Laybutt D R, Schmitz-Peiffer C, Saha A K, Ruderman N B, Biden T J, Kraegen E W
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Am J Physiol. 1999 Dec;277(6):E1070-6. doi: 10.1152/ajpendo.1999.277.6.E1070.
Chronic glucose infusion results in hyperinsulinemia and causes lipid accumulation and insulin resistance in rat muscle. To examine possible mechanisms for the insulin resistance, alterations in malonyl-CoA and long-chain acyl-CoA (LCA-CoA) concentration and the distribution of protein kinase C (PKC) isozymes, putative links between muscle lipids and insulin resistance, were determined. Cannulated rats were infused with glucose (40 mg. kg(-1). min(-1)) for 1 or 4 days. This increased red quadriceps muscle LCA-CoA content (sum of 6 species) by 1.3-fold at 1 day and 1.4-fold at 4 days vs. saline-infused controls (both P < 0.001 vs. control). The concentration of malonyl-CoA was also increased (1.7-fold at 1 day, P < 0.01, and 2.2-fold at 4 days, P < 0.001 vs. control), suggesting an even greater increase in cytosolic LCA-CoA. The ratio of membrane to cytosolic PKC-epsilon was increased twofold in the red gastrocnemius after both 1 and 4 days, suggesting chronic activation. No changes were observed for PKC-alpha, -delta, and -theta. We conclude that LCA-CoAs accumulate in muscle during chronic glucose infusion, consistent with a malonyl-CoA-induced inhibition of fatty acid oxidation (reverse glucose-fatty acid cycle). Accumulation of LCA-CoAs could play a role in the generation of muscle insulin resistance by glucose oversupply, either directly or via chronic activation of PKC-epsilon.
长期输注葡萄糖会导致大鼠肌肉出现高胰岛素血症，并引起脂质蓄积和胰岛素抵抗。为了探究胰岛素抵抗的可能机制，我们测定了丙二酰辅酶A和长链酰基辅酶A（LCA-CoA）浓度的变化以及蛋白激酶C（PKC）同工酶的分布情况，这些都是肌肉脂质与胰岛素抵抗之间可能的联系。给插管大鼠输注葡萄糖（40 mg·kg⁻¹·min⁻¹）1天或4天。与输注生理盐水的对照组相比，这使得红色股四头肌的LCA-CoA含量（6种物质的总和）在1天时增加了1.3倍，在4天时增加了1.4倍（两者与对照组相比P均<0.001）。丙二酰辅酶A的浓度也升高了（1天时增加1.7倍，P<0.01；4天时增加2.2倍，与对照组相比P<0.001），这表明胞质LCA-CoA的增加更为显著。在1天和4天后，红色腓肠肌中膜结合型与胞质型PKC-ε的比例均增加了两倍，提示出现了慢性激活。PKC-α、-δ和-θ未观察到变化。我们得出结论，在长期输注葡萄糖期间，LCA-CoA在肌肉中蓄积，这与丙二酰辅酶A诱导的脂肪酸氧化抑制（逆向葡萄糖-脂肪酸循环）一致。LCA-CoA的蓄积可能通过葡萄糖供应过多直接或通过PKC-ε的慢性激活在肌肉胰岛素抵抗的产生中发挥作用。
