title: Alpha1-antitrypsin protects beta-cells from apoptosis.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, University of Florida, Gainsville, FL 32610, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Lu
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Terry
authors.initials: T
authors.lastname: Spencer
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: 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*
chemical_list: D001786:Blood Glucose; D000515:alpha 1-Antitrypsin; D053148:Caspase 3