The effect of inhibition of
glycogen phosphorylase by
1,4-dideoxy-1,4-imino-d-arabinitol on rates of gluconeogenesis, gluconeogenic deposition into
glycogen, and
glycogen recycling was investigated in primary cultured hepatocytes, in perfused rat liver, and in fed or fasted rats in vivo clamped at high physiological levels of plasma
lactate.
1,4-Dideoxy-1,4-imino-d-arabinitol did not alter the synthesis of
glycerol-derived
glucose in hepatocytes or
lactate-derived
glucose in perfused liver or fed or fasted rats in vivo. Thus,
1,4-dideoxy-1,4-imino-d-arabinitol inhibited hepatic
glucose output in the perfused rat liver (0.77 +/- 0.19 versus 0.33 +/- 0.09, p < 0.05), whereas the rate of
lactate-derived gluconeogenesis was unaltered (0.22 +/- 0.09 versus 0.18 +/- 0.08, p = not significant) (1,4-dideoxy-1,4-imino-
d-arabinitol versus vehicle, micromol/min * g). Overall, the data suggest that
1,4-dideoxy-1,4-imino-d-arabinitol inhibited
glycogen breakdown with no direct or indirect effects on the rates of gluconeogenesis. Total end point
glycogen content (micromol of glycosyl units/g of wet liver) were similar in fed (235 +/- 19 versus 217 +/- 22, p = not significant) or fasted rats (10 +/- 2 versus 7 +/- 2, p = not significant) with or without
1,4-dideoxy-1,4-imino-d-arabinitol, respectively. The data demonstrate no
glycogen cycling under the investigated conditions and no effect of
1,4-dideoxy-1,4-imino-d-arabinitol on gluconeogenic deposition into
glycogen. Taken together, these data also suggest that inhibition of
glycogen phosphorylase may prove beneficial in the treatment of
type 2 diabetes.