Role of the glucosamine pathway in fat-induced insulin resistance
Role of the glucosamine pathway in fat-induced insulin resistance
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DOI：
10.1172/jci119390
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发表时间：
1997-05-01
影响因子：
15.9
通讯作者：
Rossetti, L
中科院分区：
文献类型：
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作者：
Hawkins, M;Barzilai, N;Rossetti, L
为了研究氨基己糖生物合成途径是否可能在脂肪诱导的胰岛素抵抗中发挥作用，我们在7小时血糖正常-高胰岛素血症（类似于500 μ U/ml）钳夹研究中监测了FFA可用性长期升高对骨骼肌UDP-N-乙酰氨基己糖水平和外周葡萄糖处置的影响。当胰岛素诱导的血浆FFA水平降低时，通过在15只清醒大鼠中输注脂肪乳剂（至类似于0.3 mM），（血浆FFA类似于1.4 mM），葡萄糖摄取（5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg/min; P < 0.01）和糖原合成（P < 0.01）显著减少。在脂质输注期间，肌肉UDP-N-乙酰葡糖胺（UDP-GlcNAc）增加两倍（3 h时为53.4+/-1.1 nmol/g，7 h时为55.5+/-1.1 nmol/g，0 h时为20.4+/-1.7 nmol/g，而葡萄糖-6-磷酸（Glc-6-P）水平在3 h时升高（475+/-49 nmol/g），并在7 h时降低（133+/-7vs337 +/-28nmol/g，0小时，P < 0.01）。为了辨别骨骼肌UDP-GlcNAc浓度的这种增加是否可以解释胰岛素抵抗的发展，我们使用三种替代的实验方法产生了肌肉UDP-GlcNAc的类似增加。在长时间高血糖（18 mM，n = 10）或葡萄糖胺（3 μ mol/kg/min; n = 10）或尿苷（30 μ mol/kg/min; n = 4）的可用性增加后进行正常血糖钳夹。这些条件都导致骨骼肌UDP-GlcNAc非常相似的增加，因此，脂肪诱导的胰岛素抵抗与以下有关：（a）骨骼肌Glc-6-P水平降低，表明葡萄糖转运/磷酸化缺陷;（B）在胰岛素抗性发生之前，己糖胺生物合成途径的终产物的显著积累。最重要的是，相同程度的胰岛素抵抗可以在FFA可用性增加的情况下通过骨骼肌UDP-N-乙酰己糖胺的类似增加来再现。总之，我们的研究结果支持这一假设，即增加FFA的可用性诱导骨骼肌胰岛素抵抗，增加流量的果糖-6-磷酸到氨基己糖途径。
To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N-acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemic-hyperinsulinemic (similar to 500 mu U/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to similar to 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA similar to 1.4 mM), glucose uptake (5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg per min; P < 0.01) and glycogen synthesis (P < 0.01) were markedly decreased. During lipid infusion, muscle UDP-N-acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4+/-1.1 at 3 h and to 55.5+/-1.1 nmol/gram at 7 h vs 20.4+/-1.7 at 0 h, P < 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475+/-49 nmol/gram) and decreased at 7 h (133+/-7 vs 337+/-28 nmol/gram at 0 h, P < 0.01).To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n = 10), or increased availability of either glucosamine (3 mu mol/kg per min; n = 10) or uridine (30 mu mol/kg per min; n = 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to similar to 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis.Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N-acetyl-hexosamines. In conclusion, our results support the hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway.