L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells

Commun Biol. 2020 Sep 8;3(1):497. doi: 10.1038/s42003-020-01226-3.


We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-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 GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Arginine / pharmacology*
  • Cell Line
  • Diabetes Mellitus, Type 2 / pathology
  • Glucokinase / metabolism*
  • Glucose-6-Phosphate / biosynthesis*
  • Glucose-6-Phosphate / metabolism
  • Glutamic Acid / metabolism
  • HEK293 Cells
  • Humans
  • Insulin Secretion / drug effects
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Proteolysis / drug effects
  • Signal Transduction / drug effects
  • Ubiquitin-Protein Ligases
  • Ubiquitination* / drug effects


  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • Glutamic Acid
  • Glucose-6-Phosphate
  • Arginine
  • Ubiquitin-Protein Ligases
  • Glucokinase

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 2