Kinetic and functional characterization of 1,4-dideoxy-1, 4-imino-d-arabinitol: a potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice.
The effects of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) were investigated on preparations of glycogen phosphorylase (GP) and in C57BL6J (ob/ob) mice by (13)C NMR in vivo. Independent of the phosphorylation state or the mammalian species or tissue from which GP was derived, DAB inhibited GP with K(i)-values of approximately 400 nM. The mode of inhibition was uncompetitive or noncompetitive, with respect to glycogen and P(i), respectively. The effects of glucose and caffeine on the inhibitory effect of DAB were investigated. Taken together, these data suggest that DAB defines a novel mechanism of action. Intraperitoneal treatment with DAB (a total of 105 mg/kg in seven doses) for 210 min inhibited glucagon-stimulated glycogenolysis in obese and lean mice. Thus, liver glycogen levels were 361 +/- 19 and 228 +/- 19 micromol glucosyl units/g with DAB plus glucagon in lean and obese mice, respectively, compared to 115 +/- 24 and 37 +/- 8 micromol glucosyl units/g liver with glucagon only. Moreover, with glucagon only end-point blood glucose levels were at 29 +/- 2 and 17.5 +/- 2 mM in obese and lean mice, respectively, compared to 17.5 +/- 1 and 12 +/- 1 mM with glucagon plus DAB. In conclusion, DAB is a novel and potent inhibitor of GP with an apparently distinct mechanism of action. Further, DAB inhibited the hepatic glycogen breakdown in vivo and displayed an accompanying anti-hyperglycemic effect, which was most pronounced in obese mice. The data suggest that inhibition of GP may offer a therapeutic principle in Type 2 diabetes.
Diabetes Biochemistry and Metabolism, Medicinal Chemistry Research, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, DK-2760, Denmark.
K
K
Fosgerau
N
N
Westergaard
B
B
Quistorff
N
N
Grunnet
M
M
Kristiansen
K
K
Lundgren
D000818:Animals; D001089:Arabinose; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050113:Imino Furanoses; D066298:In Vitro Techniques; D007700:Kinetics; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009132:Muscles / Q000201:enzymology; D006005:Phosphorylases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D013402:Sugar Alcohols / Q000494:pharmacology*; D013552:Swine
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D019344:Lactic Acid; D006003:Glycogen; D005934:Glucagon; D001089:Arabinose; D006005:Phosphorylases