Proinsulin misfolding is an early event in the progression to type 2 diabetes.
Animals
Cysteine
/ chemistry
Diabetes Mellitus, Type 2
/ genetics
Disease Progression
Disulfides
/ chemistry
Endoplasmic Reticulum
/ metabolism
Endoplasmic Reticulum Chaperone BiP
Humans
Insulin-Secreting Cells
/ metabolism
Islets of Langerhans
/ metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Obese
Proinsulin
/ chemistry
Protein Folding
Receptors, Leptin
/ deficiency
GRP78
cell biology
disulfide bonds
endoplasmic reticulum
mouse
prediabetes
protein trafficking
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
11 06 2019
11 06 2019
Historique:
received:
19
12
2018
accepted:
09
04
2019
entrez:
12
6
2019
pubmed:
12
6
2019
medline:
3
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31184302
doi: 10.7554/eLife.44532
pii: 44532
pmc: PMC6559786
doi:
pii:
Substances chimiques
Disulfides
0
Endoplasmic Reticulum Chaperone BiP
0
HSPA5 protein, human
0
Hspa5 protein, mouse
0
Receptors, Leptin
0
Proinsulin
9035-68-1
Cysteine
K848JZ4886
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK111174
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24 DK110973
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK098085
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK048280
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24DK110973
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01DK111174
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113171
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK48280
Pays : United States
Informations de copyright
© 2019, Arunagiri et al.
Déclaration de conflit d'intérêts
AA, LH, AP, FP, SK, LZ, AP, JP, BT, PI, RK, ML, PA No competing interests declared
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