Microsomal glucose-6-phosphatase- (G6Pase-) and glucose-6-phosphate transporter (G6PT) work together to increase blood glucose concentrations by performing the terminal step in both glycogenolysis and gluconeogenesis. Deficiency of the G6PT in liver gives rise to glycogen storage disease type 1b (GSD1b), whilst deficiency of G6Pase- leads to GSD1a. G6Pase- shares its substrate (glucose-6-phosphate; G6P) with hexose-6-phosphate-dehydrogenase (H6PDH), a microsomal enzyme that regenerates NADPH within the endoplasmic reticulum lumen thereby conferring reductase activity upon 11-hydroxysteroid dehydrogenase type 1 (11-HSD1). 11-HSD1 interconverts hormonally active C11-hydroxy steroids (cortisol (F) in man and corticosterone in rodents), to inactive C11-oxo steroids (cortisone (E) and 11-dehydrocorticosterone (11-DHC) respectively). In vivo reductase activity predominates, generating active glucocorticoid. We hypothesized that substrate (G6P) availability to H6PDH in patients with GSD1b and 1a will decrease or increase 11-HSD1 reductase activity, respectively. We investigated 11-HSD1 activity in GSD1b and GSD1a mice and in 2 patients with GSD1b and 5 patients diagnosed with GSD1a. We confirmed our hypothesis by assessing 11-HSD1 in vivo and in vitro, revealing a significant decrease in reductase activity in GSD1b animals and patients, whilst GSD1a patients showed a marked increase in activity. The cellular trafficking of G6P therefore directly regulates 11-HSD1 reductase activity and provides a novel link between glucose metabolism and function of the hypothalamo-pituitary-adrenal axis.