α1-Antitrypsin Protects β-Cells From Apoptosis
Abstract
β-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 α1-antitrypsin (AAT) 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 AAT significantly reduces cytokine- and streptozotocin (STZ)-induced β-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-α. In a second model system involving STZ-induced β-cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of β-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.
- AAT, α1-antitrypsin
- APC, antigen-presenting cell
- MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide
- STZ, streptozotocin
- TNF-α, tumor necrosis factor-α
- TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db06-1273.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Accepted February 15, 2007.
- Received September 9, 2006.
- DIABETES