title: Insulin protects pancreatic acinar cells from cytosolic calcium overload and inhibition of plasma membrane calcium pump.
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 Ca(2+) ([Ca(2+)](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 Ca(2+) overload likely represent key therapeutic untapped strategies for the treatment of this disease. The plasma membrane Ca(2+)-ATPase (PMCA) provides a final common path for cells to "defend" [Ca(2+)](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 Ca(2+) 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 Ca(2+) overload, even in the face of impaired mitochondrial function.
authors: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, United Kingdom.
authors: Parini
authors: P
authors: Mankad
authors: Andrew
authors: A
authors: James
authors: Ajith K
authors: AK
authors: Siriwardena
authors: Austin C
authors: AC
authors: Elliott
authors: Jason I E
authors: JI
authors: Bruce
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D046790:Pancreas, Exocrine / Q000166:cytology / Q000378:metabolism*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium