Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans.
Over short time periods glucose controls insulin biosynthesis predominantly through effects on preexisting mRNA. However, the mechanisms underlying the translational control of insulin synthesis are unknown. The present study was carried out to determine the effect of glucose on the activity and/or phosphorylation status of eukaryotic initiation and elongation factors in islets. Glucose was found to increase the activity of the guanine nucleotide-exchange factor eIF-2B over a rapid time course (within 15 min) and over the same range of glucose concentrations as those that stimulate insulin synthesis (3-20 mM). A nonmetabolizable analogue of glucose (mannoheptulose), which does not stimulate insulin synthesis, failed to activate eIF-2B. The best characterized mechanism for modulating eIF-2B activity involves changes in the phosphorylation of the alpha-subunit of its substrate eIF-2. However, in islets, no change in eIF-2 alpha phosphorylation was seen under conditions where eIF-2B activity was increased, implying that glucose regulates eIF-2B via an alternative pathway. Glucose also did not affect the phosphorylation states of three other regulatory translation factors. These are the cap-binding factor eIF-4E, 4E-binding protein-1, and elongation factor eEF-2, which do not therefore seem likely to be involved modulating the translation of the preproinsulin mRNA under these conditions.
Gilligan
M
M
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, United Kingdom.
Welsh
G I
GI
Flynn
A
A
Bujalska
I
I
Diggle
T A
TA
Denton
R M
RM
Proud
C G
CG
Docherty
K
K
D000818:Animals; D002352:Carrier Proteins; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E; D005947:Glucose / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism*; D046911:Macromolecular Substances; D010441:Peptide Chain Elongation, Translational; D010448:Peptide Initiation Factors / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011506:Proteins; D005947:Glucose