Phase Analysis of Metabolic Oscillations and Membrane Potential in Pancreatic Islet β-Cells

Metabolism in islet beta-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca2+ that result from bursting electrical activity. In this article, the dynamics of oscillatory metabolism were investigated using five different optical reporters. Reporter activity was measured simultaneously with membrane potential bursting to determine the phase relationships between the metabolic oscillations and electrical activity. Our experimental findings suggest that Ca2+ entry into beta-cells stimulates the rate of mitochondrial metabolism, accounting for the depletion of glycolytic intermediates during each oscillatory burst. We also performed Ca2+ clamp tests in which we clamped membrane potential with the K-ATP channel-opener diazoxide and KCl to fix Ca2+ at an elevated level. These tests confirm that metabolic oscillations do not require Ca2+ oscillations, but show that Ca2+ plays a larger role in shaping metabolic oscillations than previously suspected. A dynamical picture of the mechanisms of oscillations emerged that requires the restructuring of contemporary mathematical beta-cell models, including our own dual oscillator model. In the companion article, we modified our model to account for these new data.