Factors leading to an irreversible increase in the cytosolic Ca2+ concentration ([Ca2+]i) of pancreatic acinar cells have been implicated in acute pancreatitis, a sometimes-fatal inflammatory disease of the pancreas. Noting that insulin, which is produced by pancreatic β cells adjacent to pancreatic acinar cells, protects against pancreatitis, Mankad et al. explored its effects on inhibition of the plasma membrane Ca2+ ATPase (PMCA) and irreversible Ca2+ overload in response to oxidative stress. Pretreatment with 100 nM insulin attenuated the increase in resting [Ca2+]i produced by H2O2 in isolated rat pancreatic acinar cells without affecting oxidative stress per se, a protective effect that was abolished by pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K). Although insulin failed to inhibit H2O2-induced mitochondrial depolarization, it attenuated H2O2-induced ATP depletion (shifting the concentration-response curve). Analysis of the effects of insulin on autofluorescence of NAD(P)H (a measure of cell metabolism), identified pharmacologically as located in mitochondrial or cytosolic pools, indicated that insulin stimulated a switch from mitochondrial to primarily glycolytic metabolism. Insulin protected against an H2O2-dependent decrease in the activity of PMCA (a “gatekeeper” that can restore resting [Ca2+]i to near normal even when other Ca2+ transport mechanisms are impaired), an effect that was also blocked by inhibiting PI3K. Moreover, whereas insulin potentiated inhibition of PMCA by an inhibitor of glycolysis, it abolished inhibition of PMCA by a mitochondrial uncoupler. The authors thus conclude that insulin switches pancreatic acinar cells to a primarily glycolytic metabolism, allowing them to maintain ATP production and thereby PMCA activity, protecting them from Ca2+ overload when mitochondrial function is impaired.
P. Mankad, A. James, A. K. Siriwardena, A. C. Elliott, J. I. E. Bruce, Insulin protects pancreatic acinar cells from cytosolic calcium overload and inhibition of plasma membrane calcium pump. J. Biol. Chem. 287, 1823–1836 (2012). [Abstract] [Full Text]