Essentiality and Metabolic Functions of Chromium

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The essentiality of trivalent Cr in human nutrition was documented in 1977 when diabetic signs and symptoms of a patient on total parenteral nutrition (TPN) were reversed by supplemental Cr. Diabetic symptoms, including elevated blood glucose, weight loss, impaired nerve conduction, brain disorders, and abnormal respiratory quotient, that were refractory to exogenous insulin were reversed following increased intake of the essential nutrient Cr. Upon daily addition of supplemental Cr to the patient's TPN solution for 2 weeks, diabetic symptoms were alleviated and exogenous insulin requirement declined from 45 units per day to zero. These findings have been repeated and documented in the scientific literature on several occasions.

Signs and symptoms of Cr deficiency listed in Table 1 are not limited to subjects on TPN. Improvements in glucose and/or lipid concentrations have been reported in children with protein calorie malnutrition; the elderly; people with type 1 and type 2 DM, hypoglycemia, and marginally impaired glucose tolerance; and numerous animal species.

The hallmark sign of marginal Cr deficiency is impaired glucose tolerance. The effects of Cr on people with high, low, and normal glucose tolerance as well as diabetes are illustrated in Figure 1. Chromium leads to a decrease in blood glucose in people with elevated blood sugar and an increase in those with low blood sugar due to its role in normalizing insulin. In the presence of Cr in a physiologically active form, insulin is more efficient and much lower levels of insulin are required. During periods of elevated blood glucose, more efficient insulin leads to a decrease in blood glucose. In people with low blood sugar, reactive hypoglycemia, more efficient insulin leads to a rapid rise in response to a glucose challenge and a more rapid return to baseline values. This leads to less of a decline in

Table 1 Signs and symptoms of Cr deficiency

Function

Animals

Table 1 Signs and symptoms of Cr deficiency

Function

Animals

Impaired glucose tolerance

Human, rat, mouse, squirrel

monkey, guinea pig, cattle

Elevated circulating insulin

Human, rat, pig, cattle

Glycosuria

Human, rat

Fasting hyperglycemia

Human, rat, mouse

Impaired growth

Human, rat, mouse, turkey

Hypoglycemia

Human

Elevated serum cholesterol

Human, rat, mouse, cattle, pig

and triglycerides

Increased incidence of

Rabbit, rat, mouse

aortic plaques

Increased aortic intimal

Rabbit

plaque area

Nerve disorders

Human

Brain disorders

Human

Corneal lesions

Rat, squirrel monkey

Ocular eye pressure

Human

Decreased fertility and

Rat

sperm count

Decreased longevity

Rat, mouse

Decreased insulin binding

Human

Decreased insulin receptor

Human

number

Decreased lean body

Human, pig, rat

mass

Elevated percent body fat

Human, pig

Impaired humoral immune

Cattle

response

Increased morbidity

Cattle

Gestational diabetes

Human

Steroid-induced diabetes

Human

Atypical depression

Human

Adapted from Anderson RA (1998) Chromium, glucose intolerance and diabetes. Journal of the American College of Nutrition 17: 548-555.

Adapted from Anderson RA (1998) Chromium, glucose intolerance and diabetes. Journal of the American College of Nutrition 17: 548-555.

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Figure 1 Response to supplemental Cr of people with hyperglycemia, hypoglycemia, optimal glycemia (control), and type 2 diabetes mellitus (DM). The minimal amount of Cr usually showing beneficial effects in people with high or low blood sugar is 200 mg per day. People with diabetes require 400-600 mg per day or more. Bars with different superscripts denote differences at p < 0.05.

hypoglycemic glucose values. Supplemental Cr also leads to increased insulin binding and increased insulin receptor number, and evidence suggests that Cr may be involved in the phosphorylation-dephosphorylation of the insulin receptor proteins. Chromium activates insulin receptor kinase, the enzyme that phosphorylates the insulin receptor, leading to activation of insulin function, and it appears to inhibit the phosphatase enzyme that deactivates insulin function.

Recent advances in Cr nutrition research include the demonstration of an inverse relationship between toenail Cr and cardiovascular disease (CVD) in studies from the United States and Europe, supporting studies indicating that people with CVD tend to have lower levels of serum and tissue Cr and also substantiating the beneficial effects of supplemental Cr on blood cholesterol, triglycerides, and high-density lipoprotein cholesterol. Supplemental Cr as chromium picolinate (the most common form of supplemental Cr) was shown to be effective in the treatment of depression. Preliminary studies suggest that the effects of Cr are greater than those of any drugs used in the treatment of atypical depression. Supplemental Cr is also free of side effects associated with drugs, which are often quite serious in the treatment of depression. Studies also show that Cr is beneficial in the reversal of polycystic ovarian syndrome, gestational diabetes, and steroid-induced associated with administration of steroids such as prednisone given as antiinflammatory agents in the treatment of arthritis, asthma, allergies, and related diseases.

