1.
Insulin-resistant states are commonly associated with a significantly higher risk of
atherosclerosis.
Insulin resistance has also been correlated with enhanced
very low-density lipoprotein (VLDL) production, which is exacerbated by increased intestinal
lipid synthesis and
insulin-stimulated de novo lipogenesis.
Microsomal triglyceride transfer protein (MTP) catalyses the critical step in the synthesis and secretion of VLDL and
chylomicrons. The purpose of the present study was to test the hypothesis that chronic inhibition of MTP with a small molecule inhibitor would improve
insulin sensitivity and reduce atherogenic risk in a genetic model of diabetic dyslipidaemia. 2. The in vivo activity of
BMS-201038, a potent inhibitor of MTP, was evaluated in a model of
hypertriglyceridemia induced by Triton WR1339 and
corn oil in Zucker fatty rats.
Triglyceride secretion rate was significantly reduced by a single dose of
BMS-201038 by 35% at 0.3 mg/kg and 47% at 1 mg/kg, respectively. 3. Another group of Zucker fatty rats was dosed orally with
BMS-201038 (0.3 and 1 mg/kg) for 14 days. Serum levels of
triglycerides were reduced by 71% and 87%, non-esterified
free fatty acids were reduced by 33% and 40%, and
low-density lipoproteins by 26% and 29%, by 0.3 mg/kg and 1 mg/kg dose of
BMS-201038, respectively. These serum
lipid changes were accompanied by significant improvements in
glucose tolerance and
insulin sensitivity. In addition, lipid peroxidation in liver was reduced by 59% and 61%, and
superoxide dismutase activity was increased by 11% and 45% by 0.3 mg/kg and 1 mg/kg dose of
BMS-201038, respectively. Similar beneficial changes were found in aorta as well. 4. The present study provides evidence that inhibition of MTP with a small molecule inhibitor significantly improves dyslipidaemia associated with
insulin resistance and reduces the atherosclerotic risk.