Whereas the mechanisms underlying oscillatory insulin secretion remain unknown, several models have been advanced to explain if they involve generation of metabolic oscillations in beta-cells. Evidence, including measurements of oxygen consumption, glucose consumption, NADH, and ATP/ADP ratio, has accumulated to support the hypothesis that energy metabolism in beta-cells can oscillate. Where simultaneous measurements have been made, these oscillations are well correlated with oscillations in intracellular [Ca(2+)] and insulin secretion. Considerable evidence has been accumulated to suggest that entry of Ca(2+) into cells can modulate metabolism both positively and negatively. The main positive effect of Ca(2+) is an increase in oxygen consumption, believed to involve activation of mitochondrial dehydrogenases. Negative feedback by Ca(2+) includes decreases in glucose consumption and decreases in the mitochondrial membrane potential. Ca(2+) also provides negative feedback by increasing consumption of ATP. The negative feedback provided by Ca(2+) provides a mechanism for generating oscillations based on a model in which glucose stimulates a rise in ATP/ADP ratio that closes ATP-sensitive K(+) (K(ATP)) channels, thus depolarizing the cell membrane and allowing Ca(2+) entry through voltage-sensitive channels. Ca(2+) entry reduces the ATP/ADP ratio and allows reopening of the K(ATP) channel.