Dilation of the endoplasmic reticulum in beta cells due to molecular overcrowding?. Kinetic simulations of extension limits and consequences on proinsulin synthesis

F. Despa

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Insulin regulates the energy homeostasis of the human body. This is synthesized in the endoplasmic reticulum (ER) of pancreatic beta cells from proinsulin. Chronic hyperglycemia increases considerably the proinsulin secretion, overcrowding the ER. Recent experimental evidence demonstrates that such states favor the proinsulin denaturation. The biophysical mechanism of this cellular dysfunction remains largely unknown. We use basic molecular principles and numerical simulations of time-dependent crowding conditions in the ER to show that crowding effects enhance the propensity of proinsulin molecules to (mis)fold in compressed, nonnative structures. Present results suggest: i) misfolding events and toxic accumulations increase dramatically if the proinsulin load exceeds 50% of the available space and ii) insufficient lag time for the relaxation of the ER between consecutive proinsulin uploads can cause irreversible alterations of folding capabilities. Present study may prove useful in generating new testable statements on circumstances leading to the development of diabetes.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalBiophysical Chemistry
Volume140
Issue number1-3
DOIs
StatePublished - Mar 2009

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Keywords

  • Beta cell dysfunction mechanism
  • Diabetes
  • ER dilation
  • ER stress condition
  • Molecular crowding effect
  • Proinsulin denaturation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Organic Chemistry

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