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


METHODS
We induced beta-cell rest with a beta-cell selective K(ATP)-channel opener (K(ATP)CO) 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 48h 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(ATP)CO inhibited apoptosis (p<0.001). K(ATP)CO also reduced h-IAPP induced expansion of whole islets (disintegration of islet architecture) by ~70% (p<0.05). Thioflavin-binding assays show that K(ATP)CO 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(ATP)CO 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.
Ritzel
Robert A
RA
Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, CA 90095-7073, USA. Robert.Ritzel@klinikum-muenchen.de
Jayasinghe
Sajith
S
Hansen
John B
JB
Sturis
Jeppe
J
Langen
Ralf
R
Butler
Peter C
PC
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects*; D054086:KATP Channels / Q000819:agonists* / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D058228:Islet Amyloid Polypeptide; D054086:KATP Channels; C475618:NN 414