Bailey C J, Turner S L, Bates S H, Jones R B
School of Life and Health Sciences, Aston University, Birmingham, UK, UK.
Int J Obes Relat Metab Disord. 2001 Apr;25(4):478-85. doi: 10.1038/sj.ijo.0801575.
The anti-obesity agent sibutramine, a serotonin and noradrenaline reuptake inhibitor (SNRI), has been shown to reduce insulin resistance and improve glycaemic control in obese-diabetic ob/ob mice and overweight type 2 diabetic patients.
To investigate whether sibutramine or its metabolites act directly on muscle cells to improve glucose uptake and insulin action.
Uptake of the non-metabolized glucose analogue 2-deoxyglucose was measured in cultured L6 rat muscle cells after incubation with sibutramine, its two pharmacologically active metabolites and related agents.
Sibutramine itself (10(-8)-10(-6) M) did not significantly affect 2-deoxyglucose uptake during incubations up to 72 h. The primary amine metabolite M2 (10(-7) and 10(-6) M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 12% and 34%) after 24 h incubation. These effects of M2 were lost by 72 h incubation. However, the secondary amine metabolite M1 (10(-6) M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 50%) after 72 h incubation, although M1 was ineffective after 24 h. M2 stimulated 2-deoxyglucose uptake in the presence of LY-294,002 (an inhibitor of phosphatidylinositol 3-kinase) but the effect of M2 was inhibited by cytochalasin B, which acutely blocks glucose transporters. Incubations with serotoninergic, noradrenergic and dopaminergic agents, or agents known to stimulate release or inhibit reuptake of these substances in nervous tissues indicated that the sibutramine metabolites were not affecting 2-deoxyglucose uptake via mechanisms associated with their SNRI properties.
Sibutramine metabolites can improve insulin-sensitive 2-deoxyglucose uptake by cultured muscle cells independently of SNRI effects.
抗肥胖药物西布曲明是一种5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRI），已被证明可降低肥胖糖尿病ob/ob小鼠和超重2型糖尿病患者的胰岛素抵抗并改善血糖控制。
研究西布曲明及其代谢产物是否直接作用于肌肉细胞以改善葡萄糖摄取和胰岛素作用。
用西布曲明、其两种药理活性代谢产物及相关药物孵育培养的L6大鼠肌肉细胞后，测定未代谢的葡萄糖类似物2-脱氧葡萄糖的摄取。
在长达72小时的孵育过程中，西布曲明本身（10^(-8)-10^(-6) M）对2-脱氧葡萄糖摄取无显著影响。在孵育24小时后，伯胺代谢产物M2（10^(-7)和10^(-6) M）增加基础和胰岛素刺激的2-脱氧葡萄糖摄取（分别增加12%和34%）。孵育72小时后，M2的这些作用消失。然而，仲胺代谢产物M1（10^(-6) M）在孵育72小时后增加基础和胰岛素刺激的2-脱氧葡萄糖摄取（增加50%），尽管M1在24小时后无效。M2在LY-294,002（磷脂酰肌醇3激酶抑制剂）存在的情况下刺激2-脱氧葡萄糖摄取，但M2的作用被细胞松弛素B抑制，细胞松弛素B可急性阻断葡萄糖转运体。用5-羟色胺能、去甲肾上腺素能和多巴胺能药物或已知可刺激这些物质在神经组织中释放或抑制其再摄取的药物孵育表明，西布曲明代谢产物并非通过与其SNRI特性相关的机制影响2-脱氧葡萄糖摄取。
西布曲明代谢产物可独立于SNRI效应改善培养的肌肉细胞对胰岛素敏感的2-脱氧葡萄糖摄取。
