Walter Mertz

Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables

Seventy-six normal, free-living subjects were given supplements of 200 micrograms chromium (Cr) in the form of chromic chloride or a placebo in a double-blind crossover study with 3-month experimental periods. Twenty of the 76 subjects had serum glucose concentrations greater than or equal to 100 mg/dL 90 minutes after a glucose challenge (1 g glucose per kilogram of body weight). Chromium supplementation significantly decreased (P less than 0.05) the 90-minute glucose concentration of these subjects from 135 +/- 9 to 116 +/- 11 mg/dL; fasting glucose concentrations also decreased significantly. The 90-minute serum glucose levels of the 35 subjects with glucose concentrations less than the fasting serum glucose level were increased significantly by Cr supplementation, from 71 +/- 1 to 81 +/- 4 mg/dL. Fasting and 90-minute serum glucose concentrations of the remaining subjects who displayed 90-minute glucose concentrations greater than fasting levels but less than 100 mg/dL were not affected by Cr supplementation. In this study, immunoreactive serum insulin concentration, body weight, lipids, and other selected clinical variables did not change significantly during Cr supplementation. These data demonstrate that Cr supplementation decreases the serum glucose levels of subjects with 90-minute glucose concentrations greater than or equal to 100 mg/dL following a glucose challenge, increases serum glucose levels of subjects with 90-minute glucose concentrations less than fasting levels, and has no effect on the serum glucose levels of subjects with 90-minute glucose values similar to but greater than fasting levels.

Chromium research from a distance: from 1959 to 1980.

More than 50 years of work have led to the recognition of trivalent chromium as an essential element. Shortly after its identification as an essential element in 1959, its interaction with insulin in vitro and in vivo was established, and the site of action identified as the insulin-sensitive cell membrane. Despite other early clinical successes with chromium supplementation, four major problems have influenced the rate of progress since then: 1) chromium analysis; 2) interaction of chromium with other dietary factors; 3) diagnosis of chromium status; and 4) other controversies, such as the carcinogenic potential of chromium (since disproved) and the lack of an effect on glucose tolerance even in chromium deficient organisms (now explained). These controversies have mostly dissipated as new knowledge integrated seemingly irreconcilable facts and opinions. It is now known that chromium may potentiate the action of insulin either by an effect on insulin dependent functions, or by maintaining these functions with less insulin, or by a combination of both. Despite much progress in the last 30 years, major challenges in chromium research remain, such as the development of practical methods for diagnosing chromium deficiency. Of several approaches for solving this problem, the most feasible might be to standardize the urinary chromium response following an insulinogenic challenge, such as an oral load of glucose or of glucose plus fructose (for maximal stimulation) with urine collection before and during the 2-hour test.

Chromium. History and nutritional importance.

The history of chromium as an essential nutrient is closely tied to the availability of analytical technology. When I joined my former teacher from the University of Mainz, Germany, at the National Institutes of Health in Bethesda, Maryland, he had perfected the technique of inducing and preventing by dietary means a fatal liver disease in rats, dietary necrotic liver degeneration. Because the animals died acutely from hypoglycemic shock, it became of interest to find out whether disturbances of carbohydrate metabolism were the primary consequence of deficiency of the then unidentified factor 3. It was fortunate that, at that time, 1953, reliable micromethods for blood glucose determinations became available, allowing the performance of whole glucose tolerance tests in rats. Such tests clearly demonstrated a progressive impairment of iv glucose tolerance soon after the animals were fed the experimental diets and long before they became visibly ill. For a time, the glucose tolerance test appeared to predict the fate of the experimental animals, substantially reducing the time it took to assay for factor 3 activity (1). In the course of purification of factor 3 activity from natural materials, such as brewers yeast or pork kidney powder, it became evident that the activity protecting against dietary necrotic liver degeneration could be separated from that maintaining normal glucose tolerance (2). Because at that time nei-

Glucose tolerance factor: an essential dietary agent

Abstract Glucose tolerance factor (GTF), the biologically active form of chromium, is an essential dietary agent that potentiates the action of insulin and thereby functions in regulating carbohydrate metabolism. Dietary trends that show increased consumption of more highly processed foods may be leading to deficiencies ofGTF and chromium in man.

Effect of making duplicate food collections on nutrient intakes calculated from diet records

In a 1-yr study in which food intakes were recorded daily, subjects were asked to make duplicate food collections for 1 wk during each of the four seasons. Mean calculated energy intake of the 29 subjects was 12.9% less during the food collection periods than the mean for the entire year (which included collection periods). There were also significant reductions in the reported intake of all nutrients during the collection periods. Protein, vitamin A, saturated fat, and cholesterol intakes were decreased to the greatest extent. The actual decrease in energy intake was greater for the males than for the females, but the percentage was the same (12.9%). The younger group of subjects (less than or equal to 35) decreased energy intake 16.8% and the older group (greater than 35) 8.8%. Comparison of intakes during collection periods with intakes the week before and the week after showed that 28 of the 29 subjects decreased their energy intake from 1.1 to 32.3%. These data suggest that intakes of subjects during food collection periods do not represent their habitual levels of intake reported throughout the year.

