Evidence against glycogen cycling of gluconeogenic substrates in various liver preparations.
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.
Fosgerau
Keld
K
Pharmacological Research 2, MedChem Research, Hepatic Biochemistry, Discovery Management, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark. kf@novonordisk.com
Breinholt
Jens
J
McCormack
James G
JG
Westergaard
Niels
N
D000818:Animals; D001089:Arabinose; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006003:Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000378:metabolism; D050113:Imino Furanoses; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013402:Sugar Alcohols / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D019344:Lactic Acid; D006003:Glycogen; D001089:Arabinose; D024981:Glycogen Phosphorylase