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Am J Physiol Regul Integr Comp Physiol 274: R524-R528, 1998;
0363-6119/98 $5.00
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Vol. 274, Issue 2, R524-R528, February 1998

Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys

Rhonda O. Deems, Robert C. Anderson, and James E. Foley

Metabolic and Cardiovascular Diseases, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936

Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyltransferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of >= 70%, as measured by beta -hydroxybutyrate levels, the end product of beta -oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of beta -hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor 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 novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.

non-insulin-dependent diabetes mellitus; carnitine palmitoyltransferase I; cardiac hypertrophy


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