR 6.2/SUR1) channels, membrane depolarization and stimulation of insulin exocytosis by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (Ca_v). In various secretory cells cytoplasmic swelling is a potent stimulus for hormone secretion. In native and clonal beta cells glucose uptake induces cell swelling and activation of swelling-dependent Cl^- currents (termed ICl_swell, ICl_glucose or ICl_islet). In clonal INS-1E cells this process is paralleled by cytosol to membrane translocation of ICln, a protein which is crucially involved in generating ICl_swell. ICl_swell activation contributes to membrane depolarization and insulin release and therefore provides a synergistic, under certain circumstances independent, alternative pathway of SSC. Since ICl_swell activation requires intracellular ATP, this current seems to be of critical importance for insulin secretion under conditions where the classical SSC pathway is silenced. The phytostilbene resveratrol reversibly inhibits Ca_v and ICl_swell and counteracts secretagogue- and hypotonicity-induced depolarization, and electrical activity. Short-term (1 hour) as well as prolonged (24-48 hours) exposure to resveratrol significantly inhibits glucose-induced and basal insulin release and exerts an antiproliferative/proapoptotic effect as evidenced by cell cycle arrest, apoptotic volume decrease, breakdown of phosphatidylserine asymmetry and caspase activation. Likewise, reduction of the medium glucose concentration results in growth arrest. These events are accompanied by decreased phosphorylation of Akt (PKB), a downstream target in insulin receptor signaling which is crucial for beta cell survival. The inhibition of Akt phosphorylation is significantly attenuated by addition of insulin to the culture medium, thus unraveling the significance of auto/paracrine insulin signaling in the regulation and maintenance of beta cell mass.