Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an ω-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic ω-6 fatty acids from safflower oil with long-chain polyunsaturated ω-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus.