Cruz Miguel, Velasco Eduardo, Kumate Jesús
Unidad de Investigación Medica en Bioquímica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI (CMNSXXI), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
Arch Med Res. 2004 Jan-Feb;35(1):18-23. doi: 10.1016/j.arcmed.2003.08.008.
Type-2 diabetes is characterized by hyperinsulinemia, peripheral insulin resistance, and diminished tyrosine phosphorylation activity. It has been recently shown that proteasomes are implicated in the degradation of the insulin receptor substrate-1 (IRS-1) but not in that of the insulin receptor (IR). However, it is unknown whether proteasomes are involved in pro-IR degradation.
We used CHO-IR and the 3T3-L1 cells treated with insulin at different concentrations and compared the proteasome activity of IRS-1, IR, and pro-IR degradation either in presence or in absence of lactacystin.
A total of 100 nM of insulin allowed degradation of IRS-1 after 6 h of incubation. At 1,000 nM of insulin, pro-IR degradation began at 1 h of incubation, similar to IRS-1 degradation. Surprisingly, at a higher concentration (10 microM) of insulin, a drastic decrease of proteins was observed from the first minute of incubation. This activity was blocked by lactacystin, a specific proteasome inhibitor.
According to these results, we propose that pro-IR is degraded by proteasomes.
2型糖尿病的特征为高胰岛素血症、外周胰岛素抵抗以及酪氨酸磷酸化活性降低。最近研究表明，蛋白酶体参与胰岛素受体底物-1（IRS-1）的降解，但不参与胰岛素受体（IR）的降解。然而，蛋白酶体是否参与前胰岛素受体（pro-IR）的降解尚不清楚。
我们使用CHO-IR细胞和用不同浓度胰岛素处理的3T3-L1细胞，比较了在有或无乳胞素的情况下IRS-1、IR和pro-IR降解的蛋白酶体活性。
孵育6小时后，100 nM胰岛素可使IRS-1降解。在1000 nM胰岛素时，pro-IR在孵育1小时后开始降解，与IRS-1降解情况相似。令人惊讶的是，在较高浓度（10 μM）胰岛素作用下，从孵育第一分钟起就观察到蛋白质急剧减少。该活性被特异性蛋白酶体抑制剂乳胞素阻断。
根据这些结果，我们提出pro-IR由蛋白酶体降解。
