Metabolic Oscillations in Pancreatic Islets Depend on the Intracellular Calcium Level but Not Calcium Oscillations

Matthew J. Merrins, Bernard Fendler, Min Zhang, Arthur Sherman, Richard Bertram, Leslie S. Satin

Plasma insulin is pulsatile and reflects oscillatory insulin secretion from pancreatic islets. While both islet calcium and metabolism oscillate, there is disagreement over their interrelationship, and whether they can be dissociated. In some models of islet oscillations, calcium must oscillate for metabolic oscillations to occur, while in others metabolic oscillations can occur without calcium oscillations. We used NAD(P)H fluorescence to assay oscillatory metabolism in mouse islets stimulated by 11.1 mM glucose. After abolishing calcium oscillations with 200 micromolar diazoxide, we observed that oscillations in NAD(P)H persisted in 34% of islets (n=101). In the remainder of the islets (66%) both calcium and NAD(P)H oscillations were eliminated by diazoxide. However, in most of these islets NAD(P)H oscillations could be restored and amplified by raising extracellular KCl, which elevated the intracellular calcium level but did not restore calcium oscillations. Comparatively, we examined islets from ATP-sensitive K+ (KATP) channel-deficient SUR1 knockout mice. Again NAD(P)H oscillations were evident even though calcium and membrane potential oscillations were abolished. These observations are predicted by the Dual Oscillator Model, in which intrinsic metabolic oscillations and calcium feedback both contribute to the oscillatory islet behavior, but argue against other models that depend on calcium oscillations for metabolic oscillations to occur.