A NEW ANTIDIABETIC AGENT, BRL-49653, REDUCES LIPID AVAILABILITY AND IMPROVES INSULIN ACTION AND GLUCOREGULATION IN THE RAT

Thiazolidinediones offer promise as oral insulin-sensitizing agents. T he effects of a new, high-potency compound (BRL 49653, SmithKline Beec ham, Epsom, U.K.) were examined in insulin-resistant (high-fat-fed, HF ) and control (high-starch-fed, HS) rats. The diet period was 3 weeks, with a BRL 49653 (10 mu mol.kg(-1).day(-1)) or vehicle gavage on the last 4 days. Then basal or euglycemic clamp studies were performed on animals in the conscious fasted state. In the basal state, BRL 49653 p roduced many similar metabolic responses in HF and HS rats (reduced in sulin, glycerol, ketone body, and nonesterified fatty acid levels, red uced whole body glucose turnover, reduced brown adipose tissue glucose metabolism, and increased cardiac glucose metabolism and GLUT4 levels ). In contrast, under euglycemic clamp conditions (500 pmol/l insulin) , BRL 49653 only induced changes in the HF group (increased glucose in fusion rate from 12.2 +/- 0.9 to 21.6 +/- 1.1 mg.kg(-1).min(-1) [P < 0 .001], increased insulin suppressibility of hepatic glucose production [P < 0.01], and increased glucose uptake in muscle [P < 0.01]). BRL 4 9653 significantly reduced liver but not muscle triglyceride content i n HF rats. We conclude that the agent has a general effect on lowering circulating Lipid and insulin levels, manifested similarly in normal and insulin-resistant rats, but that enhancement of peripheral insulin action is confined to insulin-resistant rats. Therefore, the hypoinsu linemic action of the thiazolidinediones is probably not related simpl y to improved peripheral insulin sensitivity. The pattern of individua l tissue response to BRL 49653 suggests that altered lipid availabilit y is an important mediator of its effects glucose metabolism.