Glycogen phosphorylase inhibitor N-(3,5-dimethyl-Benzoyl)-N'-(β-D-glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism.
Glycogen phosphorylase inhibitor N-(3,5-dimethyl-Benzoyl)-N'-(β-D-glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism.
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DOI：
10.1371/journal.pone.0069420
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bai P
中科院分区：
文献类型：
--
作者：
Nagy L;Docsa T;Szántó M;Brunyánszki A;Hegedűs C;Márton J;Kónya B;Virág L;Somsák L;Gergely P;Bai P
糖原磷酸化酶（GP）催化糖原的分解，并在很大程度上有助于肝脏葡萄糖的产生，使GP抑制成为一个有吸引力的目标，以调节糖尿病的葡萄糖水平。因此，我们提出了一种新的，有效的，基于葡萄糖的GP抑制剂（KB 228）在体外和体内血糖正常和糖尿病条件下测试的代谢作用。KB 228给药增强了普通饲料喂养和肥胖糖尿病小鼠的葡萄糖敏感性，这是由于肝脏葡萄糖摄取较高。除了改善葡萄糖敏感性外，我们还观察到了进一步的意想不到的代谢重排。KB 228给药增加了耗氧量，这可能是由于在动物和细胞模型中观察到的解偶联蛋白-2（UCP 2）过表达所致。此外，KB 228处理诱导小鼠中雷帕霉素复合物2的哺乳动物靶标（mTORC 2）。我们的数据表明，基于葡萄糖的GP抑制剂能够在正常和高血糖条件下降低小鼠的葡萄糖水平。此外，这些GP抑制剂除了GP抑制之外还诱导调节-例如增强的线粒体氧化和mTORC 2信号传导-以科普细胞中葡萄糖内流和增加的糖原沉积，然而调节的分子机制尚未探索。
Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition - such as enhanced mitochondrial oxidation and mTORC2 signaling – to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored.
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影响因子：
29
作者：
Bai P;Canto C;Brunyánszki A;Huber A;Szántó M;Cen Y;Yamamoto H;Houten SM;Kiss B;Oudart H;Gergely P;Menissier-de Murcia J;Schreiber V;Sauve AA;Auwerx J
通讯作者：
Auwerx J
影响因子：
3.4
作者：
Docsa, Tibor;Czifrak, Katalin;Gergely, Pal
通讯作者：
Gergely, Pal
影响因子：
4.1
作者：
Aiston, S;Green, A;Agius, L
通讯作者：
Agius, L
影响因子：
29
作者：
Hagiwara, Asami;Cornu, Marion;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
8
作者：
Chrysina, ED;Kosmopoulou, MN;Oikonomakos, NG
通讯作者：
Oikonomakos, NG