The substrates oxygen and glucose are important for the appropriate regulation of metabolism, angiogenesis, tumorigenesis and embryonic development. The knowledge about an interaction between these two signals is limited. We demonstrated that the regulation of glucagon receptor, insulin receptor and L-type pyruvate kinase (L-PK) gene expression in liver is dependent upon a cross-talk between oxygen and glucose. We then demonstrated for the L-PK gene that this cross talk appeared to be mediated via an interference between hypoxia inducible factor-1 (HIF-1)and the glucose-responsive transcription factors at the glucose responsive element (GlcPKRE). The glucose response element also functioned as a weak hypoxia response element and, vice versa, a hypoxia responsive element was fuctioning as a glucose response element. Thus, our findings implicate that the cross-talk between oxygen and glucose might have a fundamental role in the regulation of several physiological and pathophysiological processes. Therfore, our aim is to identify the signalling pathways and molecular switches which are involved in these processes.

Fig. 3 Model of the competition between HIF-1 and the glucose responsive transcription factors at the glucose responsive element of the L-PK gene. High glucose at arterial pO2 induces binding of the glucose-sensitive transcription factors to the GlcPKRE and thus mediates the glucose-dependent activation of L-PK gene expression. In the presence of high glucose under venous pO2 it is likely that a HIF-1a containing complex could replace an USF or ChREBP protein complex.