Ruzzin J, Wagman A S, Jensen J
Department of Physiology, National Institute of Occupational Health, P.O. Box 8149 Dep., 0033 Oslo, Norway.
Diabetologia. 2005 Oct;48(10):2119-30. doi: 10.1007/s00125-005-1886-0. Epub 2005 Aug 3.
AIMS/HYPOTHESIS: Treatment with glucocorticoids, especially at high doses, induces insulin resistance. The aims of the present study were to identify the potential defects in insulin signalling that contribute to dexamethasone-induced insulin resistance in skeletal muscles, and to investigate whether the glycogen synthase-3 (GSK-3) inhibitor CHIR-637 could restore insulin-stimulated glucose metabolism.
Skeletal muscles were made insulin-resistant by treating male Wistar rats with dexamethasone, a glucocorticoid analogue, for 12 days. Insulin-stimulated glucose uptake, glycogen synthesis and insulin signalling were studied in skeletal muscles in vitro.
Dexamethasone treatment decreased the ability of insulin to stimulate glucose uptake, glycogen synthesis and glycogen synthase fractional activity. In addition, the dephosphorylation of glycogen synthase by insulin was blocked. These defects were paralleled by reduced insulin-stimulated protein kinase B (PKB) and GSK-3 phosphorylation. While expression of PKB, GSK-3 and glycogen synthase was not reduced by dexamethasone treatment, expression of the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) was increased. Inhibition of GSK-3 by CHIR-637 increased glycogen synthase fractional activity in soleus muscle from normal and dexamethasone-treated rats, although the effect was more pronounced in control rats. CHIR-637 did not improve insulin-stimulated glucose uptake in muscles from dexamethasone-treated rats.
CONCLUSIONS/INTERPRETATION: We demonstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles. Acute pharmacological inhibition of GSK-3 activated glycogen synthase in muscles from dexamethasone-treated rats, but GSK-3 inhibition did not restore insulin-stimulated glucose uptake.
目的/假设：使用糖皮质激素进行治疗，尤其是高剂量使用时，会诱发胰岛素抵抗。本研究的目的是确定胰岛素信号传导中的潜在缺陷，这些缺陷导致骨骼肌中地塞米松诱导的胰岛素抵抗，并研究糖原合酶-3（GSK-3）抑制剂CHIR-637是否能恢复胰岛素刺激的葡萄糖代谢。
通过给雄性Wistar大鼠注射糖皮质激素类似物地塞米松12天，使骨骼肌产生胰岛素抵抗。在体外研究骨骼肌中胰岛素刺激的葡萄糖摄取、糖原合成及胰岛素信号传导。
地塞米松治疗降低了胰岛素刺激葡萄糖摄取、糖原合成及糖原合酶活性分数的能力。此外，胰岛素对糖原合酶的去磷酸化作用受阻。这些缺陷伴随着胰岛素刺激的蛋白激酶B（PKB）和GSK-3磷酸化的减少。虽然地塞米松治疗并未降低PKB、GSK-3和糖原合酶的表达，但磷脂酰肌醇3激酶（PI 3激酶）的p85α亚基表达增加。CHIR-637抑制GSK-3可增加正常和地塞米松处理大鼠比目鱼肌中的糖原合酶活性分数，尽管在对照大鼠中效果更明显。CHIR-637并未改善地塞米松处理大鼠肌肉中胰岛素刺激的葡萄糖摄取。
结论/解读：我们证明，长期地塞米松治疗会损害胰岛素刺激的PKB和GSK-3磷酸化，这可能导致骨骼肌中的胰岛素抵抗。急性药理学抑制GSK-3可激活地塞米松处理大鼠肌肉中的糖原合酶，但抑制GSK-3并不能恢复胰岛素刺激的葡萄糖摄取。
