Farese R V, Standaert M L, Yamada K, Huang L C, Zhang C, Cooper D R, Wang Z, Yang Y, Suzuki S, Toyota T
J. A. Haley Veterans' Hospital, Tampa, FL 33612.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11040-4. doi: 10.1073/pnas.91.23.11040.
Type II diabetic Goto-Kakizaki (GK) rats were insulin-resistant in euglycemic-hyperinsulinemic clamp studies. We therefore examined insulin signaling systems in control Wistar and diabetic GK rats. Glycerol-3-phosphate acyltransferase (G3PAT), which is activated by headgroup mediators released from glycosyl-phosphatidylinositol (GPI), was activated by insulin in intact and cell-free adipocyte preparations of control, but not diabetic, rats. A specific chiro-inositol-containing inositol phosphoglycan (IPG) mediator, prepared from beef liver, bypassed this defect and comparably activated G3PAT in cell-free adipocyte preparations of both diabetic GK and control rats. A myo-inositol-containing IPG mediator did not activate G3PAT. Relative to control adipocytes, labeling of GPI by [3H]glucosamine was diminished by 50% and insulin failed to stimulate GPI hydrolysis in GK adipocytes. In contrast to GPI-dependent G3PAT activation, insulin-stimulated hexose transport was intact in adipocytes and soleus and gastrocnemius muscles of the GK rat, as was insulin-induced activation of mitogen-activated protein kinase and protein kinase C. We conclude that (i) chiro-inositol-containing IPG mediator activates G3PAT during insulin action, (ii) diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing IPG, and (iii) defective IPG-regulated intracellular glucose metabolism contributes importantly to insulin resistance in diabetic GK rats.
在正常血糖 - 高胰岛素钳夹实验中，II型糖尿病Goto - Kakizaki（GK）大鼠存在胰岛素抵抗。因此，我们研究了对照Wistar大鼠和糖尿病GK大鼠的胰岛素信号系统。甘油 - 3 - 磷酸酰基转移酶（G3PAT）可被糖基磷脂酰肌醇（GPI）释放的头部基团介质激活，在对照大鼠（而非糖尿病大鼠）完整的和无细胞脂肪细胞制剂中，G3PAT可被胰岛素激活。一种从牛肝制备的含手性肌醇的肌醇磷酸聚糖（IPG）介质可绕过这一缺陷，并在糖尿病GK大鼠和对照大鼠的无细胞脂肪细胞制剂中同等程度地激活G3PAT。含肌醇的IPG介质不能激活G3PAT。相对于对照脂肪细胞，GK脂肪细胞中[3H]葡糖胺对GPI的标记减少了50%，并且胰岛素不能刺激GK脂肪细胞中的GPI水解。与GPI依赖性G3PAT激活不同，胰岛素刺激的己糖转运在GK大鼠的脂肪细胞、比目鱼肌和腓肠肌中是完整的，胰岛素诱导的丝裂原活化蛋白激酶和蛋白激酶C的激活也是如此。我们得出结论：（i）含手性肌醇的IPG介质在胰岛素作用过程中激活G3PAT；（ii）糖尿病GK大鼠在合成或释放功能性含手性肌醇的IPG方面存在缺陷；（iii）IPG调节的细胞内葡萄糖代谢缺陷对糖尿病GK大鼠的胰岛素抵抗有重要影响。
