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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.

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


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.


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

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