PIOGLITAZONE TIME-DEPENDENTLY REDUCES TUMOR-NECROSIS-FACTOR-ALPHA LEVEL IN MUSCLE AND IMPROVES METABOLIC ABNORMALITIES IN WISTAR FATTY RATS

In order to evaluate the relationship between tumour necrosis factor-a lpha (TNF-alpha) level in muscle and metabolic abnormalities in obesit y and diabetes mellitus, pioglitazone, a novel insulin-sensitizing age nt, was administered to Wistar fatty rats and time-dependent changes i n muscle TNF-alpha content and plasma indicators of diabetes and obesi ty were measured. Wistar fatty rats were hyperglycaemic, hyperlipidaem ic and hyperinsulinaemic, and their plasma and muscle TNF-alpha levels were two or more times higher than those in normal lean rats at 16 we eks 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-alp ha levels in plasma and muscle decreased time-dependently, and reached the levels of lean rats within 4 days. Plasma glucose and insulin lev els also decreased time-dependently with pioglitazone, but on day 4, t hese levels were still much higher than the levels in lean rats. Neutr al sphingomyelinase (SMase) activity in muscle of fatty rats was two t imes higher than that in lean rats and was lowered to the level of tha t in lean rats by 4 days' pioglitazone administration. The plasma lept in 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 abnor malities in obesity and diabetes and that antidiabetic activity of pio glitazone is deeply associated with the suppression of TNF-alpha produ ction.