HYPOGLYCEMIC EFFECTS OF A NOVEL FATTY-ACID OXIDATION INHIBITOR IN RATS AND MONKEYS

Increased fatty acid oxidation contributes to hyperglycemia in patient s With non-insulin-dependent diabetes mellitus. To improve glucose hom eostasis in these patients, we have designed a novel, reversible inhib itor of carnitine palmitoyltransferase I (CPT I) that potently inhibit s fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose leve ls in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of greater than or e qual to 70%, as measured by beta-hydroxybutyrate levels, the end produ ct of beta-oxidation. In cynomolgus monkeys, comparable glucose loweri ng was achieved with more modest lowering of beta-hydroxybutyrate leve ls. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce car diac hypertrophy. This was in contrast to the irreversible CPT I inhib itor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of nov el hypoglycemic agents that inhibit fatty acid oxidation without induc ing cardiac hypertrophy.