Proinsulin misfolding is an early event in the progression to type 2 diabetes
Files
(Published version)
Date
2019
Authors
Arunagiri, A.
Haataja, L.
Pottekat, A.
Pamenan, F.
Kim, S.
Zeltser, L.M.
Paton, A.W.
Paton, J.C.
Tsai, B.
Ansari, P.I.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
eLife, 2019; 8:e44532-1-e44532-25
Statement of Responsibility
Anoop Arunagiri, Leena Haataja, Anita Pottekat, Fawnnie Pamenan, Soohyun Kim, Lori M. Zeltser, Adrienne W. Paton, James C. Paton, Billy Tsai, Pamela Itkin-Ansari, Randal J. Kaufman, Ming Liu, Peter Arvan
Conference Name
Abstract
Biosynthesis of insulin – critical to metabolic homeostasis – begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© Arunagiri et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.