REVIEW OF THE SCIENTIFIC BASIS FOR ESTABLISHING THE ESSENTIALITY OF TRACE ELEMENTS

The recent Expert Consultation of World Health Organization (WHO)/Food and Agricultural Organization (FAO)/International Atomic Energy Agency (IAEA) defined essentiality of a trace element as follows: “An element is considered essential to an organism when reduction of its exposure below a certain limit results consistently in a reduction in a physiologically important function, or when the element is an integral part of an organic structure performing a vital function in the organism.” This definition omits a previous postulate that the mechanism of action of an essential trace element should be well defined; it also supersedes another criterion, once suggested for essentiality, a normal, rather than log-normal distribution of an element’s tissue concentrations. The Expert Consultation offers no generally applicable criteria for the physiological importance of functions, and that determination is left to expert groups charged with setting national and other nutritional recommendations. The use of the term “physiological” rather than “biochemical” strongly implies that neither changes of an element’s concentration nor of a specific enzyme function alone are proof of essentiality. Among physiologically important functions are growth, reproduction, longevity, and all metabolic and hormonal functions that bear a clear, inverse relation to disease risk. Finally, the term “consistent” states the need for independent confirmation of the original data, before an element can be recognized as essential. These definitions will be discussed as background for further discussions of our present knowledge of boron (B).

Evaluation of long-term dietary intakes of adults consuming self-selected diets.

Mean daily intakes of calories and 19 nutrients were calculated for 13 males and 16 females, ages 20 to 53 yr, who kept daily diet records for 1 yr. Mean daily caloric and 19 selected nutrient intakes of the subjects met or exceeded the 1980 recommended dietary allowances except for iron and calcium for females. Males had higher intakes than females for all nutrients studied except crude fiber, vitamin A, and vitamin C. However, nutrient density values were comparable for both sexes, except that the females had higher nutrient density values for vitamin A than did the males. The younger subjects had higher intakes of calories and saturated fat than the older ones. The younger males had higher intakes of total fat, saturated fat, and oleic acid than the older males. The consistency of reporting food intakes examined by applying a systematic sampling method designed for this study did not vary considerably when diet records kept over a long period of time were evaluated by four methods.

Chromium and its relation to carbohydrate metabolism

Chromium is an essential nutrient and can be expected to be effective only in the treatment or prevention of a deficiency. Chromium occurs in numerous foods in the form of a complex with nicotinic acid and, possibly, three amino acids. This complex is called glucose tolerance factor. In this form, chromium is better absorbed, it is excreted almost exclusively via the urine. Therefore, the measurement of daily urinary chromium excretion is a promising tool for the diagnosis of gross abnormalities in chromium metabolism in animals and man.

Interaction of the glucose tolerance factor (GTF) with insulin

Abstract Partially purified glucose tolerance factor (GTF) which had been extracted from Brewers yeast was mixed with 125 I-insulin, and the solution was chromatographed on Sephadex G-50. Similarly, 125 I-insulin which had not been reacted with GTF was chromatographed. Insulin reacted with GTF produced a significantly greater effect on glucose uptake in epididymal tissue than that of native insulin. When GTF, exclusive of insulin, was chromatographed, the fraction which potentiated insulin activity had an elution volume greater than that of insulin. These results demonstrate that GTF binds to insulin. When insulin was reacted with acetic anhydride under conditions which acetylate the α and e amino groups, GTF binding to insulin was inhibited. These results suggest that the α and e amino groups of insulin may be involved in the binding of GTF to insulin.

The newer essential trace elements, chromium, tin, vanadium, nickel and silicon

Introduction Although markedly different in their chemistry, mode of action, and effective levels, the newer essential trace elements have in common that they were first known for their toxic actions in excessive concentrations and that the induction of a dietary deficiency is very difficult. (Although not a trace element in the strict sense, silicon is included in the discussion because of its low concentration in the animal organism.) Deficiencies severe enough to cause death have not yet been demonstrated for any of these, and this fact has necessitated the adoption of a new, more liberal definition of essentiality. Chromium was identified as essential for maintenance of normal glucose metabolism in 1959. It is not surprising, therefore, that more biochemical and nutritional information is available for this element than for the others. The rapid sequence of discoveries identifying essential functions for new elements which began in I 970 was based on the concepts of the low-trace-metal environment and of the metal-free isolator system for raising animals (Schwarz, 1970). Through the application of these systems and with advances in trace element analytical techniques, the essentiality of four elements, tin, vanadium, nickel, and Si, was demonstrated within a period of only 3 years.