THE INSULIN SENSITIZER, BRL-49653, REDUCES SYSTEMIC FATTY-ACID SUPPLYAND UTILIZATION AND TISSUE LIPID AVAILABILITY IN THE RAT

Thiazolidinediones are oral insulin-sensitizing agents that may be use ful for the treatment of non-insulin-dependent diabetes mellitus (NIDD M). BRL 49653 ameliorates insulin resistance and improves glucoregulat ion in high-fat-fed (HF) rats. It is known that thiazolidinediones bin d to the peroxisome proliferator-activated receptor (PPAR gamma) in fa t cells, but the extent to which the improved glucoregulation and hypo lipidemic effects relate to adipose tissue requires clarification. We therefore examined BRL 49653 effects on lipid metabolism in HF and con trol (high-starch-fed [HS]) rats. The diet period was 3 weeks, with BR L 49653 (10 mu mol/kg/d) or vehicle gavage administered over the last 4 days. Studies were performed on animals in the conscious fasted stat e. In HF rats, rate constants governing H-3-palmitate clearance were u naffected by BRL 49653. This finding, taken with a concurrent decrease of fasting plasma nonesterified fatty acids (NEFA) (P < .01, ANOVA), demonstrated that systemic NEFA supply and hence absolute utilization are reduced by BRL 49653. Hepatic triglyceride (TG) production (HTGP) assessed using Triton WR1339 was unaffected by diet or BRL 49653. In l iver, BRL 49653 increased insulin-stimulated conversion of glucose int o fatty acid in both HF (by 270%) and HS (by 30%) groups (P < .05). Re lative to HS rats, HF animals had substantially elevated levels of mus cle diglyceride (diacylglycerol [DG] by 240%, P < .001). BRL 49653 sig nificantly reduced muscle DG in HF (by 30%, P < .05) but not in HS rat s. The agent did not reduce the intake of dietary lipid. In conclusion , these results are consistent with a primary action of BRL 49653 in a dipose tissue to conserve lipid by reducing systemic lipid supply and subsequent utilization. The parallel effects of diet and BRL 49653 tre atment on insulin resistance and muscle acylglyceride levels support t he involvement of local lipid oversupply in the generation of muscle i nsulin resistance. Copyright (C) 1997 by W.B. Saunders Company.