Beta-cell selective K ATP-channel activation protects beta-cells and human islets from human islet amyloid polypeptide induced toxicity

Abstract

Background and aims In type 2 diabetes mellitus (T2DM) chronic beta-cell stimulation and oligomers of aggregating human islet amyloid polypeptide (h-IAPP) cause beta-cell dysfunction and induce beta-cell apoptosis. Therefore we asked whether beta-cell rest prevents h-IAPP induced beta-cell apoptosis. Materials and methods We induced beta-cell rest with a beta-cell selective K ATP-channel opener (K ATPCO) in RIN cells and human islets exposed to h-IAPP versus r-IAPP. Apoptosis was quantified by time-lapse video microscopy (TLVM) in RIN cells and TUNEL staining in human islets. Whole islets were also studied with TLVM over 48 h to examine islet architecture. Results In RIN cells and human islets h-IAPP induced apoptosis (p < 0.001 h-IAPP versus r-IAPP). Concomitant incubation with K ATPCO inhibited apoptosis (p < 0.001). K ATPCO also reduced h-IAPP induced expansion of whole islets (disintegration of islet architecture) by ~ 70% (p < 0.05). Thioflavin-binding assays show that K ATPCO does not directly inhibit amyloid formation. Conclusions Opening of K ATP-channels reduces beta-cell vulnerability to apoptosis induced by h-IAPP oligomers. This effect is not due to a direct interaction of K ATPCO with h-IAPP, but might be mediated through hyperpolarization of the beta-cell membrane induced by opening of K ATP-channels. Induction of beta-cell rest with beta-cell selective K ATP-channel openers may provide a strategy to protect beta-cells from h-IAPP induced apoptosis and to prevent beta-cell deficiency in T2DM.