Author:
Cho Jaeyong,Miyagawa Atsushi,Yamaguchi Kazuki,Abe Wakana,Tsugawa Yoji,Yamamura Hatsuo,Imai Takeshi
Abstract
AbstractInsulin 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.
Funder
Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology Agency
National Center for Geriatrics and Gerontology
Publisher
Springer Science and Business Media LLC
Reference37 articles.
1. Rhodes, C. J., Shoelson, S., & Halban, P. A. Insulin biosynthesis, processing, and chemistry, Joslin’s Diabetes Mellitus Fourteenth Edition 2005 Chapter 5 (65–82) (2005).
2. Herquin, J.C. Cell biology of insulin secretion, Joslin’s Diabetes Mellitus Fourteenth Edition 2005 Chapter 6 (83–108) (Lippincott Williams and Wilkins) (2005).
3. Chen, C., Cohrs, C. M., Stertmann, J., Bozsak, R. & Speier, S. Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol. Metab. 6, 943–957. https://doi.org/10.1016/j.molnet.2017.06.019 (2017).
4. Boland, B. B., Rhodes, C. J. & Grimsby, J. S. The dynamic plasticity of insulin production in beta-cells. Mol. Metab. 6, 958–973. https://doi.org/10.1016/j.molnet.2017.04.010 (2017).
5. Pueyo, M. E. et al. Arginine-induced insulin release in glucokinase-deficient subjects. Diabet. Care 17, 1015–1021. https://doi.org/10.2337/diacare.17.9.1015 (1994).
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献