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J. Biol. Chem. 287 (3): 1823-1836

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Background: Impaired metabolism and cytosolic Ca2+ overload in pancreatic acinar cells can trigger pancreatitis.

Results: Insulin protected cells from oxidant-induced Ca2+ overload, inhibition of the plasma membrane calcium pump (PMCA), and ATP depletion.

Conclusion: Insulin switches metabolism toward glycolysis and fuels the PMCA even when mitochondria are impaired.

Significance: This mechanism may provide an important therapeutic strategy for pancreatitis.


Insulin Protects Pancreatic Acinar Cells from Cytosolic Calcium Overload and Inhibition of Plasma Membrane Calcium Pump*

Parini Mankad{ddagger}1, Andrew James{ddagger}, Ajith K. Siriwardena§, Austin C. Elliott{ddagger}, , and Jason I. E. Bruce{ddagger}2

From the {ddagger}Faculty of Life Sciences, The University of Manchester and
the §Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Manchester M13 9NT, United Kingdom

ABSTRACT Back to Top

Abstract: Acute pancreatitis is a serious and sometimes fatal inflammatory disease of the pancreas without any reliable treatment or imminent cure. In recent years, impaired metabolism and cytosolic Ca2+ ([Ca2+]i) overload in pancreatic acinar cells have been implicated as the cardinal pathological events common to most forms of pancreatitis, regardless of the precise causative factor. Therefore, restoration of metabolism and protection against cytosolic Ca2+ overload likely represent key therapeutic untapped strategies for the treatment of this disease. The plasma membrane Ca2+-ATPase (PMCA) provides a final common path for cells to "defend" [Ca2+]i during cellular injury. In this paper, we use fluorescence imaging to show for the first time that insulin treatment, which is protective in animal models and clinical studies of human pancreatitis, directly protects pancreatic acinar cells from oxidant-induced cytosolic Ca2+ overload and inhibition of the PMCA. This protection was independent of oxidative stress or mitochondrial membrane potential but appeared to involve the activation of Akt and an acute metabolic switch from mitochondrial to predominantly glycolytic metabolism. This switch to glycolysis appeared to be sufficient to maintain cellular ATP and thus PMCA activity, thereby preventing Ca2+ overload, even in the face of impaired mitochondrial function.


Key Words: Calcium ATPase • Calcium Signaling • Insulin • Metabolic Regulation • Pancreas • PMCA • Warburg Effect • Calcium Overload • Pancreatic Acinar Cells • Pancreatitis

Received for publication November 22, 2011. Revision received November 29, 2011.

FOOTNOTES Back to Top

1 Supported by a Biotechnology and Biological Sciences Research Council Ph.D. studentship.

2 To whom correspondence should be addressed: Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9NT, UK. Tel: + 44–161-275–5484; Fax: +44–161-275–5600. Email Address: jason.bruce{at}manchester.ac.uk


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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A. D. James, A. Chan, O. Erice, A. K. Siriwardena, and J. I. E. Bruce (2013)
J. Biol. Chem. 288, 36007-36019
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Calcium Channels and Pumps in Cancer: Changes and Consequences.
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