MDL 29311, an analogue of probucol, administered to rats as a 1% dietary admixture for 2 wk before and 5 days after intravenous injection of 40 mg/kg of ALX significantly (P < 0.05) reduced plasma glucose (6.9 +/- 0.3 vs. 19.2 +/- 1.3 mM) and serum triglyceride (0.17 +/- 0.01 vs. 1.82 +/- 0.39 mM) levels in overnight-fasted ALX-plus-MDL 29311-administered rats vs. ALX-administered rats. A cross-over study indicated that MDL 29311 did not attenuate the diabetogenic action of ALX, but rather, directly lowered glucose and triglycerides. In rats injected intravenously with 45, 65, or 85 mg/kg of STZ and then administered control or MDL 29311 diet for 7 days, MDL 29311 decreased fasted plasma glucose to nondiabetic levels, decreased fasted and nonfasted plasma triglycerides by 49-79%, but did not affect plasma insulin levels. In STZ-induced (65 mg/kg) diabetic rats, MDL 29311 attenuated the increase in plasma nonesterified fatty acids during an 18-h fast; had little or no effect on glucagon, pyruvate, lactate, beta-hydroxybutyrate, acetoacetate, or cholesterol; and did not induce hypoglycemia in rats fasted up to 64 h. In nonfasted hyperinsulinemic db/db mice treated for 10 wk, MDL 29311 significantly lowered glucose levels by 14-40%, triglyceride levels by 31-63% and GHb from 8.0 to 5.4%, and had no consistent effect on plasma insulin levels. Because of its marked glucose- and lipid-lowering activity in both nonfasted hyperinsulinemic and fasted insulinopenic animals, MDL 29311 merits additional investigation as a potential antidiabetic agent.