Cell Biology
Reduced Cytochrome c Is an Essential Regulator of Sustained Insulin Secretion by Pancreatic Islets*

https://doi.org/10.1074/jbc.M110.202820Get rights and content
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Influx of calcium is an essential but insufficient signal in sustained nutrient-stimulated insulin secretion, and increased metabolic rate of the beta cell is also required. The aim of the study was to test the hypothesis that the reduced state of cytochrome c is a metabolic co-factor necessary for insulin secretion, over and above its participation in the ATP-generating function of electron transport/oxidative phosphorylation. We found that nutrient stimulation of insulin secretion by isolated rat islets was strongly correlated with reduced cytochrome c, and agents that acutely and specifically reduced cytochrome c led to increased insulin secretion, even in the face of decreased oxygen consumption and calcium influx. In contrast, neither sites 1 nor 4 of the electron transport chain were both necessary and essential for the stimulation of insulin secretion to occur. Importantly, stimulation of islets with glucose, α-ketoisocaproate, or glyceraldehyde resulted in the appearance of cytochrome c in the cytosol, suggesting a pathway for the regulation of exocytotic machinery by reduction of cytochrome c. The data suggest that the metabolic factor essential for sustained calcium-stimulated insulin secretion to occur is linked to reduction and translocation of cytochrome c.

Calcium
Cytochrome c
Electron Transport
Insulin Secretion
Pancreatic Islet

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*

This work was supported, in whole or in part, by National Institutes of Health Grant DK17047 (a DERC Islet Core and an R24 seed grant supplement) and National Science Foundation Grant IIP-0750508.