HYPOGLYCEMIC EFFECT OF AICARIBOSIDE IN MICE

We have previously demonstrated that in isolated hepatocytes from fast ed rats, AICAriboside (5-amino 4-imidazolecarboxamide riboside), after its conversion into AICAribotide (AICAR or ZMP), exerts a dose-depend ent inhibition on fructose-1,6-bisphosphatase and hence on gluconeogen esis. To assess the effect of AICAriboside in vivo, we measured plasma glucose and liver metabolites after intraperitoneal administration of AICAriboside in mice, In fasted animals, in which gluconeogenesis is activated, AICAriboside (250 mg/kg body weight) induced a 50 % decreas e of plasma glucose within 15 min, which lasted about 3 h. In fed mice , glucose decreased by 8 % at 30 min, and normalized at 1 h, Under bot h conditions, ZMP accumulated to approximately 2 mu mol/g of liver at 1 h. It decreased progressively thereafter, although much more slowly in the fasted state. Inhibition of fructose-1,6-bisphosphatase was evi denced by time-wise linear accumulations of fructose-1,6-bisphosphate, from 0.006 to 3.9 mu mol/g of liver at 3 h in fasted mice, and from 0 .010 to 0.114 mu mol/g of liver at 1 h in fed animals. AICAriboside di d not significantly influence plasma insulin or glucose utilization by muscle. We conclude that in vivo as in isolated hepatocytes, AICAribo side, owing to its conversion into ZMP inhibits fructose-1,6-bisphosph atase and consequently gluconeogenesis.