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

eLife

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[1] 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 Cell and Developmental Biology, University of Michigan, Ann Arbor, United States;Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, Columbia University, New York, United States;Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States;Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, United States;Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, United States;Department of Endocrinology and Metabolism, Tianjin Medical University, Tianjin, China;Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia;

关键词: mouse;    endoplasmic reticulum;    GRP78;    disulfide bonds;    prediabetes;    protein trafficking;    Mouse;   

DOI  :  10.7554/eLife.44532

来源: publisher

【 摘 要 】

10.7554/eLife.44532.001Biosynthesis 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.

【 授权许可】

CC BY