An oscillatory increase in pancreatic β cell cytoplasmic free Ca²⁺ concentration, [Ca²⁺]_i, is a key feature in glucose-induced insulin release. The role of the voltage-gated Ca²⁺ channel β₃ subunit in the molecular regulation of these [Ca²⁺]_i oscillations has now been clarified by using β₃ subunit-deficient β cells. β₃ knockout mice showed a more efficient glucose homeostasis compared to wild-type mice due to increased glucose-stimulated insulin secretion. This resulted from an increased glucose-induced [Ca²⁺]_i oscillation frequency in β cells lacking the β₃ subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP₃) and increased Ca²⁺ mobilization from intracellular stores. Hence, the β₃ subunit negatively modulated InsP₃-induced Ca²⁺ release, which is not paralleled by any effect on the voltage-gated L type Ca²⁺ channel. Since the increase in insulin release was manifested only at high glucose concentrations, blocking the β₃ subunit in the β cell may constitute the basis for a novel diabetes therapy.