Barshop Institute for Longevity and Aging Studies and.
Diabetes Division, Department of Medicine, UT Health San Antonio, San Antonio, Texas, USA.
J Clin Invest. 2022 Nov 1;132(21):e162291. doi: 10.1172/JCI162291.
BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.ResultsIn protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).ConclusionsAcute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registrationClinicalTrials.gov NCT02321111 and NCT02267317.FundingNIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645.
细胞培养和啮齿动物研究表明 TLR4 参与了胰岛素抵抗的发病机制，但人类的直接数据有限。我们检验了这样一个假设，即通过竞争性抑制剂埃替莫兰抑制 TLR4，可改善人类的胰岛素抵抗。
在方案 I 中，10 名健康的瘦人以随机交叉设计接受了以下 72 小时静脉输注：生理盐水（30 mL/h）加载体；中链甘油三酯（30 mL/h）加载体；或中链甘油三酯（30 mL/h）加埃替莫兰（每 12 小时静脉注射 12 mg）。在方案 II 中，同样采用随机交叉设计，9 名患有肥胖症的非糖尿病个体接受埃替莫兰或载体 72 小时。通过正葡萄糖高胰岛素钳夹试验评估埃替莫兰的作用。
在方案 I 中，脂质输注使外周胰岛素敏感性（M 值）降低了 14%，并分别使空腹血糖（FPG）浓度、空腹血浆胰岛素（FPI）浓度和胰岛素抵抗的稳态模型评估（HOMA-IR）指数升高了 7%、22%和 26%。埃替莫兰并不能预防这些代谢参数的脂质诱导改变。埃替莫兰也未能改善肥胖和胰岛素抵抗个体的任何基线代谢参数（方案 II）（M、FPG、FPI、HOMA-IR）。
用埃替莫兰急性抑制 TLR4 并不能防止脂质引起的胰岛素抵抗。短期埃替莫兰给药也未能改善肥胖相关的胰岛素抵抗。这些数据不支持 TLR4 在胰岛素抵抗中的作用。可能需要使用不同类别的 TLR4 抑制剂、更长的药物暴露时间和/或富含饱和脂肪的脂质增强干预措施进行进一步研究，以阐明 TLR4 在人类代谢功能障碍中的作用。
ClinicalTrials.gov NCT02321111 和 NCT02267317。
美国国立卫生研究院授予 R01DK080157、P30AG044271、P30AG013319 和 UL1TR002645 拨款。
