Intracellular Ca2+ concentration ([Ca2+]i) handling during K(+)-induced Ca2+ loads was studied in single islets of Langerhans. K(+)-induced depolarization caused a rapid and transient rise in [Ca2+]i. After K+ removal [Ca2+]i declined with a time course usually fitted by the sum of two exponential functions. Partial Na+ removal increased the resting [Ca2+]i level, indicating the existence of a Na+/Ca2+ exchange, but only slightly impaired the recovery from Ca2+ loads. Metabolic poisoning with CN- increased the resting Ca2+ level and slowed down the recovery from Ca2+ loads. Removal of external Na+ in islets poisoned with CN- strongly inhibited Ca2+ removal mechanisms. An increase in the glucose concentration from 0 to 16 mM (in the presence of diazoxide) resulted in a decrease in the resting [Ca2+]i and an acceleration of [Ca2+]i recovery from K+ loads. These results suggest that the main mechanism responsible for Ca2+ homeostasis is dependent on metabolic energy and that such energy can be provided by glucose metabolism.