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 predomin antly through effects on preexisting mRNA. However, the mechanisms und erlying the translational control of insulin synthesis are unknown. Th e present study was carried out to determine the effect of glucose on the activity and/or phosphorylation status of eukaryotic initiation an d elongation factors in islets, Glucose was found to increase the acti vity of the guanine nucleotide-exchange factor eIF-2B over a rapid tim e course (within 15 min) and over the same range of glucose concentrat ions as those that stimulate insulin synthesis (3-20 mM). A nonmetabol izable analogue of glucose (mannoheptulose), which does not stimulate insulin synthesis, failed to activate eIF-2B. The best characterized m echanism for modulating eIF-2B activity involves changes in the phosph orylation of the cu-subunit of its substrate eIF-2. However, in islets , no change in eIF-2 alpha phosphorylation was seen under conditions w here eIF-2B activity was increased, implying that glucose regulates eI F-2B via an alternative pathway. Glucose also did not affect the phosp horylation states of three other regulatory translation factors. These are the cap-binding factor eIF-4E, 4E-binding protein-1, and elongati on factor eEF-2, which do not therefore seem likely to be involved in modulating the translation of the preproinsulin mRNA under these condi tions.