It is a long-standing enigma how
glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous
glucose production despite the loss of
glucose-6-phosphatase activity. Insight into the source of residual endogenous
glucose production is of clinical importance given the risk of
sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous
glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc-/- mice) and performed real-time analysis of hepatic
glucose fluxes and
glycogen metabolism in L-G6pc-/- mice using state-of-the-art stable
isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing
glucose. In vivo analysis of hepatic
glucose metabolism revealed that the hepatic
glucokinase flux was decreased by 95% in L-G6pc-/- mice. It also showed increased
glycogen phosphorylase flux in L-G6pc-/- mice, which is coupled to the release of free
glucose through
glycogen debranching. Although the ex vivo activities of debranching
enzyme and lysosomal
acid maltase, two major hepatic α-
glucosidases, were unaltered in L-G6pc-/- mice, pharmacological inhibition of α-
glucosidase activity almost completely abolished residual
glucose production by G6pc-deficient hepatocytes.
CONCLUSION: Our data indicate that hepatocytes contribute to residual
glucose production in GSD Ia. We show that α-
glucosidase activity, i.e.
glycogen debranching and/or lysosomal
glycogen breakdown, contributes to residual
glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free
glucose synthesized by G6pc-deficient hepatocytes, allowing the release of
glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual
glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).