Carlson Christian J, Koterski Sandra, Sciotti Richard J, Poccard German Braillard, Rondinone Cristina M
Insulin Signaling, Metabolic Diseases Division, Global Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
Diabetes. 2003 Mar;52(3):634-41. doi: 10.2337/diabetes.52.3.634.
Serine and threonine kinases may contribute to insulin resistance and the development of type 2 diabetes. To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients.
丝氨酸和苏氨酸激酶可能与胰岛素抵抗及2型糖尿病的发生发展有关。为了测试丝裂原活化蛋白（MAP）激酶家族成员导致2型糖尿病的可能性，我们检测了从健康个体和2型糖尿病患者分离出的脂肪细胞中基础状态及胰岛素刺激后的细胞外信号调节激酶1/2（Erk 1/2）、c-Jun氨基末端激酶（JNK）和p38的磷酸化情况。最大程度的胰岛素刺激可增加健康对照者脂肪细胞中Erk 1/2和JNK的磷酸化水平，但在2型糖尿病患者中却没有这种作用。胰岛素刺激在健康对照者或2型糖尿病患者中均未增加p38的磷酸化水平。在2型糖尿病患者的脂肪细胞中，这些MAP激酶的基础磷酸化状态显著升高，并且与这些脂肪细胞中胰岛素受体底物-1（IRS-1）和葡萄糖转运蛋白4（GLUT4）的减少有关。为了确定MAP激酶是否参与了IRS-1和GLUT4蛋白水平的下调，我们使用选择性抑制剂在长期用胰岛素处理的3T3-L1脂肪细胞中抑制这些MAP激酶。抑制Erk 1/2、JNK或p38对胰岛素刺激引起的IRS-1蛋白水平降低没有影响。然而，抑制p38信号通路可阻止胰岛素刺激引起的GLUT4蛋白水平下降。总之，2型糖尿病与MAP激酶家族基础激活增加有关。此外，p38信号通路的上调可能导致2型糖尿病患者脂肪组织中GLUT4表达的丧失。
