Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in β-cells

Biochem Biophys Res Commun. 2011 Jul 22;411(1):150-5. doi: 10.1016/j.bbrc.2011.06.119. Epub 2011 Jun 23.

Abstract

Disproportionate hyperproinsulinemia is an indicator of β-cell dysfunction in diabetes and the basis underlying this abnormality remains obscure. Recently, we have found proinsulin is an aggregation-prone molecule inherent with a low relative folding rate and maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) in normal β-cells as a result of the integration of maturation and disposal processes. PIHO is susceptible to environmental and genetic influences. Perturbation of PIHO produces a number of toxic consequences with known association to β-cell failure in diabetes. To explore whether the perturbation of PIHO has a link to disproportionate hyperproinsulinemia, we investigated proinsulin conversion and the involved prohormone convertase 1/3 (PC1/3) and 2 (PC2) in mouse Ins2(+/Akita) islets/β-cells that preserve a primary PIHO disorder due to a mutation (C96Y) in the insulin 2 (Ins2) gene. Our metabolic-labeling studies found an increased ratio of proinsulin to insulin in the cellular or released proteins of Ins2(+/Akita) islets. Histological, metabolic-labeling, and RT-PCR analyses revealed decreases of the PC1/3 and PC2 immunoreactivities in the β-cells of Ins2(+/Akita) islets in spite of no declines of these two convertases at the transcriptional and translational levels. Immunoblot analyses in cloned Ins2(+/Akita) β-cells further confirmed the increased ratio of proinsulin to insulin despite the levels of PC1/3 and PC2 proteins were not reduced somehow. The findings demonstrate that the perturbation of PIHO results in defects in the subsequent conversion process of proinsulin and is a contributor to the occurrence of disproportionate hyperproinsulinemia in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hyperinsulinism / metabolism*
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Proinsulin / genetics
  • Proinsulin / metabolism*

Substances

  • Insulin
  • Proinsulin