Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA.
Diabetologia. 2011 Nov;54(11):2878-89. doi: 10.1007/s00125-011-2271-9. Epub 2011 Aug 18.
AIMS/HYPOTHESIS: IRS-1 serine phosphorylation is often elevated in insulin resistance models, but confirmation in vivo in humans is lacking. We therefore analysed IRS-1 phosphorylation in human muscle in vivo.
We used HPLC-electrospray ionisation (ESI)-MS/MS to quantify IRS-1 phosphorylation basally and after insulin infusion in vastus lateralis muscle from lean healthy, obese non-diabetic and type 2 diabetic volunteers.
Basal Ser323 phosphorylation was increased in type 2 diabetic patients (2.1 ± 0.43, p ≤ 0.05, fold change vs lean controls). Thr495 phosphorylation was decreased in type 2 diabetic patients (p ≤ 0.05). Insulin increased IRS-1 phosphorylation at Ser527 (1.4 ± 0.17, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) and Ser531 (1.3 ± 0.16, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) in the lean controls and suppressed phosphorylation at Ser348 (0.56 ± 0.11, p ≤ 0.01, fold change, 240 min after insulin infusion vs basal), Thr446 (0.64 ± 0.16, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal), Ser1100 (0.77 ± 0.22, p ≤ 0.05, fold change, 240 min after insulin infusion vs basal) and Ser1142 (1.3 ± 0.2, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal).
CONCLUSIONS/INTERPRETATION: We conclude that, unlike some aspects of insulin signalling, the ability of insulin to increase or suppress certain IRS-1 phosphorylation sites is intact in insulin resistance. However, some IRS-1 phosphorylation sites do not respond to insulin, whereas other Ser/Thr phosphorylation sites are either increased or decreased in insulin resistance.
目的/假设：IRS-1 丝氨酸磷酸化在胰岛素抵抗模型中经常升高，但在人体内的证实尚缺乏。因此，我们分析了人体内 IRS-1 的磷酸化。
我们使用 HPLC-电喷雾电离（ESI）-MS/MS 定量分析了来自瘦健康、肥胖非糖尿病和 2 型糖尿病志愿者的股外侧肌基础状态和胰岛素输注后的 IRS-1 磷酸化。
2 型糖尿病患者的基础状态下 Ser323 磷酸化增加（2.1±0.43，p≤0.05，与瘦对照组相比的倍数变化）。2 型糖尿病患者 Thr495 磷酸化减少（p≤0.05）。胰岛素增加了 IRS-1 在 Ser527（1.4±0.17，p≤0.01，胰岛素输注 60 分钟后与基础状态相比的倍数变化）和 Ser531（1.3±0.16，p≤0.01，胰岛素输注 60 分钟后与基础状态相比的倍数变化）的磷酸化，同时抑制了 Ser348（0.56±0.11，p≤0.01，胰岛素输注 240 分钟后与基础状态相比的倍数变化）、Thr446（0.64±0.16，p≤0.05，胰岛素输注 60 分钟后与基础状态相比的倍数变化）、Ser1100（0.77±0.22，p≤0.05，胰岛素输注 240 分钟后与基础状态相比的倍数变化）和 Ser1142（1.3±0.2，p≤0.05，胰岛素输注 60 分钟后与基础状态相比的倍数变化）的磷酸化。
结论/解释：我们的结论是，与胰岛素信号的某些方面不同，胰岛素增加或抑制某些 IRS-1 磷酸化位点的能力在胰岛素抵抗中是完整的。然而，一些 IRS-1 磷酸化位点对胰岛素没有反应，而其他 Ser/Thr 磷酸化位点在胰岛素抵抗中要么增加要么减少。
