Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 380, Issue 2, Pages 274-284Publisher
ELSEVIER SCIENCE INC
DOI: 10.1006/abbi.2000.1930
Keywords
glycogen phosphorylase; anti-hyperglycaemic; C57BL/6J (ob/ob); glucagon; Type 2 diabetes
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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 C-13 NMR in vivo. Independent of the phosphorylation state or the mammalian species or tissue from which GP was derived, DAB inhibited GP with Ki-values of approximately 400 nM, The mode of inhibition was uncompetitive or noncompetitive, with respect to glycogen and Pi, 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 mu mol glucosyl units/g with DAB plus glucagon in lean and obese mice, respectively, compared to 115 +/- 24 and 37 +/- 8 mu mol 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. (C) 2000 Academic Press.
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