Alpha 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic β-cells

alpha(1)-antitrypsin (AA T) is a serine protease inhibitor, which recently has been shown to prevent type 1 diabetes (T1D) development, to prolong islet allograft survival and to inhibit beta-cell apoptosis in vivo. It has also been reported that T1D patients have significantly lower plasma concentrations of AA T suggesting the potential role of AA T in the pathogenesis of T1D. We have investigated whether plasma-purified AA T can affect beta-cell function in vitro. INS-1E cells or primary rat pancreatic islets were used to study the effect of AA T on insulin secretion after glucose, glucagon-like peptide-1 (GLP-1) and forskolin stimulation and on cytokine-mediated apoptosis. The secreted insulin and total cyclic AMP (cAMP) were determined using radioimmunoassay and enzyme immunoassay, respectively. Apoptosis was evaluated by propidium iodide staining followed by FACS analysis. We found that AA T increases insulin secretion in a glucose-dependent manner, potentiates the effect of GLP-1 and forskolin and neutralizes the inhibitory effect of clonidine on insulin secretion. The effect of AA T on insulin secretion was accompanied by an increase in cAMP levels. In addition, AA T protected INS-1E cells from cytokine-induced apoptosis. Our findings show that AA T stimulates insulin secretion and protects beta-cells against cytokine-induced apoptosis, and these effects of AA T seem to be mediated through the cAMP pathway. In view of these novel findings we suggest that AA T may represent a novel anti-inflammatory compound to protect beta-cells under the immunological attack in T1D but also therapeutic strategy to potentiate insulin secretion in type 2 diabetes (T2D).