Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters - Transcription factor FKHR binds the insulin response sequence

Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6- Pase) in both type 1 and type 2 diabetes may contribute to the characterist ic increased rate of hepatic glucose production, we have investigated wheth er the insulin response unit (IRU) identified in the mouse G-6-Pase promote r is conserved in the human promoter. A series of human G-6-Pase-chloramphe nicol acetyltransferase (CAT) fusion genes was transiently transfected into human HepG2 hepatoma cells, and the effect of insulin on basal CAT express ion was analyzed. The results suggest that the IRU identified in the mouse promoter is conserved in the human promoter, but that an upstream multimeri zed insulin response sequence (IRS) motif that is only found in the human p romoter appears to be functionally inactive. The G-6-Pase IRU comprises two distinct promoter regions, designated A and B, Region B contains an TRS, w hereas region A acts as an accessory element to enhance the effect of insul in, mediated through region B, on basal G-6-Pase gene transcription. We hav e previously shown that the accessory factor binding region A is hepatocyte nuclear factor-1, and we show here that the forkhead protein FKHR is a can didate for the insulin-responsive transcription factor binding region B.