Murase K, Odaka H, Suzuki M, Tayuki N, Ikeda H
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Osaka, Japan.
Diabetologia. 1998 Mar;41(3):257-64. doi: 10.1007/s001250050901.
In order to evaluate the relationship between tumour necrosis factor-alpha (TNF-alpha) level in muscle and metabolic abnormalities in obesity and diabetes mellitus, pioglitazone, a novel insulin-sensitizing agent, was administered to Wistar fatty rats and time-dependent changes in muscle TNF-alpha content and plasma indicators of diabetes and obesity were measured. Wistar fatty rats were hyperglycaemic, hyperlipidaemic and hyperinsulinaemic, and their plasma and muscle TNF-alpha levels were two or more times higher than those in normal lean rats at 16 weeks of age. When pioglitazone was administered to fatty rats at a dose of 3 mg kg(-1) day(-1), the plasma triglyceride level and TNF-alpha levels in plasma and muscle decreased time-dependently, and reached the levels of lean rats within 4 days. Plasma glucose and insulin levels also decreased time-dependently with pioglitazone, but on day 4, these levels were still much higher than the levels in lean rats. Neutral sphingomyelinase (SMase) activity in muscle of fatty rats was two times higher than that in lean rats and was lowered to the level of that in lean rats by 4 days' pioglitazone administration. The plasma leptin level in fatty rats was 8 times higher than that in lean rats, but pioglitazone did not affect the level during the 4-day administration period. These results suggest that an increase in TNF-alpha production and subsequent activation of SMase in muscle leads to metabolic abnormalities in obesity and diabetes and that antidiabetic activity of pioglitazone is deeply associated with the suppression of TNF-alpha production.
为了评估肌肉中肿瘤坏死因子-α（TNF-α）水平与肥胖和糖尿病代谢异常之间的关系，将新型胰岛素增敏剂吡格列酮给予Wistar肥胖大鼠，并测量肌肉TNF-α含量以及糖尿病和肥胖相关血浆指标随时间的变化。Wistar肥胖大鼠存在高血糖、高血脂和高胰岛素血症，在16周龄时，它们的血浆和肌肉TNF-α水平比正常瘦大鼠高出两倍或更多。当以3 mg kg⁻¹ day⁻¹的剂量给肥胖大鼠施用吡格列酮时，血浆甘油三酯水平以及血浆和肌肉中的TNF-α水平随时间下降，并在4天内达到瘦大鼠的水平。血浆葡萄糖和胰岛素水平也随吡格列酮的使用而随时间下降，但在第4天，这些水平仍远高于瘦大鼠。肥胖大鼠肌肉中的中性鞘磷脂酶（SMase）活性比瘦大鼠高两倍，通过4天的吡格列酮给药可将其降至瘦大鼠的水平。肥胖大鼠的血浆瘦素水平比瘦大鼠高8倍，但在4天给药期间，吡格列酮并未影响该水平。这些结果表明，肌肉中TNF-α产生增加以及随后SMase的激活导致肥胖和糖尿病中的代谢异常，并且吡格列酮的抗糖尿病活性与TNF-α产生的抑制密切相关
