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Chromium, Glucose Tolerance, and Diabetes

RICHARD A. ANDERSON

Vitamin and ?4inerai Nutrition Laboratory, Beltsville Human Nutrition Research Center, US Department of Agriculture, ARS,

Beltsville, ND 20705

Received January 31, 1991; Accepted February 20, 1991

Chromium functions in maintaining normal glucose tolerance primarily by regulating insulin action. In the presence of sufficient amounts of chromium, in a biologically active form, much lower amounts of insulin are required.

At the onset of maturity-onset diabetes, there is no decline in insulin as in juvenile or type I diabetes, but usually a gradual increase in circulat- ing insulin levels. Insulin efficiency declines, and as the efficiency of insulin declines, the body responds by producing more insulin to control blood glucose. There is obviously a limit to this adaptation, and severely impaired glucose tolerance and ultimately maturity-onset diabetes may develop.

Chromium functions by increasing the activity of insulin and, there- fore, reducing the amount of insulin required to control blood sugar and related processes. It is important to keep insulin at low levels to prevent secondary signs of diabetes (1). For example, arterial plaque formation is an insulin-sensitive process, and increased levels of circulating insulin often stimulate increased plaque formation leading to arteriosclerosis.

The role of chromium in diabetes should be considered primarily as a means of preventing maturity-onset diabetes rather than as a "cure" or treatment. There is very strong evidence that insufficient dietary chromi- um leads to impaired glucose tolerance that can be alleviated by supple- mental chromium. Since essentially all those who go on to develop maturity-onset diabetes will have initially impaired glucose tolerance, prevention of impaired glucose tolerance should lead to prevention of maturity-onset diabetes. Impaired glucose tolerance is the leading indica-

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tor of maturity-onset diabetes (2). However, not everyone with impaired glucose tolerance will go on to develop maturity-onset diabetes.

GLUCOSE VARIABLES IMPROVED BY CHROMIUM

The hallmark sign of chromium deficiency is impaired glucose toler- ance. This is usually the most reproducible variable to improve following improved chromium nutrition. Fasting glucose, circulating insulin, insu- lin binding, circulating glucagon, and 13-cell sensitivity improve with increased chromium status (3). Hypoglycemic symptoms, glucose val- ues, insulin binding, and insulin receptor number also improve in hypo- glycemic patients following chromium supplementation (4). Beneficial effects of supplemental chromium on lipid variables will be discussed elsewhere.

CHROMIUM AND GLUCOSE INTOLERANCE

Response to chromium is related to degree of glucose intolerance. Subjects with hypoglycemia, hyperglycemia, and maturity-onset dia- betes all have been shown to respond to supplemental chromium (3). Subjects with normal glucose tolerance who display no detectable signs of marginal chromium deficiency do not respond to supplemental chro- mium. These subjects are presumably getting adequate amounts of di- etary chromium and, therefore, do not respond to additional chromium.

Impaired glucose tolerance of six malnourished Jordanian infants and six from Nigeria improved within 18 h of a single oral dose of 250 p~g of chromium as chromium chloride (5). There were no significant im- provements in glucose removal rates of five children from each area who were not given supplemental chromium. A similar study involving mal- nourished children in Egypt reported no beneficial effects of supplemen- tal chromium on glucose tolerance (6). However, those children were consuming water and medications that were high in chromium and, therefore, would not be expected to respond to additional chromium. Glucose removal rates of 9 of 14 marasmic Turkish children also im- proved following chromium supplementation (7). Response of young children to chromium is usually within 18 h of chromium supplementa- tion.

Adults usually respond to chromium within weeks. Doisy et al. (8) reported a reduction in endogenous insulin output during a glucose tolerance test in young (20-25 yr) normal subjects following supplemen- tation with chromium in 10 g brewer's yeast daily for 1 mo. Upon closer examination of their data, subjects did have 90-min glucose >100 mg/dL (5.56 retool/L). According to the criteria of Anderson et al. (9) (90-rain

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Chromium and Glucose Metabolism 21

glucose >100 mg/dL), these subjects would have been predicted and, in fact, did respond to supplemental chromium. Glucose tolerance of 18 out of 20 subjects, 21-69 yr, with 90-min glucose >100 mg/dL improved following 3 mo of supplementation with 200 i~g of inorganic chromium (9). Fasting glucose also improved in these subjects. Glucose tolerance of eight males, 32-61-yr-old rotary club members, improved following 6 wk of supplementation with 200 b~g chromium as chromium chloride (10). Glucose values increased after 12 wk, but were still lower than prestudy values.

Glucose tolerance declines with age (2). Chromium status also ap- pears to decline with age (3). The development of overt signs of chromi- um deficiency, such as maturity-onset diabetes and cardiovascular dis- eases, often takes decades. Therefore, the association of marginal chromium status with impaired glucose and lipid metabolism of the elderly has been evaluated in several chromium nutrition studies. Re- cent, well-controlled, double-blind studies have been completed to sub- stantiate earlier results that reported that glucose tolerance of roughly half of the elderly subjects given either supplemental inorganic chromi- um or high chromium yeast samples improved. Offenbacher and Pi- Sunyer (11) reported improved glucose tolerance and insulin sensitivity in elderly subjects following supplementation with chromium-rich brewer's yeast. Glucose tolerance of controls receiving a chromium-poor torula yeast supplement was unchanged. In a followup study, glucose tolerance of 23 elderly free-living subjects was not improved by 200 >g of chromium as CrC13 or 5 g of brewer's yeast (12). However, subjects in the followup study were eating well-balanced diets containing 100% of the Recommended Dietary Allowances for eight nutrients with a mean chro- mium intake of more than 37 b~g/d. That study is not a negative study reporting no beneficial effects of supplemental chromium, but rather a positive result substantiating the postulate that chromium functions as a nutrient and not a therapeutic agent. If one is consuming sufficient amounts of a nutrient, additional intake should not lead to improved health.

Glucose tolerance of elderly women (59-82 yr) with 120-min glucose >100 mg/dL also improved following supplementation with 200 p.g of chromium as CrCI 3 (13). Glucose tolerance as well as [3-cell sensitivity, measured using glucose clamp technique, have also been shown to improve in elderly subjects following chromium supplementation with 200 I~g Cr as CrCI 3 for 12 wk (14).

Fasting glucose and glucose tolerance of elderly subjects also im- proved following daily supplementation with 200 i~g of Cr as CrC13 plus 100 mg of nicotinic acid, but not with chromium alone (15). That study may help explain why some subjects do not respond to supplemental chromium, namely subjects who are not only low in chromium, but also nicotinic acid, a postulated component of the biologically active form of chromium.

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22 Anderson

CHROMIUM AND DIABETES

Insulin-requiring diabetics absorb significantly more chromium than normal, elderly, or maturity-onset diabetics (8). Accompanying the in- creased chromium absorption, insulin-requiring diabetics also display increased urinary chromium excretion. Despite increased absorption, tissue and hair chromium concentrations of diabetics are lower.

Insulin-requiring subjects appear to display an increased require- ment for chromium that is manifest in increased chromium absorption, but once the chromium is absorbed, it is not utilized, but rapidly excreted in the urine. Some diabetics appear to lose the ability to convert inorganic chromium to a usable form and are therefore dependent upon performed physiologically active chromium complexes found in some foods (16). This may help explain the erratic shifts in insulin requirements of brittle diabetics. On days when little or no physiologically active forms of chromium are consumed, the insulin requirement would be high. How- ever, when significant amounts of chromium are consumed in a usable form, the insulin requirement would be low owing to the significant insulin-potentiating activity of biologically active chromium complexes.

Diabetic mice also lose the ability to convert inorganic chromium to a usable form (17). Supplementation of inorganic chromium to diabetic mice was without effect, whereas the addition of chromium, in a biolog- ically active form, caused a reduction in glucose to normal levels.

CHROMIUM IN THE TREATMENT OF DIABETES

The large majority of the subjects with marginally impaired glucose tolerance respond to supplementation with 200 ~g of inorganic chromi- um, whereas diabetic subjects may require greater levels or chromium in a biologically active form. In our last three human studies involving subjects with impaired glucose tolerance, 18 of 20 (9), seven of eight (18), and eight of nine (19) subjects responded to supplemental chromium with improved glucose tolerance.

Studies involving diabetic subjects often report lower percentages of improved subjects following chromium supplementation (see review, 20). Glinsmann and Mertz (21) reported that three of six diabetics improved after long-term supplementation with inorganic chromium, but not after 1 wk. Sixty days of supplementation with 500 ~g inorganic chromium/d led to decreased glucose and insulin in 12 maturity-onset diabetics (22). Doisy et al. (8) reported reductions in insulin requirement of 20 to 45 U daily in five diabetics whose daily insulin requirement ranged from 60- 130 U over a 1- to 2-mo period of supplementation with high chromium yeast. Impaired glucose tolerance of offspring of insulin-dependent dia- betics also returned to normal following supplementation.

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Chromium and Glucose Metabolism 23

Fasting blood glucose of 13 diabetic patients on either exogenous insulin or oral hypoglycemic agents dropped from 14.4 mmol/L (259 mg/ dL) to 6.6 (119 mg/dL) following 2-4 mo of supplementation with 600 b~g of chromium as chromium chloride (23). The treatment with either exog- enous insulin or hypoglycemic drugs was reduced in 5 of the 13 patients on chromium, whereas treatment rose in 4 of 13 patients receiving placebo. Glucose of patients on placebo did not change significantly over the 4 mo of the study. Sixty-minute insulin of ten noninsulin-dependent diabetics decreased following 6 wk of supplementation with 200 btg of inorganic chromium (24). Changes in other parameters were not signifi- cant. During a 6-wk period, fasting blood glucose decreased an average of 32 mg/dL (18%), and hemoglobin AjC (glycosylated hemoglobin) decreased 1.2 mg/dL (10%) of 11 noninsulin-dependent diabetic subjects consuming 200 ~g of chromium daily as chromium picolinate (25).

Diabetic symptoms of patients on total parenteral nutrition (TPN) have also been shown to return to normal following addition of inorganic chromium to TPN solutions (26). A female patient who displayed severe diabetic symptoms, even while receiving 50 U insulin/d, returned to normal upon addition of 250 bLg of inorganic chromium to her TPN solutions. Exogenous insulin requirement dropped from 50 U/d to 0. This work has subsequently been verified (27,28).

Not all studies involving diabetics reported beneficial effects of sup- plemental chromium (see review, 20). Response to supplemental chromi- um appears to be related to stage of diabetes, form and amount of supplemental chromium, duration of supplementation and chromium status of subjects. Abnormal glucose tolerance of diabetics is the result of a number of causes in addition to insufficient dietary chromium. Since chromium is a nutrient and not a therapeutic agent, only those subjects whose impaired glucose metabolism is related to dietary chromium will respond to improved chromium nutrition.

SUMMARY

Chromium functions in maintaining normal glucose tolerance pri- marily by regulating insulin action. In the presence of optimal amounts of biologically active chromium, much lower amounts of insulin are required. Glucose intolerance, related to insufficient dietary chromium, appears to be widespread. Improved chromium nutrition leads to im- proved sugar metabolism in hypoglycemics, hyperglycemics, and diabet- ics.

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