Oscillations of insulin secretion can be triggered by imposed oscillationsof cytoplasmic Ca2+ or metabolism in normal mouse islets

Glucose-induced insulin secretion depends on an acceleration of glucose met abolism, requires a rise in the cytoplasmic free Ca2+ concentration C[Ca2+] (i)), and is modulated by activation of protein kinases in beta-cells. Norm al mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion . The approach was to minimize or abolish spontaneous oscillations and to c ompare the impact of forced oscillations of each signal on insulin secretio n. In a control medium, repetitive increases in the glucose concentration t riggered oscillations in metabolism [NAD(P)H fluorescence], [Ca2+](i) (fura -PE3 method), and insulin secretion. In the presence of diazoxide, metaboli c oscillations persisted, but [Ca2+], and insulin oscillations were abolish ed. When the islets mere depolarized with high K+ with or without diazoxide , [Ca2+], was elevated, and insulin secretion was stimulated. Forced metabo lic oscillations transiently decreased or did not affect [Ca2+](i) and pote ntiated insulin secretion with oscillations of small amplitude. These oscil lations of secretion followed metabolic oscillations only when [Ca2+](i) di d not change. When [Ca2+](i) fluctuated, these changes prevailed over those of metabolism for timing secretion. Repetitive depolarizations with high K + in the presence of stable glucose (10 mmol/l) induced synchronous pulses of [Ca2+](i) and insulin secretion with only small oscillations of metaboli sm. Continuous stimulation of protein kinase A (PKA) and protein kinase C ( PKC) did not dissociate the [Ca2+](i) and insulin pulses from the high K+ p ulses. However, the amplitude of the insulin pulses was consistent ly incre ased, whereas that of the [Ca2+](i) pulses was either increased (PKA) or de creased (PKC). In conclusion, metabolic oscillations can induce oscillation s of insulin secretion independently of but with a lesser effectiveness tha n [Ca2+](i) oscillations. Although oscillations in metabolism may cyclicall y influence secretion through an ATP-sensitive K+ channel (K+-ATP channel)- independent pathway, their regulatory effects are characterized by a hyster esis that makes them unlikely drivers of fast oscillations, unless they als o involve [Ca2+](i) changes through the K+-ATP channel-dependent pathway.