ELEVATED GLUCOSE-CONCENTRATIONS INHIBIT DNA-SYNTHESIS AND EXPRESSION OF C-MYC IN CULTURED-HEPATOCYTES

Glucose depressed DNA synthesis in rat hepatocytes in primary culture. As compared to controls cultured with 5.6 mM glucose, maximal (greate r than or equal to 75%) inhibition was obtained at 20-30 mM, and half- maximal effect at 10-15 mM. Comparison of D- and L-glucose showed that the effect was specific for the D-form. Maximal inhibition required t he presence of glucose during the first 24 hours of culture. The expre ssion of the c-myc gene was reduced when the hepatocytes were cultured in the presence of elevated glucose. The responses to epidermal growt h factor, insulin and vasopressin, in terms of percentual stimulation of DNA synthesis, were qualitatively similar at 5.6 and 16.8 mM glucos e, while glucagon stimulated more strongly when the glucose concentrat ion was increased; glucagon at concentrations greater than or equal to 1 nM reversed the inhibition by glucose. 8-Br-cAMP mimicked the effec t of glucagon. These results suggest that an increase in the level of glucose depresses hepatocyte DNA synthesis, The effect is assosiated w ith lowered expression of the c-myc gene and is counteracted by cAMP. (C) 1994 Academic Press, Inc.