Recent reports point out the importance of the complex GK-GKRP in controlling
glucose and
lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the
enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GK(A456V), described in a patient with
persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo. GK(A456V) was overexpressed in the liver of
streptozotocin diabetic mice. Metabolite profiling in serum and
liver extracts, together with changes in key components of
glucose and
lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation. GK(A456V) overexpression markedly reduced
blood glucose in the absence of
dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in
glucose utilization did not correlate with increased
glycogen nor
lactate levels in the liver. PEPCK
mRNA was not affected, whereas the
mRNA for the catalytic subunit of
glucose-6-phosphatase was upregulated ~4 folds in the liver of GK(A456V)-treated animals, suggesting that
glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes
therapy.