New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system

Gérald Van De Werve, Alex Lange, Christopher Newgard, Marie Claire Méchin, Yazhou Li, Alfred Berteloot

Research output: Contribution to journalReview articlepeer-review

110 Scopus citations


The operation of glucose 6-phosphatase (EC (Glc6Pase) stems from the interaction of at least two highly hydrophobic proteins embedded in the ER membrane, a heavily glycosylated catalytic subunit of m 36 kDa (P36) and a 46-kDa putative glucose 6-phosphate (Glc6P) translocase (P46). Topology studies of P36 and P46 predict, respectively, nine and ten transmembrane domains with the N-terminal end of P36 oriented towards the lumen of the ER and both termini of P46 oriented towards the cytoplasm. P36 gene expression is increased by glucose, fructose 2,6-bisphosphate (Fru-2,6-P2) and free fatty acids, as well as by glucocorticoids and cyclic AMP; the latter are counteracted by insulin. P46 gene expression is affected by glucose, insulin and cyclic AMP in a manner similar to P36. Accordingly, several response elements for glucocorticoids, cyclic AMP and insulin regulated by hepatocyte nuclear factors were found in the Glc6Pase promoter. Mutations in P36 and P46 lead to glycogen storage disease (GSD) type-1a and type-1 non a (formerly 1b and 1c), respectively. Adenovirusmediated overexpression of P36 in hepatocytes and in vivo impairs glycogen metabolism and glycolysis and increases glucose production; P36 overexpression in INS-1 cells results in decreased glycolysis and glucoseinduced insulin secretion. The nature of the interaction between P36 and P46 in controling Glc6Pase activity remains to be defined. The latter might also have functions other than Glc6P transport that are related to Glc6P metabolism.

Original languageEnglish (US)
Pages (from-to)1533-1549
Number of pages17
JournalEuropean Journal of Biochemistry
Issue number6
StatePublished - 2000


  • Glucose 6-phosphatase
  • Glycogen storage disease type 1
  • Microsomes
  • Putative glucose 6-phosphate translocase
  • Recombinant adenovirus


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