Treatment of segments of ileum from 8-week streptozotocin-induced diabetic rats with phorbol 12,13-dibutyrate (PDBu) in vitro resulted in restoration of the diabetes-induced changes in the expression of enteric VIP- and galanin-like immunoreactive nerve fibers. The increase in fluorescence intensity and density of VIP- and galanin-like immunoreactivity observed in 8-week streptozotocin-treated rats was reduced to a near normal level after 40 min incubation of diabetic tissues in Krebs solution containing PDBu (100 nM). The tissue content of VIP was also affected (control = 2.1 +/- 0.31 pmol/cm; diabetic = 4.6 +/- 0.48 pmol/cm; diabetic + PDBu = 2.9 +/- 0.9 pmol/cm) after incubation with PDBu. The significance of these findings in relation to the possible role of protein kinase C in the regulation of expression and/or storage of these enteric neuropeptides in normal and diabetic states is discussed.