MDL-29311 - ANTIOXIDANT WITH MARKED LIPID-LOWERING AND GLUCOSE-LOWERING ACTIVITY IN DIABETIC RATS AND MICE

MDL 29311, an analogue of probucol, administered to rats as a 1% dieta ry 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 2931 1 - a dministered rats vs. ALX-administered rats. A cross-over study indicat ed that MDL 29311 did not attenuate the diabetogenic action of ALX, bu t rather, directly lowered glucose and triglycerides. In rats injected intravenously with 45, 65, or 85 mg/kg of STZ and then administered c ontrol 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 increas e in plasma nonesterified fatty acids during an 18-h fast; had little or no effect on glucagon, pyruvate, lactate, beta-hydroxybutyrate, ace toacetate, or cholesterol; and did not induce hypoglycemia in rats fas ted up to 64 h. In nonfasted hyperinsulinemic db/db mice treated for 1 0 wk, MDL 29311 significantly lowered glucose levels by 14-40%, trigly ceride levels by 31-63% and GHb from 8.0 to 5.4%, and had no consisten t effect on plasma insulin levels. Because of its marked glucose-and l ipid-lowering activity in both nonfasted hyperinsulinemic and fasted i nsulinopenic animals, MDL 29311 merits additional investigation as a p otential antidiabetic agent.