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 o n preparations of glycogen phosphorylase (GP) and in C57BL6J (ob/ob) mice b y C-13 NMR in vivo. Independent of the phosphorylation state or the mammali an species or tissue from which GP was derived, DAB inhibited GP with Ki-va lues of approximately 400 nM, The mode of inhibition was uncompetitive or n oncompetitive, with respect to glycogen and Pi, respectively. The effects o f glucose and caffeine on the inhibitory effect of DAB were investigated. T aken together, these data suggest that DAB defines a novel mechanism of act ion. Intraperitoneal treatment with DAB (a total of 105 mg/kg in seven dose s) for 210 min inhibited glucagon-stimulated glycogenolysis in obese and le an mice. Thus, liver glycogen levels were 361 +/- 19 and 228 +/- 19 mu mol glucosyl units/g with DAB plus glucagon in lean and obese mice, respectivel y, compared to 115 +/- 24 and 37 +/- 8 mu mol glucosyl units/g liver with g lucagon only. Moreover, with glucagon only end-point blood glucose levels w ere at 29 +/- 2 and 17.5 +/- 2 mM in obese and lean mice, respectively, com pared 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 mecha nism of action. Further, DAB inhibited the hepatic glycogen breakdown in vi vo 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. (C) 2000 Academic Press.