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UDP-glucose, cereblon-dependent proinsulin degrader
Jaeyong Cho1, Atsushi Miyagawa2, Kazuki Yamaguchi2
1Department of Chemical Biology, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
Scientific Reports
|August 26, 2022
Summary
UDP-glucose triggers proinsulin ubiquitination by cereblon, marking it for degradation. Uridine and related compounds block this, acting as sustainable insulin secretagogues that promote long-term insulin release.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- Insulin secretion regulation involves multiple steps, including crucial processes within the endoplasmic reticulum (ER).
- Proinsulin misfolding and degradation in the ER are implicated in diabetes pathogenesis.
Purpose of the Study:
- To investigate the role of UDP-glucose and uridine in regulating proinsulin stability and insulin secretion.
- To identify endogenous regulators of proinsulin degradation in the ER.
Main Methods:
- Utilized insulin mutagenesis (neonatal diabetes variant-C43G, MODY10 variant-R46Q) and studied the effects of UDP-glucose and uridine-containing compounds.
- Assessed proinsulin ubiquitination by cereblon and its regulation by UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1).
- Measured insulin secretion from beta-cell lines and mice following administration of uridine-containing compounds.
Main Results:
- UDP-glucose induces proinsulin ubiquitination via cereblon (a ligand-inducible E3 ubiquitin ligase), identifying it as an endogenous proinsulin degrader.
- UGGT1 protects against cereblon-dependent proinsulin ubiquitination.
- Uridine, UMP, UTP, and UDP-galactose inhibit cereblon-mediated proinsulin degradation.
- These compounds stimulate insulin secretion for up to 24 hours, termed 'day sustainable insulin secretion stimulation'.
Conclusions:
- Uridine-containing compounds act as novel proinsulin degradation regulators.
- These compounds offer a potential therapeutic strategy for enhancing long-term insulin secretion in diabetes.
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