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J. Biol. Chem., Vol. 277, Issue 32, 28648-28655, August 9, 2002

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Evidence against Glycogen Cycling of Gluconeogenic Substrates in Various Liver Preparations^*

Keld Fosgerau^§, Jens Breinholt^¶, James G. McCormack, and Niels Westergaard^**

From the  Pharmacological Research 2, ^¶ MedChem Research, ^** Hepatic Biochemistry,  Discovery Management, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark

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, µmol/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 (µmol 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.

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