Control of precursor maturation and disposal is an early regulative mechanism in the normal insulin production of pancreatic β-cells.

PloS One
Jie WangKwame Osei

Abstract

The essential folding and maturation process of proinsulin in β-cells is largely uncharacterized. To analyze this process, we improved approaches to immunoblotting, metabolic labeling, and data analysis used to determine the proportion of monomers and non-monomers and changes in composition of proinsulin in cells. We found the natural occurrence of a large proportion of proinsulin in various non-monomer states, i.e., aggregates, in normal mouse and human β-cells and a striking increase in the proportion of proinsulin non-monomers in Ins2(+/Akita) mice in response to a mutation (C96Y) in the insulin 2 (Ins2) gene. Proinsulin emerges in monomer and abundant dual-fate non-monomer states during nascent protein synthesis and shows heavy and preferential ATP/redox-sensitive disposal among secretory proteins during early post-translational processes. These findings support the preservation of proinsulin's aggregation-prone nature and low relative folding rate that permits the plentiful production of non-monomer forms with incomplete folding. Thus, in normal mouse/human β-cells, proinsulin's integrated maturation and degradation processes maintain a balance of natively and non-natively folded states, i.e., proinsulin homeostasis (PIHO)...Continue Reading

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Citations

May 28, 2013·Experimental Physiology·Ning WangJayasri Nanduri
Jan 30, 2018·Annals of the New York Academy of Sciences·Anoop ArunagiriPeter Arvan
Sep 20, 2018·Diabetes, Obesity & Metabolism·Ming LiuPeter Arvan
Jun 1, 2013·The Journal of Clinical Investigation·Jordan WrightPeter Arvan
Jan 20, 2021·The Journal of Clinical Investigation·Ming LiuPeter Arvan
Feb 16, 2021·American Journal of Physiology. Endocrinology and Metabolism·Mario A MirandaHeather A Lawson

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Methods Mentioned

BETA
protein folding
electrophoresis
immunoprecipitation

Software Mentioned

Image J

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