Glucose-6-phosphate disposal and regulation of 11β-hydroxysteroid Dehydrogenase type 1: A new link between cellular glucose metabolism and the HPA axis

Adeeba Ahmed; Gareth Lavery; Jeremy Tomlinson; Mark Cooper; Janice Chou; Patrick McKiernan; Elwyn Elias; Elizabeth Walker; Paul Stewart

Microsomal glucose-6-phosphatase (G6Pase) and glucose-6-phosphate transporter (G6PT) are key enzymes in regulation of blood glucose concentration. Deficiency of G6Pase gives rise to glycogen storage disease type Ia (GSDIa) whilst mutations in G6PT cause GSDIb. Both are characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly. G6Pase shares its substrate (G6P) with hexose-6-phosphate-dehydrogenase (H6PDH), an ER enzyme functionally coupled with, and which confers reductase activity upon, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 interconverts hormonally active steroids, cortisol (F) in man and corticosterone (B) in rodents, to inactive cortisone (E) and 11-dehydrocorticosterone (A) respectively. In vivo reductase activity predominates, generating active glucocorticoid. We hypothesized that patients with GSDIa may have enhanced 11β-HSD1 reductase activity because of build up of ER G6P. Conversely, activity should be reduced in GSDIb since G6P will not be available to H6PDH.

Urinary 5αTHF+THF/THE ratio, reflecting global 11β-HSD activity, was significantly elevated in five patients with GSDIa (1.86±0.36(mean±S.E.M.)) compared with 60 normal controls (1.15±0.25; P<0.01). Cortisol generation following 25 mg oral cortisone acetate was also significantly elevated in GSDIa compared to 34 controls (mean AUC (μmol.L.min) 214.9±4.0 vs. 72.5±4.2; P=0.004); in keeping with elevated 11β-HSD1 activity. Urine analysis from patients with GSDIb showed a significant reduction in the 5αTHF+THF/THE ratio indicating reduced 11β-HSD1 reductase activity (mean ratio, 0.28±0.005 vs. 1.15±0.05; P=0.001). 11β-HSD1 reductase activity was also measured in GSDIb KO mice. KO liver microsomes produced 0.95 μmol/B/mg/h (±0.4 S.D.; n=3) whereas WT microsomes produced 4.16 μmolB/mg/h (±1.4 S.D.; n=3). Urine analysis of WT and KO animals (n=3) also showed KO animals excreted 60.2% of A metabolites versus 7.7% in WT mice, indicative of reduced reductase activity.

These data provide proof of concept that G6P concentrations in the ER lumen are crucial in determining the set point of 11β-HSD1 reductase activity. An exciting ER system has been uncovered that links cellular glucose metabolism to function of the HPA axis via H6PDH and 11β-HSD1.

Endocrine Abstracts

P288