Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus.

There are elevated fatty acid levels in non-insulin-dependent diabetes mellitus that are due to diminished insulin action in inhibiting fatty acid release from adipocytes. Insulin therapy and other inhibitors of fatty acid release from adipocytes (e.g., nicotinic acid) suppress these elevated fatty acid levels and bring about a reduction in hyperglycemia. One mechanism by which fatty acids may be causal in hyperglycemia is in stimulating gluconeogenesis in the liver in the postabsorptive state. Another mechanism is in attenuating glucose disposal in skeletal muscle in the fed state. Potential nonglycemia-related effects of fatty acids are in substrate utilization in the heart and lipid synthesis in the liver. Inhibition of fatty acid oxidation is useful in reducing hyperglycemia by inhibiting glucose production in humans. However, there is less evidence that such inhibition can be useful in increasing glucose utilization in muscle, as predicted by the Randle hypothesis. This, coupled with potential adverse effects on heart muscle, make liver targeting of fatty acid oxidation inhibitors an important factor in their potential for development. Although such agents have advantageous effects on lipid metabolism, overdosing can lead to adverse liver lipid effects via the same mechanism. These adverse liver lipid effects could be minimized by development of reversible inhibitors that allow fatty acid oxidation to occur only during the overnight fast. The potential usefulness of such agents is evident; however, no drug that meets these objectives has been developed.