Ren Tingting, He Jinhan, Jiang Hongfeng, Zu Luxia, Pu Shenshen, Guo Xiaohui, Xu Guoheng
Department of Physiology and Pathophysiology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, China.
J Mol Endocrinol. 2006 Aug;37(1):175-83. doi: 10.1677/jme.1.02061.
In patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM), the biguanide, metformin, exerts its antihyperglycemic effect by improving insulin sensitivity, which is associated with decreased level of circulating free fatty acids (FFA). The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-alpha (TNF-alpha), a cytokine largely expressed in adipose tissue, stimulates chronic lipolysis, which may be associated with increased systemic FFA and insulin resistance in obesity and NIDDM. In this study, we examined the role of metformin in inhibiting lipolytic action upon various lipolytic stimulations in primary rat adipocytes. Treatment with metformin attenuated TNF-alpha-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 and reversing the downregulation of perilipin protein in TNF-alpha-stimulated adipocytes. The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by metformin. A high concentration of glucose in the adipocyte culture promoted the basal rate of glycerol release and significantly enhanced the lipolytic action stimulated by either TNF-alpha or isoproterenol. Metformin not only inhibits the basal lipolysis simulated by high glucose, but also suppresses the high glucose-enhanced lipolysis response to TNF-alpha or isoproterenol. The antilipolytic action in adipocytes could be the mechanism by which cellular action by metformin reduces systemic FFA concentration and thus improves insulin sensitivity in obese patients and the hyperglycemic conditions of NIDDM.
在2型非胰岛素依赖型糖尿病（NIDDM）患者中，双胍类药物二甲双胍通过提高胰岛素敏感性发挥其降糖作用，这与循环游离脂肪酸（FFA）水平降低有关。FFA和甘油从脂肪组织向血流的通量主要取决于脂肪细胞中三酰甘油的脂解作用。脂肪细胞脂解作用在生理上受儿茶酚胺激素刺激。肿瘤坏死因子-α（TNF-α）是一种在脂肪组织中大量表达的细胞因子，可刺激慢性脂解作用，这可能与肥胖和NIDDM患者体内FFA水平升高及胰岛素抵抗增加有关。在本研究中，我们检测了二甲双胍在抑制原代大鼠脂肪细胞各种脂解刺激的脂解作用中的作用。二甲双胍处理通过抑制细胞外信号相关激酶1/2的磷酸化并逆转TNF-α刺激的脂肪细胞中围脂滴蛋白的下调，减弱了TNF-α介导的脂解作用。二甲双胍也限制了对异丙肾上腺素肾上腺素能刺激的急性脂解反应。脂肪细胞培养物中高浓度的葡萄糖促进了甘油释放的基础速率，并显著增强了TNF-α或异丙肾上腺素刺激的脂解作用。二甲双胍不仅抑制高糖模拟的基础脂解作用，还抑制高糖增强的对TNF-α或异丙肾上腺素的脂解反应。脂肪细胞中的抗脂解作用可能是二甲双胍的细胞作用降低全身FFA浓度从而改善肥胖患者胰岛素敏感性及NIDDM患者高血糖状况的机制。
