The discovery of a vitamin role for carnitine: The first 50 years.

The discovery of carnitine as an essential nutrient for one species of insect led rapidly to the elucidation of its central role in fat oxidation and its function in mitochondria. The history of this discovery illustrates how an unexpected result in one extremely narrow area of nutrition can lead to the opening up of an entire field in basic metabolism. Carnitine belongs to a special class of nutrients termed ‘‘quasivitamins’’ or ‘‘conditionally-essential’’ nutrients (1). These nutrients include taurine, lipoic acid, choline, and carnitine. They are normally synthesized by the mammalian organism, but may be required under special conditions, such as during long-term parenteral nutrition, by hemodialysis patients, or by premature infants. Choline, for instance, appears to be essential for adult men (2). Carnitine is used as a drug in cases of carnitine deficiency syndrome and is available as a dietary supplement; it is advertised as an aid to weight loss and improved exercise performance. As pointed out by Fraenkel and Friedman (3), the history of research into carnitine falls into 4 periods: first, the period of its simultaneous discovery as a constituent of vertebrate muscle, by Gulewitsch and Krimberg (4) and by Kutscher (5) in 1905; then, the period in which its chemical structure was established (6) (;1927); and next, the delineation of its major physiological function (1935–1965). Finally, the discoveries of its biosynthetic pathway, transport mechanisms, and primary and secondary carnitine deficiency and syndromes, occurred from 1961 to the present. Investigations of its metabolic role began in the 1940s, as a result of studies by Fraenkel (7) (Fig. 1) of the nutritional requirements of insects. What insects eat is not only of interest from a purely scientific viewpoint, but is, of course, of the greatest importance to agriculture in the search for ways to protect crops from insect damage. Early work on insect nutrition, reviewed by Trager (8,9), established that the basic food needs of insects were proteins, carbohydrates, minerals, and accessory food factors. Fraenkel and Blewett (10), working at the Imperial College in London, beginning in 1943, set out to determine the vitamin and sterol requirements of insects. For their studies, they selected 6 different insect species that were pests found in flour, 5 flour beetles and 1 species of moth. They all thrived on a diet of whole-wheat flour. Each test was performed with 20 larvae. Insects were fed a diet of purified casein (41%), glucose (41%), McCollum’s salt mixture (1%), cholesterol (1%), yeast or the equivalent of yeast extract (4%), and water (12%). The authors gave no explanation for using such high levels of protein beyond stating: ‘‘We do not know whether 15-20% casein would be sufficient.To be on the safe side, the quantity of protein was increased’’ (10). In earlier work, McCay (11) used insect diets containing between 15 and 30% casein. The total number of pupae formed from the larvae, or adults surviving, was plotted against time, resulting in curves of different steepness, according to the completeness of the diets (Fig. 2). Both the soluble and the insoluble fractions of yeast were found to be essential, as was cholesterol. Although whole-wheat flour does not contain cholesterol, earlier work by the authors (12) determined that the related steroid sitosterol, present in the wheat germ (13), was as effective as cholesterol for survival of the insects. Fat was not required. In later work (14), it was established that yeast could be replaced by a mixture of thiamin, riboflavin, nicotinic acid, biotin, and folic acid. The fatsoluble vitamins A, D, E, and K were not required. Omission of choline resulted in a somewhat reduced growth rate. One particular species of mealworm, Tenebrio molitor, required an additional substance for survival.