Glucose toxicity is responsible for the development of impaired regulation of endogenous glucose production and hepatic glucokinase in Zucker diabetic fatty rats
Glucose toxicity is responsible for the development of impaired regulation of endogenous glucose production and hepatic glucokinase in Zucker diabetic fatty rats
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DOI：
10.2337/db05-1511
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发表时间：
2006-09-01
期刊：
影响因子：
7.7
通讯作者：
Shiota, Masakazu
中科院分区：
文献类型：
--
作者：
Fujimoto, Yuka;Torres, Tracy P.;Shiota, Masakazu
在14周龄Zucker糖尿病脂肪（ZDF）大鼠中，研究了新型钠依赖性葡萄糖转运蛋白抑制剂（T-1095）恢复正常血糖对受损肝脏葡萄糖摄取的影响。未治疗组表现出持续的内源性葡萄糖产生（EGP），尽管显着的高血糖症。葡萄糖异生和葡萄糖循环（GC）分别占葡萄糖-6-磷酸酶（G6 β）通量的46%和51%。血浆葡萄糖向肝糖原的净掺入可忽略不计。葡萄糖激酶（GK）及其抑制蛋白GK调节蛋白（GKRP）共定位于肝细胞胞浆。给药第7天，EGP略有降低，但G6 β通量和GC明显低于未治疗组。在这种情况下，GK和GKRP共定位于肝细胞核中。当血浆葡萄糖和胰岛素水平升高时，EGP被完全抑制，GC，从血浆葡萄糖的糖原合成，以及血浆葡萄糖对尿苷二磷酸葡萄糖通量的贡献率显着增加。GK从细胞核转位到细胞质，而GKRP则没有。在ZDF大鼠中，葡萄糖毒性可能导致肝脏葡萄糖通量对升高的血糖和/或胰岛素的迟钝反应，与GKRP对GK的调节受损相关。
The effect of restoration of normoglycemia by a novel sodium-dependent glucose transporter inhibitor (T-1095) on impaired hepatic glucose uptake was examined in 14-week-old Zucker diabetic fatty (ZDF) rats. The nontreated group exhibited persistent endogenous glucose production (EGP) despite marked hyperglycemia. Gluconeogenesis and glucose cycling (GC were responsible for 46 and 51% of glucose-6-phosphatase (G6Pase) flux, respectively. Net incorporation of plasma glucose into hepatic glycogen was negligible. Glucokinase (GK) and its inhibitory protein, GK regulatory protein (GKRP), were colocalized in the cytoplasm of hepatocytes. At day 7 of drug administration, EGP was slightly reduced, but G6Pase flux and GC were markedly lower compared with the nontreated group. In this case, GK and GKRP were colocalized in the nuclei of hepatocytes. When plasma glucose and insulin levels were raised during a clamp, EGP was completely suppressed and GC, glycogen synthesis from plasma glucose, and the fractional contribution of plasma glucose to uridine diphosphoglucose flux were markedly increased. GK, but not GKRP, was translocated from the nucleus to the cytoplasm. Glucotoxicity may result in the blunted response of hepatic glucose flux to elevated plasma glucose and/or insulin associated with impaired regulation of GK by GKRP in ZDF rats.