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Alpha 1 Antitrypsin Protects ß-Cells from Apoptosis

¹Department of Pharmaceutics, University of Florida, Gainesville, Florida
²Department of Pathology, University of Florida, Gainesville, Florida
³Department of Pediatrics, University of Florida, Gainesville, Florida

Correspondence: shsong{at}ufl.edu

ß-cell apoptosis appears to represent a key event in the pathogenesis of type 1 diabetes. Previous studies have demonstrated that administration of the serine proteinase inhibitor alpha 1 antitrypsin, prevents type 1 diabetes development in NOD mice and prolongs islet allograft survival in rodents; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that alpha 1 antitrypsin significantly reduces cytokine- and streptozotocin-induced ß-cell apoptosis. Specifically, strong anti-apoptotic activities for alpha 1 antitrypsin (Prolastin®, human) were observed when murine insulinoma cells (Min6) were exposed to TNF-. In a second model system involving streptozotocin induced ß-cell apoptosis, treatment of Min6 cells with alpha 1 antitrypsin similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment of alpha 1 antitrypsin completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with alpha 1 antitrypsin prevented streptozotocin-induced diabetes and in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of ß-cell apoptosis. These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse type 1 diabetes.

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