期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 411, 期 1, 页码 150-155出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.06.119
关键词
Islets; Proinsulin maturation disorder; Defective conversion; Convertase post-translational defects; Hyperproinsulinemia
资金
- Start-up Fund
- Ohio State University School of Medicine
Disproportionate hyperproinsulinemia is an indicator of beta-cell dysfunction in diabetes and the basis underlying this abnormality remains obscure. Recently, we have found proinsulin is an aggregationprone 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 beta-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 beta-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/beta-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, metaboliclabeling, and RT-PCR analyses revealed decreases of the PC1/3 and PC2 immunoreactivities in the beta-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)beta-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. (C) 2011 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据