Park Sunmin, Hong Sang Mee, Lee Ji Eun, Sung So Ra
Department of Food and Nutrition, College of Natural Science, Hoseo University, Asan-Si, Chungnam-Do, Republic of Korea.
Life Sci. 2007 Jun 6;80(26):2428-35. doi: 10.1016/j.lfs.2007.04.001. Epub 2007 Apr 22.
Investigated in this study are the effects and mechanisms of exercise and chlorpromazine (CPZ), a widely used conventional antipsychotic drug, on the hepatic insulin sensitivity of 90% pancreatectomized (Px) male Sprague-Dawley rats. The Px diabetic rats were provided with 0, 5, or 50 mg CPZ per kg of body weight (No-CPZ, LCPZ, or HCPZ) for 8 weeks, and half of each group had regular exercise. LCPZ did not exacerbate hepatic insulin sensitivity through insulin and leptin signaling in diabetic rats. However, HCPZ decreased whole-body glucose infusion rates in hyperinsulinemic clamped states, but not whole-body glucose uptake. This was due to the elevated hepatic glucose output in hyperinsulinemic states. The decreased hepatic insulin sensitivity was associated with insulin receptor substrate-2 (IRS2) protein levels in the liver. Decreased IRS2 levels attenuated hepatic insulin and leptin signaling pathways in hyperinsulinemic states, which elevated glucose production by inducing phosphoenolpyruvate carboxykinase expression. Long-term exercise recovered hepatic insulin sensitivity attenuated by HCPZ to reduce the hepatic glucose output in hyperinsulinemic clamped states. This recovery was related to enhanced insulin and leptin signaling via increased IRS2 gene and protein levels by activating the cAMP responding element-binding protein, but exercise improved only insulin signaling. In conclusion, HCPZ exacerbates hepatic insulin action by attenuating insulin and leptin signaling in type 2 diabetic rats, while regular exercise partially reverses the attenuation of hepatic insulin sensitivity by improving insulin signaling. Enhancement of insulin and leptin signaling through an induction of IRS2 may play an important role in improving hepatic glucose homeostasis.
本研究调查了运动和氯丙嗪（CPZ，一种广泛使用的传统抗精神病药物）对90%胰腺切除（Px）的雄性Sprague-Dawley大鼠肝脏胰岛素敏感性的影响及机制。给Px糖尿病大鼠按每千克体重0、5或50毫克CPZ给药（无CPZ组、低剂量CPZ组或高剂量CPZ组），持续8周，每组的一半大鼠进行规律运动。低剂量CPZ并未通过胰岛素和瘦素信号通路加重糖尿病大鼠的肝脏胰岛素敏感性。然而，高剂量CPZ降低了高胰岛素钳夹状态下的全身葡萄糖输注率，但未降低全身葡萄糖摄取。这是由于高胰岛素状态下肝脏葡萄糖输出增加。肝脏胰岛素敏感性降低与肝脏中胰岛素受体底物2（IRS2）蛋白水平有关。IRS2水平降低减弱了高胰岛素状态下的肝脏胰岛素和瘦素信号通路，通过诱导磷酸烯醇式丙酮酸羧激酶表达增加了葡萄糖生成。长期运动可恢复被高剂量CPZ减弱的肝脏胰岛素敏感性，以降低高胰岛素钳夹状态下的肝脏葡萄糖输出。这种恢复与通过激活环磷酸腺苷反应元件结合蛋白增加IRS2基因和蛋白水平从而增强胰岛素和瘦素信号有关，但运动仅改善了胰岛素信号。总之，高剂量CPZ通过减弱2型糖尿病大鼠的胰岛素和瘦素信号通路加重肝脏胰岛素作用，而规律运动通过改善胰岛素信号部分逆转肝脏胰岛素敏感性的减弱。通过诱导IRS2增强胰岛素和瘦素信号可能在改善肝脏葡萄糖稳态中起重要作用。
