To link glucose signaling to its long‐term pleiotropic effects in the pancreatic β‐cell, we have investigated whether glucose regulates immediate‐early response genes (IEGs) coding for transcription factors implicated in cell proliferation and differentiation. Glucose causes a coordinated transcriptional activation of the IEGs c‐fos, c‐jun, JunB, zif‐268, and nur‐77 in the pancreatic β‐cell line INS‐1. This activation is entirely dependent on the presence of the cell‐permeant cAMP analog chlorophenylthio‐cAMP, which has only a modest effect by itself. The 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 does not further increase intracellular cAMP in response to GLP‐1 and PACAP‐38. A role for Ca²⁺ signaling is inferred, since the L‐type Ca²⁺ channel blocker nifedipine markedly reduces the induction of c‐fos and nur‐77 by glucose and GLP‐1. The induction of IEGs by glucose and chlorophenylthio‐cAMP or GLP‐1 and the inhibitory effect of nifedipine are also observed in the βHC9 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 effect of glucose and glucoincretins on IEG expression plays an important role in the adaptive processes of the β‐cell to hyperglycemia.—Susini, S., Roche, E., Prentki, M., Schlegel, W. Glucose and glucoincretin peptides synergize to induce c‐fos, c‐jun, junB, zif‐268, and nur‐77 gene expression in pancreatic β(INS‐1) cells. FASEB J. 12, 1173–1182 (1998)