GLUCOSE AND GLUCOINCRETIN PEPTIDES SYNERGIZE TO INDUCE C-FOS, C-JUN, JUNB, ZIF-268, AND NUR-77 GENE-EXPRESSION IN PANCREATIC BETA(INS-1) CELLS

To link glucose signaling to its longterm pleiotropic effects in the p ancreatic p-cen, we have investigated whether glucose regulates immedi ate-early response genes (IEGs) coding for transcription factors impli cated in cell proliferation and differentiation. Glucose causes a coor dinated transcriptional activation of the IEGs c-fos, c-jun,JunB, zif- 268, and nur-77 in the pancreatic beta-cell line INS-1. This activatio n is entirely dependent on the presence of the cell-permeant cAMP anal og chlorophenylthio-cAMP, which has only a modest effect by itself. Th e accumulation of c-fos, JunB, and nur-77 mRNA occurs at physiological concentrations of glucose (3 to 11 mM), requires a 1-2 h period, and is mimicked by other nutrient stimuli including mannose, leucine plus glutamine, and pyruvate. Glucose is synergistic with the glucoincretin peptides GLP-1 and PACAP-38, whereas these neurohormonal agents have no effect at low (3 mM) glucose. Mechanistically, the synergy between glucose and the glucoincretins is not based on cAMP alone as glucose d oes not further increase intracellular cAMP in response to GLP-1 and P ACAP-38. A role for Ca2+ signaling is inferred, since the L-type Ca2channel blocker nifedipine markedly reduces the induction of c-fos and nur-77 by glucose and GLP-1. The induction of IEGs by glucose and chl orophenylthioc-cAMP or GLP-1 and the inhibitory effect of nifedipine a re also observed in the beta HC9 cell Line. The results indicate that GLP-1 and PACAP-38 act as competence factors for the action of glucose on c-fos,JunB, and nur-77. It is suggested that the synergistic effec t of glucose and glucoincretins on IEG expression plays an important r ole in the adaptive processes of the beta-cell to hyperglycemia.