Insulin Protects Pancreatic Acinar Cells from Palmitoleic Acid-induced Cellular Injury |
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Authors: | Aysha Samad Andrew James James Wong Parini Mankad John Whitehouse Waseema Patel Marta Alves-Simoes Ajith K Siriwardena Jason I E Bruce |
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Institution: | From the ‡Faculty of Life Sciences, The University of Manchester, M13 9NT Manchester and ;the §Hepatobiliary Surgery Unit, Manchester Royal Infirmary, M13 9WL Manchester, United Kingdom |
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Abstract: | Acute pancreatitis is a serious and sometimes fatal inflammatory disease where the pancreas digests itself. The non-oxidative ethanol metabolites palmitoleic acid (POA) and POA-ethylester (POAEE) are reported to induce pancreatitis caused by impaired mitochondrial metabolism, cytosolic Ca2+ (Ca2+]i) overload and necrosis of pancreatic acinar cells. Metabolism and Ca2+]i are linked critically by the ATP-driven plasma membrane Ca2+-ATPase (PMCA) important for maintaining low resting Ca2+]i. The aim of the current study was to test the protective effects of insulin on cellular injury induced by the pancreatitis-inducing agents, ethanol, POA, and POAEE. Rat pancreatic acinar cells were isolated by collagenase digestion and Ca2+]i was measured by fura-2 imaging. An in situ Ca2+]i clearance assay was used to assess PMCA activity. Magnesium green (MgGreen) and a luciferase-based ATP kit were used to assess cellular ATP depletion. Ethanol (100 mm) and POAEE (100 μm) induced a small but irreversible Ca2+ overload response but had no significant effect on PMCA activity. POA (50–100 μm) induced a robust Ca2+ overload, ATP depletion, inhibited PMCA activity, and consequently induced necrosis. Insulin pretreatment (100 nm for 30 min) prevented the POA-induced Ca2+ overload, ATP depletion, inhibition of the PMCA, and necrosis. Moreover, the insulin-mediated protection of the POA-induced Ca2+ overload was partially prevented by the phosphoinositide-3-kinase (PI3K) inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002. These data provide the first evidence that insulin directly protects pancreatic acinar cell injury induced by bona fide pancreatitis-inducing agents, such as POA. This may have important therapeutic implications for the treatment of pancreatitis. |
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Keywords: | Calcium Calcium ATPase Calcium Transport Insulin Pancreas PMCA Pancreatitis |
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