Alpha1-antitrypsin protects beta-cells from apoptosis.
Beta-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 alpha1-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 beta-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-alpha. In a second model system involving STZ-induced beta-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 beta-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.
Zhang
Bin
B
Department of Pharmaceutics, University of Florida, Gainsville, FL 32610, USA.
Lu
Yuanqing
Y
Campbell-Thompson
Martha
M
Spencer
Terry
T
Wasserfall
Clive
C
Atkinson
Mark
M
Song
Sihong
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D001786:Blood Glucose; D000515:alpha 1-Antitrypsin; D053148:Caspase 3