Metabolic Oscillations in Pancreatic Islets Depend on the Intracellular Ca 2+ Level but Not Ca 2+ Oscillations

Abstract

Plasma insulin is pulsatile and reflects oscillatory insulin secretion from pancreatic islets. Although both islet Ca 2+ and metabolism oscillate, there is disagreement over their interrelationship, and whether they can be dissociated. In some models of islet oscillations, Ca 2+ must oscillate for metabolic oscillations to occur, whereas in others metabolic oscillations can occur without Ca 2+ oscillations. We used NAD(P)H fluorescence to assay oscillatory metabolism in mouse islets stimulated by 11.1 mM glucose. After abolishing Ca 2+ oscillations with 200 μM diazoxide, we observed that oscillations in NAD(P)H persisted in 34% of islets ( n = 101). In the remainder of the islets (66%) both Ca 2+ 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 Ca 2+ level but did not restore Ca 2+ oscillations. Comparatively, we examined islets from ATP-sensitive K + (K ATP) channel-deficient SUR1 −/− mice. Again NAD(P)H oscillations were evident even though Ca 2+ and membrane potential oscillations were abolished. These observations are predicted by the dual oscillator model, in which intrinsic metabolic oscillations and Ca 2+ feedback both contribute to the oscillatory islet behavior, but argue against other models that depend on Ca 2+ oscillations for metabolic oscillations to occur.