Zierath J R, Houseknecht K L, Gnudi L, Kahn B B
Department of Medicine at Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts, USA.
Diabetes. 1997 Feb;46(2):215-23. doi: 10.2337/diab.46.2.215.
Glucose transport in skeletal muscle can be mediated by two separate pathways, one stimulated by insulin and the other by muscle contraction. High-fat feeding impairs glucose transport in muscle, but the mechanism remains unclear. FVB mice (3 weeks old) were fed a high-fat diet (55% fat, 24% carbohydrate, 21% protein) or standard chow for 3-4 weeks or 8 weeks. Insulin-stimulated glucose transport, assessed with either 2-deoxyglucose or 3-O-methylglucose was decreased 35-45% (P < 0.001) in isolated soleus muscle, regardless of diet duration. Similarly, glucose transport stimulated by okadaic acid, a serine/threonine phosphatase inhibitor, was also 45% lower with high-fat feeding, but the glucose transport response to hypoxia or N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (which are stimulators of the "contraction pathway") was intact. Hexokinase I, II, and total activity were normal in soleus muscle from high-fat-fed mice. GLUT4 expression in soleus muscle from the high-fat-fed mice was also normal, but the insulin-stimulated cell surface recruitment of GLUT4 assessed by exofacial photolabeling with [3H]-ATB bis-mannose was reduced by 50% (P < 0.001). Insulin-receptor substrate 1 (IRS-1) associated phosphatidylinositol (PI) 3-kinase activity stimulated by insulin was also reduced by 36% (P < 0.001), and expression of p85 and p110b subunits of PI 3-kinase was normal. In conclusion, high-fat feeding selectively impairs insulin-stimulated, but not contraction-pathway-mediated, glucose transport by reducing GLUT4 translocation to the plasma membrane. This appears to result from an acquired defect in insulin activation of PI 3-kinase. Since effects of okadaic acid on glucose transport are independent of PI 3-kinase, a second signaling defect may also be induced.
骨骼肌中的葡萄糖转运可由两条独立的途径介导，一条由胰岛素刺激，另一条由肌肉收缩刺激。高脂喂养会损害肌肉中的葡萄糖转运，但其机制尚不清楚。将3周龄的FVB小鼠喂以高脂饮食（55%脂肪、24%碳水化合物、21%蛋白质）或标准饲料3至4周或8周。无论饮食持续时间如何，用2-脱氧葡萄糖或3-O-甲基葡萄糖评估的胰岛素刺激的葡萄糖转运在分离的比目鱼肌中降低了35 - 45%（P < 0.001）。同样，丝氨酸/苏氨酸磷酸酶抑制剂冈田酸刺激的葡萄糖转运在高脂喂养时也降低了45%，但对缺氧或N-(6-氨基己基)-5-氯-1-萘磺酰胺（W-7）（“收缩途径”的刺激剂）的葡萄糖转运反应是完整的。高脂喂养小鼠的比目鱼肌中己糖激酶I、II和总活性正常。高脂喂养小鼠的比目鱼肌中GLUT4表达也正常，但通过用[3H]-ATB双甘露糖进行外表面光标记评估的胰岛素刺激的GLUT4细胞表面募集减少了50%（P < 0.001）。胰岛素刺激的胰岛素受体底物1（IRS-1）相关的磷脂酰肌醇（PI）3-激酶活性也降低了36%（P < 0.001），PI 3-激酶的p85和p110b亚基的表达正常。总之，高脂喂养通过减少GLUT4向质膜的转位选择性地损害胰岛素刺激的而非收缩途径介导的葡萄糖转运。这似乎是由PI 3-激酶的胰岛素激活中获得性缺陷导致的。由于冈田酸对葡萄糖转运的作用独立于PI 3-激酶，可能还诱导了第二种信号缺陷。
