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Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not

Soo-Young Park1, Honggang Ye, Donald F Steiner

  • 1Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 1027, Chicago, IL 60637, USA. sooyoung@uchicago.edu

Biochemical and Biophysical Research Communications
|December 26, 2009
PubMed

Insights

Mutations in human proinsulin cause diabetes by impairing protein secretion. Most mutant proinsulins accumulate in the endoplasmic reticulum (ER), unlike wild-type proteins, hindering insulin secretion and leading to disease.

Area of Science:

  • Molecular Endocrinology
  • Cell Biology
  • Genetics

Background:

  • Mutations in the preproinsulin protein can disrupt its processing or folding, leading to diabetes.
  • Understanding the cellular fate of these mutant proteins is crucial for elucidating disease mechanisms.

Purpose of the Study:

  • To investigate the subcellular localization and secretion of 13 neonatal diabetes-associated human proinsulin mutants.
  • To compare the behavior of these mutants with wild-type and hyperproinsulinemia-associated mutants.
  • To assess the impact of a specific mutant (C96Y) on wild-type insulin synthesis and secretion.

Main Methods:

  • Expression of 13 neonatal diabetes-associated human proinsulin mutants in rat INS-1 insulinoma cells.
  • Analysis of subcellular localization (ER vs. secretory granules) and secretion efficiency.
  • Examination of the effect of C96Y mutant proinsulin on wild-type insulin production and secretion.

Main Results:

  • Most mutant proinsulins accumulated in the endoplasmic reticulum (ER) and were poorly secreted.
  • The G84R mutant showed efficient secretion, similar to wild-type and hyperproinsulinemia mutants (H34D, R89H).
  • The C96Y mutant exhibited a dominant-negative effect, impairing wild-type insulin secretion by inducing the unfolded protein response and reducing overall translation.

Conclusions:

  • Neonatal diabetes-associated proinsulin mutations often lead to ER accumulation and impaired secretion.
  • Specific mutations can have distinct cellular trafficking and secretion profiles.
  • Mutant proinsulins can interfere with the normal processing and secretion of wild-type insulin, contributing to diabetes pathogenesis.

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