We studied the effect of troglitazone on the plasma concentrations of homocysteine (tHcy), the erythrocyte and hepatic concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and the hepatic activities of cystathionine-β-synthase (CβS) and methylenetetrahydrofolate reductase (MTHFR) in lean and fatty Zucker rats (a model of insulin resistance). Four groups of female Zucker rats were studied. Troglitazone (200 mg/kg) was administered by gavage daily for 3 weeks to lean and fatty Zucker rats. The other 2 groups served as controls. The blood parameters were determined at days 0, 10, and 21. The hepatic SAM and SAH concentrations and MTHFR and CβS were measured in the 3-week liver samples. Plasma homocysteine fell significantly in all troglitazone-treated animals from a mean ± SD of 7.6 ± 1.5 μmol/L to 4.5 ± 1.1 μmol/L (P < .02) but not in control animals (5.7 ± 1.8 μmol/L to 5.9 ± 1.8 μmol/L). The decreases induced by troglitazone in homocysteine were seen in both the lean and the fatty Zucker rats. This was accompanied by significant rises in the hepatic concentrations of SAH and SAM + SAH. In addition, a significant decline in the hepatic SAM/SAH ratio was observed. The mean ± SD hepatic CβS (expressed as nmol of cystathionine formed at 37°C) in the troglitazone-treated rats was 1,226 ± 47 nmol/h/mg protein, which was significantly higher than that in the control group (964 ± 64 nmol/h/mg protein; P = .03). We conclude that troglitazone lowers plasma homocysteine in insulin-resistant animals. The homocysteine-lowering effects of troglitazone may be mediated in part by a shift in the concentrations of tHcy and its related metabolites from the blood to the liver as well as by an upregulation of hepatic CβS activity. These data support the hypothesis that insulin may regulate homocysteine metabolism through regulation of hepatic CβS activity, although activity of other hepatic enzymes not studied here may also contribute to these observations.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism