Department of Medicine, University of Leipzig, Leipzig, Germany.
PLoS One. 2012;7(6):e38744. doi: 10.1371/journal.pone.0038744. Epub 2012 Jun 22.
Linagliptin (TRADJENTA™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3-4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67-89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (-16.5% to -20.3%; P<0.01) or 30 mg/kg/day (-14.5% to -26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic-hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity.
利拉利汀（TRADJENTA™）是一种选择性二肽基肽酶-4（DPP-4）抑制剂。DPP-4 抑制可减轻胰岛素抵抗并改善人类外周葡萄糖利用。然而，长期 DPP-4 抑制对胰岛素敏感性的影响尚不清楚。在饮食诱导肥胖的 C57BL/6 小鼠中，确定了每日 3 毫克/千克或 30 毫克/千克利拉利汀治疗 3-4 周对胰岛素敏感性和肝脂肪含量的影响。正常饮食的动物作为对照。利拉利汀（P<0.001）显著抑制 DPP-4 活性（67-89%）。口服葡萄糖耐量试验后，3 毫克/千克/天（-16.5%至-20.3%；P<0.01）或 30 毫克/千克/天（-14.5%至-26.4%；P<0.05）利拉利汀治疗后血糖浓度（曲线下面积表示）显著降低（均 P<0.01）。利拉利汀以剂量依赖性方式显著降低肝脂肪含量（均 P<0.001）。4 周用 3 毫克/千克/天或 30 毫克/千克/天利拉利汀治疗的饮食诱导肥胖的小鼠与载体相比，糖化血红蛋白显著改善（均 P<0.001）。在稳定的正常血糖高胰岛素钳夹期间观察到葡萄糖处置率的显著剂量依赖性改善：3 毫克/千克/天和 30 毫克/千克/天利拉利汀组分别为 27.3 毫克/千克/分钟和 32.2 毫克/千克/分钟；与载体相比，分别为 20.9 毫克/千克/分钟（P<0.001）。在钳夹期间，肝葡萄糖生成显著受到抑制：3 毫克/千克/天和 30 毫克/千克/天利拉利汀组分别为 4.7 毫克/千克/分钟和 2.1 毫克/千克/分钟；与载体相比，分别为 12.5 毫克/千克/分钟（P<0.001）。此外，30 毫克/千克/天利拉利汀治疗导致脂肪组织浸润的巨噬细胞数量显著减少（P<0.05）。利拉利汀治疗还降低了肝脏 PTP1B、SOCS3、SREBP1c、SCD-1 和 FAS 的表达（P<0.05）。其他组织，如肌肉、心脏和肾脏，不受利拉利汀胰岛素增敏作用的显著影响。长期利拉利汀治疗可降低饮食诱导的肝脂肪变性和胰岛素抵抗动物的肝脂肪含量，并可能改善胰岛素敏感性。
