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
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
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DOI：
10.1006/abbi.2000.1930
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发表时间：
2000-08-15
影响因子：
3.9
通讯作者：
Lundgren, K
中科院分区：
文献类型：
--
作者：
Fosgerau, K;Westergaard, N;Lundgren, K
本文用~（13）C NMR研究了1，4-二脱氧-1，4-亚氨基-D-阿拉伯糖醇（DAB）对糖原磷酸化酶（GP）的影响。独立的磷酸化状态或哺乳动物物种或组织从GP的衍生，DAB抑制GP与Ki值约400 nM，抑制模式是非竞争性或非竞争性，相对于糖原和Pi，分别。研究了葡萄糖和咖啡因对DAB抑制作用的影响。总之，这些数据表明DAB定义了一种新的作用机制。DAB（共105 mg/kg，分7次给药）腹腔内给药210 min可抑制肥胖和瘦小鼠胰高血糖素刺激的糖原分解。因此，在瘦小鼠和肥胖小鼠中，DAB加胰高血糖素的肝糖原水平分别为361 +/- 19和228 +/- 19 μ mol葡萄糖基单位/g，而仅胰高血糖素的肝糖原水平为115 +/- 24和37 +/- 8 μ mol葡萄糖基单位/g。此外，仅使用胰高血糖素时，肥胖小鼠和瘦小鼠的终点血糖水平分别为29 +/- 2和17.5 +/- 2 mM，而胰高血糖素加DAB时为17.5 +/- 1和12 +/- 1 mM。总之，DAB是一种新型且有效的GP抑制剂，具有明显不同的作用机制。此外，DAB在体内抑制肝糖原分解，并显示出伴随的抗高血糖作用，这在肥胖小鼠中最为明显。这些数据表明，抑制GP可能提供2型糖尿病的治疗原则。(C)北京大学出版社.
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.