Fukuoka Hidenori, Iida Keiji, Nishizawa Hitoshi, Imanaka Mari, Takeno Ryoko, Iguchi Genzo, Takahashi Michiko, Okimura Yasuhiko, Kaji Hidesuke, Chihara Kazuo, Takahashi Yutaka
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Growth Horm IGF Res. 2010 Jun;20(3):212-9. doi: 10.1016/j.ghir.2010.02.001. Epub 2010 Feb 24.
IGF-I is known to enhance insulin sensitivity in whole body mainly via the IGF-I receptors in muscles. However, the effect of IGF-I on the regulation of insulin sensitivity in the adipose tissue is yet unclear. Insulin sensitivity was found to be higher in the IGF-I receptor-deficient adipocytes than that in wild-type adipocytes, suggesting that IGF-I signaling induces insulin resistance in adipocytes. However, the underlying mechanism has not yet been elucidated. In addition, the effect of superphysiological levels of IGF-I, as is observed in patients with acromegaly, on insulin sensitivity remains unclear.
To clarify the role of IGF-I on insulin sensitivity in adipocytes, we determined insulin-induced glucose uptake and IRS-1 status in 3T3-L1 adipocytes treated with IGF-I. Since reactive oxygen species (ROS) are causally related to insulin resistance, we investigated the effect of IGF-I on ROS production to elucidate the molecular mechanism underlying insulin resistance.
Preincubation of the adipocytes with IGF-I attenuated insulin-dependent glucose uptake. Interestingly, we found that IGF-I significantly stimulated ROS production. Furthermore, preincubation of adipocytes with an antioxidant, N-acetyl-cysteine (NAC) restored the IGF-I-induced attenuation of insulin-dependent glucose uptake; this indicates that IGF-I induces insulin resistance via ROS. Serine phosphorylation of IRS-1 was strongly induced and the insulin-dependent tyrosine phosphorylation of IRS-1 was suppressed by preincubating the adipocytes with IGF-I. Further, NAC restored these changes induced by IGF-I on both serine and tyrosine phosphorylation of IRS-1.
These data indicate that IGF-I inhibited insulin activity in the 3T3-L1 adipocytes via ROS production, which affects IRS-1 phosphorylation status.
已知胰岛素样生长因子-I（IGF-I）主要通过肌肉中的IGF-I受体增强全身胰岛素敏感性。然而，IGF-I对脂肪组织中胰岛素敏感性调节的影响尚不清楚。研究发现IGF-I受体缺陷型脂肪细胞的胰岛素敏感性高于野生型脂肪细胞，这表明IGF-I信号传导诱导脂肪细胞产生胰岛素抵抗。然而，其潜在机制尚未阐明。此外，肢端肥大症患者体内观察到的超生理水平IGF-I对胰岛素敏感性的影响仍不清楚。
为了阐明IGF-I在脂肪细胞胰岛素敏感性中的作用，我们测定了用IGF-I处理的3T3-L1脂肪细胞中胰岛素诱导的葡萄糖摄取和胰岛素受体底物-1（IRS-1）状态。由于活性氧（ROS）与胰岛素抵抗存在因果关系，我们研究了IGF-I对ROS产生的影响，以阐明胰岛素抵抗的分子机制。
用IGF-I预孵育脂肪细胞可减弱胰岛素依赖性葡萄糖摄取。有趣的是，我们发现IGF-I能显著刺激ROS产生。此外，用抗氧化剂N-乙酰半胱氨酸（NAC）预孵育脂肪细胞可恢复IGF-I诱导的胰岛素依赖性葡萄糖摄取减弱；这表明IGF-I通过ROS诱导胰岛素抵抗。用IGF-I预孵育脂肪细胞可强烈诱导IRS-1的丝氨酸磷酸化，并抑制IRS-1的胰岛素依赖性酪氨酸磷酸化。此外，NAC恢复了IGF-I诱导的IRS-1丝氨酸和酪氨酸磷酸化的这些变化。
这些数据表明，IGF-I通过影响IRS-1磷酸化状态的ROS产生抑制3T3-L1脂肪细胞中的胰岛素活性。
