TY - JOUR
T1 - Dilation of the endoplasmic reticulum in beta cells due to molecular overcrowding?. Kinetic simulations of extension limits and consequences on proinsulin synthesis
AU - Despa, F.
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
KW - Beta cell dysfunction mechanism
KW - Diabetes
KW - ER dilation
KW - ER stress condition
KW - Molecular crowding effect
KW - Proinsulin denaturation
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U2 - 10.1016/j.bpc.2008.12.003
DO - 10.1016/j.bpc.2008.12.003
M3 - Article
C2 - 19121888
AN - SCOPUS:58549117847
SN - 0301-4622
VL - 140
SP - 115
EP - 121
JO - Biophysical Chemistry
JF - Biophysical Chemistry
IS - 1-3
ER -