Thiazolidinediones are oral
insulin-sensitizing agents that may be useful for the treatment of
non-insulin-dependent diabetes mellitus (
NIDDM).
BRL 49653 ameliorates
insulin resistance and improves glucoregulation in high-fat-fed (HF) rats. It is known that
thiazolidinediones bind to the
peroxisome proliferator-activated receptor (
PPAR gamma) in fat cells, but the extent to which the improved glucoregulation and hypolipidemic effects relate to adipose tissue requires clarification. We therefore examined
BRL 49653 effects on lipid metabolism in HF and control (high-
starch-fed [HS]) rats. The diet period was 3 weeks, with
BRL 49653 (10 mumol/kg/d) or vehicle gavage administered over the last 4 days. Studies were performed on animals in the conscious fasted state. In HF rats, rate constants governing 3H-palmitate clearance were unaffected 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 liver,
BRL 49653 increased
insulin-stimulated conversion of
glucose into
fatty acid in both HF (by 270%) and HS (by 30%) groups (P < .05). Relative to HS rats, HF animals had substantially elevated levels of muscle diglyceride (
diacylglycerol[DG] by 240%, P < .001).
BRL 49653 significantly reduced muscle DG in HF (by 30%, P < .05) but not in HS rats. The agent did not reduce the intake of dietary
lipid. In conclusion, these results are consistent with a primary action of
BRL 49653 in adipose tissue to conserve
lipid by reducing systemic
lipid supply and subsequent utilization. The parallel effects of diet and
BRL 49653 treatment on
insulin resistance and muscle acylglyceride levels support the involvement of local
lipid oversupply in the generation of muscle
insulin resistance.