Journal article
L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic beta-cells
Communications biology, Vol.3(1), pp.497-497
09/08/2020
DOI: 10.1038/s42003-020-01226-3
PMCID: PMC7479149
PMID: 32901087
Abstract
We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in beta -cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCK(E442*) demonstrated lower C-peptide-to-glucose ratio after arginine administration. In beta -cell line, GCK(E442*) reduced L-arginine-induced insulin secretion compared with GCK(WT). In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation. Using arginine-immobilized magnetic nanobeads, Cho et al. show that glucokinase, the key regulator of glucose-stimulated insulin secretion, binds L-arginine, which protects glucokinase from ubiquitination-mediated degradation while inducing insulin secretion. This study provides mechanistic insights into how L-arginine increases insulin production.
Details
- Title: Subtitle
- L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic beta-cells
- Creators
- Jaeyong Cho - National Center for Geriatrics and GerontologyYukio Horikawa - Gifu UniversityMayumi Enya - Gifu UniversityJun Takeda - Gifu UniversityYoichi Imai - Tokyo University of ScienceYumi Imai - University of IowaHiroshi Handa - Tokyo Medical UniversityTakeshi Imai - National Center for Geriatrics and Gerontology
- Resource Type
- Journal article
- Publication Details
- Communications biology, Vol.3(1), pp.497-497
- DOI
- 10.1038/s42003-020-01226-3
- PMID
- 32901087
- PMCID
- PMC7479149
- NLM abbreviation
- Commun Biol
- ISSN
- 2399-3642
- eISSN
- 2399-3642
- Publisher
- Springer Nature
- Number of pages
- 8
- Grant note
- MEXT 18659493 / Ministry of Education, Culture, Sports, Science and Technology; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) 28-25; 19-27 / NCGG S1411011 / MEXT; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) R01-DK090490 / National Institutes of Health, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1-17-IBS-132 / American Diabetes Association A-STEP-AS2312036G / Japan Science and Technology Agency; Japan Science & Technology Agency (JST)
- Language
- English
- Date published
- 09/08/2020
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984360160002771
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