Response to Cr is due to not only the Cr status of the subjects but also the forms and amount of Cr consumed. Subjects with diabetes or glucose intolerance who consume 200 mg daily of supplemental Cr or less often do not respond to supplemental Cr, but they may respond to 400-600 mg daily or more. A dose response to Cr for subjects with type 2 DM is shown in Figure 2. Subjects had been diagnosed with diabetes for approximately 5 years and had taken no Cr supplements. There was a progressive decline in the hemoglobin A1c after 2 and 4 months of consuming 200 or 1000 mg daily of Cr as Cr picolinate, respectively. There were also dose-dependent improvements in glucose, insulin, and cholesterol. These results were confirmed in a separate double-blind, placebo-controlled study.

The responses to Cr are difficult to predict and the phenotypic characteristics of the individual may be important. Phenotype is also important in insulin signaling and may explain, in part, the wide range a

Figure 2 Chromium effects on hemoglobin A1C and 2-h insulin. The study involved chromium supplementation (200 or 1000 mg/day) for 4 months in 180 people with type 2 diabetes mellitus. Bars with different superscripts denote differences at p <0.05. (Adapted from Anderson RA, Cheng N, Bryden NA et al. (1997) Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46: 1786-1791.)

Figure 2 Chromium effects on hemoglobin A1C and 2-h insulin. The study involved chromium supplementation (200 or 1000 mg/day) for 4 months in 180 people with type 2 diabetes mellitus. Bars with different superscripts denote differences at p <0.05. (Adapted from Anderson RA, Cheng N, Bryden NA et al. (1997) Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46: 1786-1791.)

of individual responses to Cr supplementation. Data demonstrate that Cr has beneficial effects in insulin-resistant obese but not lean JCR:LA corpulent rats, which are used as a model for insulin resistance. Although Cr had no effect on the weight of lean and obese rats, obese rats consuming supplemental Cr displayed lower insulin, improved glucose control, and increased phosphoinositol-3-kinase activity. This work documents a specific effect of Cr in a key control site in the insulin signaling pathway, which is the system responsible for the overall control of sugar, fat, and energy metabolism.

Chromium and Stress

Stresses that have been shown to alter Cr metabolism in humans are glucose loading, high simple sugar diets, lactation, infection, acute exercise, chronic exercise, and physical trauma. Urinary losses can be used as a measure of the response to stress since once Cr is mobilized in response to stress it is not reabsorbed by the kidney but is lost in the urine. The degree of stress as measured by the stress hormone, cortisol, is correlated with the amount of Cr lost in the urine.

The administration of glucocorticoids also leads to increased urinary Cr losses as well as insulin resistance. These steroids are often employed as antiinflammatory agents in the treatment of common chronic diseases, such as asthma, allergies, and arthritis, and they are also administered following organ transplantation, but a side effect of gluco-corticoid administration is steroid-induced diabetes.

The mechanisms responsible for steroid-induced diabetes are unknown, but decreased insulin sensitivity is an overlying cause. Impaired Cr metabolism also appears to be a related cause since supplementation of 50 people who had uncontrolled steroid-induced diabetes with Cr for 10 days resulted in the reversal of the steroid-induced diabetes in 47 of these patients, with no adverse side effects, and a decrease of at least 50% of the medication needed prior to the supplementation of Cr.

Dietary Intake and Requirements of Chromium

A panel on micronutrients convened by the Institute of Medicine defined an adequate intake for Cr of 25 mg for women and 35 mg for men 19-50 years old and 20 mg for women and 30 mg for men older than age 50 years. Adequate intake is ''the recommended average daily intake based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate— used when an RDA cannot be determined.'' The adequate intake for Cr is nearly identical to the average Cr intake but much lower than earlier committee recommendations.

It is unclear why the adequate intake for Cr should be lower for people older than 50 years when the primary function of Cr is to combat problems associated with insulin and glucose metabolism, which tend to increase with age. Indices of Cr status, such as the Cr content of hair, sweat, and urine, were shown to decrease with age in a study of more than 40 000 people. The recommended intakes in France are higher and more in line with studies demonstrating that a large segment of the population may not be consuming adequate Cr. The French Conseil National d'Etudes et de Recherche sur la nutrition et l'Alimentation has proposed daily intakes of 55 mg for adult French women 19-65 years old and 60 mg/day for those older than 65 years and 65 and 70 mg, respectively, for men. Since Cr losses are increased by high intake of simple sugars such as glucose, sucrose, and fructose, modern diets high in these sugars appear to be increasing the requirements for Cr.

More than 34 studies have reported beneficial effects of supplemental Cr for people with blood glucose values ranging from hypoglycemia to diabetes when consuming diets of average Cr content. In a controlled diet study, consumption of diets in the lowest quartile of normal Cr intakes, but near the new adequate intakes, led to detrimental effects on glucose and insulin in subjects with marginally impaired glucose tolerance (90-minute glucose between 5.6 and 11.1mmol/l or 100-200 mg/dl) following an oral glucose load of 1 g/kg body weight. The average person older than 25 years of age has blood glucose in this range. Consumption of these same diets by people with good glucose tolerance (90-minute glucose less than 5.6 mmol/l) did not lead to changes in glucose and insulin variables. This is consistent with previous studies demonstrating that the requirement for Cr is related to the degree of glucose intolerance and demonstrates that an intake of 20 mg Cr per day is not adequate for people with decreased insulin sensitivity, such as those with marginally impaired glucose tolerance, and certainly not for those with impaired glucose tolerance or diabetes.

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