Beta-cell Selective K(ATP)-channel Activation Protects Beta-Cells and Human Islets From Human Islet Amyloid Polypeptide Induced Toxicity

Regul Pept. 2010 Dec 10;165(2-3):158-62. doi: 10.1016/j.regpep.2010.06.009. Epub 2010 Jul 6.

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(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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cyclic S-Oxides / pharmacology
  • Diabetes Mellitus, Type 2
  • Humans
  • In Vitro Techniques
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Islet Amyloid Polypeptide / toxicity*
  • Islets of Langerhans / drug effects*
  • KATP Channels / agonists*
  • KATP Channels / metabolism

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclic S-Oxides
  • Islet Amyloid Polypeptide
  • KATP Channels
  • NN 414