UDP-glucose, cereblon-dependent proinsulin degrader.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
26 08 2022
26 08 2022
Historique:
received:
01
02
2022
accepted:
22
08
2022
entrez:
26
8
2022
pubmed:
27
8
2022
medline:
31
8
2022
Statut:
epublish
Résumé
Insulin secretion is regulated in multiple steps, and one of the main steps is in the endoplasmic reticulum (ER). Here, we show that UDP-glucose induces proinsulin ubiquitination by cereblon, and uridine binds and competes for proinsulin degradation and behaves as sustainable insulin secretagogue. Using insulin mutagenesis of neonatal diabetes variant-C43G and maturity-onset diabetes of the young 10 (MODY10) variant-R46Q, UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) protects cereblon-dependent proinsulin ubiquitination in the ER. Cereblon is a ligand-inducible E3 ubiquitin ligase, and we found that UDP-glucose is the first identified endogenous proinsulin protein degrader. Uridine-containing compounds, such as uridine, UMP, UTP, and UDP-galactose, inhibit cereblon-dependent proinsulin degradation and stimulate insulin secretion from 3 to 24 h after administration in β-cell lines as well as mice. This late and long-term insulin secretion stimulation is designated a day sustainable insulin secretion stimulation. Uridine-containing compounds are designated as proinsulin degradation regulators.
Identifiants
pubmed: 36028536
doi: 10.1038/s41598-022-18902-5
pii: 10.1038/s41598-022-18902-5
pmc: PMC9418190
doi:
Substances chimiques
Insulin
0
Proinsulin
9035-68-1
Glucose
IY9XDZ35W2
Uridine Diphosphate Glucose
V50K1D7P4Y
Uridine
WHI7HQ7H85
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14568Informations de copyright
© 2022. The Author(s).
Références
Nat Commun. 2018 Sep 10;9(1):3659
pubmed: 30201971
J Clin Invest. 2020 Jul 1;130(7):3499-3510
pubmed: 32182217
J Org Chem. 2013 Aug 16;78(16):8105-16
pubmed: 23924266
Diabetologia. 2017 Aug;60(8):1423-1431
pubmed: 28478482
J Pediatr Endocrinol Metab. 2014 Jul;27(7-8):745-8
pubmed: 24566359
Nature. 2014 Aug 7;512(7512):49-53
pubmed: 25043012
Clin Exp Gastroenterol. 2015 Jul 02;8:175-82
pubmed: 26170710
Vitam Horm. 2014;95:35-62
pubmed: 24559913
J Biol Chem. 2010 Mar 12;285(11):7847-51
pubmed: 20106974
J Diabetes Investig. 2013 Mar 18;4(2):157-67
pubmed: 24843647
Sci Rep. 2017 Sep 22;7(1):12142
pubmed: 28939828
Mol Metab. 2017 Jul 08;6(9):943-957
pubmed: 28951820
Diabetes. 2020 May;69(5):940-953
pubmed: 32086291
Diabetes. 2010 Mar;59(3):653-61
pubmed: 20007936
Chem Soc Rev. 2022 Aug 1;51(15):6234-6250
pubmed: 35796627
Int J Mol Sci. 2022 Aug 13;23(16):
pubmed: 36012359
Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E403-10
pubmed: 19952343
Cell Rep. 2018 Jul 3;24(1):181-196
pubmed: 29972779
J Med Chem. 2019 Jul 25;62(14):6615-6629
pubmed: 31251063
Clin Exp Gastroenterol. 2019 Jul 22;12:331-336
pubmed: 31413616
J Immunol Res. 2017;2017:9130608
pubmed: 28894755
J Biol Chem. 2014 Jun 6;289(23):16290-302
pubmed: 24770419
Mol Metab. 2017 May 04;6(9):958-973
pubmed: 28951821
Biochem Biophys Res Commun. 2010 Jan 15;391(3):1449-54
pubmed: 20034470
Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15040-4
pubmed: 17855560
Biochem Biophys Res Commun. 2020 Jun 30;527(3):668-675
pubmed: 32423812
Biochem Biophys Res Commun. 2019 Apr 9;511(3):592-596
pubmed: 30826053
Commun Biol. 2020 Sep 8;3(1):497
pubmed: 32901087
Biochem Biophys Res Commun. 2015 Oct 30;466(4):717-22
pubmed: 26348775
Genes Cells. 2015 Mar;20(3):217-23
pubmed: 25495062
Diabetes Care. 1994 Sep;17(9):1015-21
pubmed: 7988299
Science. 2010 Mar 12;327(5971):1345-50
pubmed: 20223979
Diabetes. 2012 Apr;61(4):828-37
pubmed: 22357960
J Diabetes Investig. 2011 Apr 7;2(2):92-100
pubmed: 24843467