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Elife. 2019 Jun 11;8. pii: e44532. doi: 10.7554/eLife.44532.

Proinsulin misfolding is an early event in the progression to type 2 diabetes.

Author information

1
Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, United States.
2
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States.
3
Department of Biomedical Science and Technology, Konkuk University, Gwangjin-gu, Republic of Korea.
4
Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, Columbia University, New York, United States.
5
Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
6
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States.
7
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States.
8
Department of Endocrinology and Metabolism, Tianjin Medical University, Tianjin, China.

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.

KEYWORDS:

GRP78; cell biology; disulfide bonds; endoplasmic reticulum; mouse; prediabetes; protein trafficking

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