Robert C. Anderson

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

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 palmitoyl-transferase 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 > or = 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.

Pharmacological Strategies for Reduction of Lipid Availability

The chronic elevation of circulating free fatty acid (FFA) levels is associated with insulin resistance.’ In normal individuals, excess energy is converted to FFAs by the liver and stored as triglyceride in adipocytes. The stored energy can be mobilized as needed via an increase in the rate of FFA release from the adipocytes. However, if the balance between storage and release is disturbed such that the FFAs become chronically elevated, insulin resistance is usually manifest. Elevated FFA levels have been implicated in inducing metabolic derangements. For example, over 30 years ago, Randle demonstrated that FFAs have an impact on peripheral glucose utilization in muscle, principally via a FFA-induced suppression of pyruvate dehydrogenase (PDH).* Felber has recently shown that FFAs may be playing a role in glycogen storage3 and Grill has suggested that they have an important role in regulating beta-cell function and thereby altering insulin secretion profile^.^ Furthermore, recent studies by Bergman demonstrate that lowering of circulating FFAs is required for suppression of hepatic glucose production following a meal.5 The causative role of FFAs in the development or maintenance of insulin resistance has been difficult to assess. One reason for this could be that measurement of circulating FFA levels may be an inadequate measure of the role of FFAs since stored triglycerides and local fluxes may be major factors as well. In a normal individual, the stored triglyceride in tissues such as the liver, the muscle, and even the islet is relatively low. However, with chronic elevation of circulating FFA, as occurs in obesity, the triglyceride content of all of these tissues is predicted to be higher than normal, so local storage and release of FFAs may become important. One may ask the following question: “If the circulating FFAs were reduced, would insulin sensitivity improve?” Acute experiments in humans suggest that the answer is no. However, such conclusions may be flawed because the locally stored triglyc-