TNF-α诱导的胰岛素抵抗小鼠胰岛素敏感性及糖脂代谢的变化

The changes of insulin sensitivity and glucose-lipid metabolism in mice with TNF-α induced insulin resistance

目的探讨TNF-α诱导的胰岛素抵抗(IR)小鼠胰岛素敏感性及糖脂代谢的变化。方法23只健康雄性C57BL/6J小鼠随机分为4组:高剂量(H)组、中剂量(M)组、低剂量(L)组分别给予腹腔注射6、3、1μg·kg-1.d-1的TNF-α,正常对照(NC)组注射等体积的生理盐水,共7天。采用静脉葡萄糖耐量试验(IVGTT)和3-[3H]葡萄糖为示踪剂的扩展胰岛素钳夹技术,评价小鼠胰岛素敏感性和糖脂代谢的变化。结果TNF-α处理后,小鼠FBG、血浆胰岛素(Ins)和FFA水平均增高,且H组明显高于NC、M和L组。IVGTT结果显示H组糖耐量减低,Ins释放水平明显高于其他组。在胰岛素钳夹术中,H组基础葡萄糖清除率(GDR)和肝糖输出率(HGP)明显高于NC组(P<0.01)。在钳夹稳态时,H组血浆Ins水平明显高于NC组(P<0.01),Ins对FFA的抑制作用较NC组明显降低(P<0.01),H组葡萄糖输注率(GIR)明显低于NC组(P<0.01);钳夹稳态时小鼠GDR明显增加,但H组GDR的增加仍明显低于NC组(P<0.01);钳夹结束时,NC组HGP被完全抑制,而H组仅被抑制59%。结论高剂量TNF-α(6μg·kg-1.d-1)处理可导致小鼠糖脂代谢紊乱以及肝和外周组织的IR。

Objective To investigate the effects of tumor necrosis factor-alpha （TNF-α） on insulin sensitivity and glucose-lipid metabolism in TNF-α-indueed IR mice. Methods Male C57BL/6J mice were given an intraperitoneal injection of TNF-α （H group, 6μg/kg; M group, 3μg/kg; L group, 1μg/kg;twice daily） and saline （NC group） for 7 days. The plasma glucose and insulin were assayed during intravenous glucose tolerance test （IVGTT） and hyperinsulinemic-euglycemic clamp combined with 3-[^3H] glucose as a tracer was carried out. Results After TNF-a treatment, fasting blood glucose （FBG）, plasma insulin and free fatty acids （FFA） were significantly elevated in H group compared with NC, L and M groups （P〈0. 01 and P〈0. 05, respectively）. There was a lower glucose tolerance in H group versus other three groups during IVGTT. The insulin release by glucose stimulation was higher in H group versus NC and L groups （P〈0. 01 and P〈0. 05）. Basal glucose disappearance rate （GDR） and hepatic glucose production （HGP） were significantly increased in H group compared with NC group （P〈0.01）. During the steady-state of clamp, plasma insulin levels were significantly increased in H group versus NC group （341.7±17. 7 vs 84. 7±5.5mU/L,P〈0.01）. The suppressive effect of insulin on FFA was significantly blunted in H group compared with NC group （0.82±0.03 vs 0.43±0.07mmol/L,P〈0. 01）. Steady-state glucose infusion rate （GIR） was significantly decreased in H group compared with NC group （39.1±2.3 vs 54.2±2. 2 mg·kg-1 ·min^-1 ,P〈0.01）. Although GDR was increased in both group, but it was still lower in H group than in control group（47.9±0. 8 vs 53. 9±2. 0 mg. kg^-1. min^-1 ,P〈0. 01）. As compared with baseline, HGP in the controls was almost completely suppressed during steady state of clamp, but in H group suppressed by approximately 41 %. Conclusions High-dose TNF-α treatment induces the abnormality of glucose-lipid metabolism and the insulin resistance of hepatic and peripheral tissue in mice.