Abstract

Troglitazone is a new, orally effective antidiabetic agent that decreases plasma glucose in obese patients with non-insulin-dependent diabetes mellitus. Unfortunately, troglitazone also has a propensity to cause edema. This study was designed to determine how troglitazone affects intestinal ion transport and water absorption. Short circuit current (I_sc) was measured in rat and human duodenal mucosa in Ussing chambers. Five minutes later, the serosal addition of troglitazone caused I_sc to decrease gradually, and after 50 min, I_sc reached the peak of decrease. EC₅₀values and maximum response to I_sc in rat and human mucosa were 8.4 and 8.7 μM and 8.56 ± 1.0 and 8.00 ± 2.0 μA/cm², respectively. In an HCO₃⁻/CO₂-free system, the decrease in I_sc caused by troglitazone was 1.31 ± 0.83 μA/cm². When 10 mM acetazolamide was preadministered, the small decrease in I_sc evoked by troglitazone (20 μM) was 4.56 ± 0.22 μA/cm², whereas the preadministration of 100 μM amiloride and 100 nM tetrodotoxin did not influence the decrease in I_sc evoked by troglitazone. The serosal preadministration of 100 nM vasoactive intestinal peptide potently enhanced the decrease in I_scevoked by 20 μM troglitazone (21.1 ± 1.63 μA/cm²). The cyclic AMP contents of rat duodenal mucosa incubated with and without troglitazone (20 μM) for 50 min were 3.2 ± 0.25 and 5.8 ± 0.46 pmol/mg protein, respectively (P < .01). These results indicate that the ionic basis for the decrease in I_sc that is induced by troglitazone may be inhibition of electrogenic bicarbonate secretion. The alteration of intestinal ion transport by troglitazone could cause edema.