Hypoxia-inducible factors (HIFs) are key mediators of cellular adaptation to hypoxia, but also respond to non-hypoxic stimuli. To clarify involvement in metabolic disturbances, HIFs were characterised in rats subjected to insulin-induced hypoglycaemia or cellular glucoprivation provoked by 2-deoxy-D-glucose (2-DG). Using real-time qPCR, organ-specific expression of HIF-1 alpha, -2 alpha, -3 alpha, -1 beta, and of the target gene GLUT-I was determined. Distribution of HIF-3 alpha proteins was examined by immunohistochemistry. Both, insulin and 2-DG resulted in a widespread increase in HIF-3 alpha mRNA. HIF-2 alpha mRNA increased in lung and heart after 2-DG only, whereas other HIFs remained unaffected. A pronounced increase of protein levels in cerebral cortex was observed for HIF-3 alpha. Functional significance of HIF induction was reflected in enhancement of GLUT-I mRNA. Transcriptional up-regulation of HIF-3 alpha represents a typical response to in vivo hypoglycaemia and glucoprivation. These data suggest an involvement of the HIF system in metabolic derangements as for instance caused by diabetes. (c) 2006 Elsevier Inc. All rights reserved.