Chromium for Type 2 Diabetes Mellitus and Weight Loss
Chromium for Type 2 Diabetes Mellitus and Weight Loss
By Jay Udani, MD, Ben Kavoussi, MS, Mary L. Hardy, MD. Dr. Udani is Assistant Clinical Professor at UCLA David Geffen School of Medicine, and Medical Director of the Integrative Medicine Program at Northridge Hospital, Northridge, CA; Mr. Kavoussi is a Biomedical Informatician at Medicus Research in Northridge, CA; and Dr. Hardy is Associate Director of UCLA Center for Dietary Supplement Research and Botanicals, and Medical Director at Cedars-Sinai Integrative Medicine Program in Los Angeles. They report no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Chromium(III), or Cr(III), is a micronutrient that plays an essential role in glucose and insulin homeostasis. Also known as trivalent chromium, it is widely available as a dietary supplement and is sold in various complexed forms such as chromium picolinate, chromium nicotinate, chromium citrate, chromium chloride, and high-chromium yeast.
The various chromium supplements are proven to differ in their absorption, bioavailability, and safety. The literature reports chromium nicotinate and chromium picolinate as being the most absorbable forms of Cr(III). However, as noted later in this article, there also exist safety concerns associated with chromium picolinate, because the picolinate moiety is believed to be mutagenic beyond a certain dose, and because picolinic acid alone has been shown to be a clastogen.1 Other Cr(III) compounds are believed to be relatively safe for human consumption.
Proposed Mechanism of Action
The physiological role of Cr(III) was first recognized in 1977, when a patient receiving total parenteral nutrition developed severe diabetes refractory to insulin. The symptoms of glucose intolerance completely resolved when chromium chloride was added to the patient's total parenteral nutrition.2 But until recently, not much was known about the mechanism of action of Cr(III) other than that it appeared to improve the effects of insulin and that it worked at the level of the cell membrane.3 The mechanism of action was then elucidated by the discovery of low-molecular weight chromium-binding substance, which binds Cr(III) and the insulin receptor, activating the cell's insulin receptor kinase activity.4,5 This leads to an increase in insulin sensitivity.
It has been shown that diabetic patients have an increased urinary excretion of chromium leading to plasma chromium deficiency,6 although tissue chromium levels do not correlate well with plasma levels. In chromium-deficiency states, peripheral cells become desensitized to insulin. The possible role of chromium in diabetes appears to be related to the insulin-resistant state often found in Type 2 diabetes. It is therefore believed that reversal of relative chromium deficiency may improve insulin sensitivity of target organs.
The only postulated weight-loss mechanism of chromium also involves the insulin-sensitization pathway. It is theoretically possible that by reducing insulin resistance, one may observe lower post-prandial insulin spikes, leading to less post-prandial hypoglycemia-induced hunger. In a small pilot study of patients with depression, the subpopulation of subjects with high levels of carbohydrate cravings benefited from relatively high doses of chromium (600 μg of elemental chromium), experiencing a significant reduction in carbohydrate craving.7
Human Studies
In reviewing the human data on Cr(III), only published studies or studies using chromium as a single ingredient were evaluated; studies in which chromium was part of a multi-ingredient product were excluded.
Studies were then graded according to the classification guidelines of evidence-based medicine (EBM), which are based on the strength of the evidence derived from their data-collection and research methodology. Grade M studies constitute the meta-analyses, a statistical method that combines, compares, and contrasts results obtained from several studies that address the same medical question. Grade A studies are randomized controlled trials and represent consistent and good-quality, patient-oriented evidence. Grade B studies present lesser-quality or limited-quality patient-oriented evidence, and consist of nonrandomized studies. These include comparisons made between current patients, or between current and former patients. Grade C studies are retrospective studies that use questionnaires and/or data already collected for other purposes. This methodology is often used when randomized controlled trial are unfeasible or unethical; for instance when one cannot deliberately expose subjects to trauma, toxins, infectious agents, or incurable diseases for the sake of research.
Blood Sugar and Insulin
Grade M Study. The only meta-analysis of chromium for glycemic control was published in 2002.8 The authors identified 20 randomized controlled clinical trials of chromium and its effects on glucose, insulin, or HbA1c. Fifteen of the trials were deemed of acceptable quality for inclusion in the meta-analysis and these trials included 618 subjects (193 diabetic and 425 healthy volunteers). When the data were combined in a meta-analysis, chromium supplementation did not alter glucose or insulin levels in healthy subjects. The data on diabetic subjects were inconclusive because the largest study (155 subjects from China) showed a positive impact on HbA1c, fasting blood sugar, and two-hour post-prandial glucose while the rest of the studies failed to show any improvement. The authors concluded that the data are inconclusive for diabetics and that further study is necessary. Because the doses of elemental chromium were not standardized across the different studies, the results of this meta-analysis are difficult to interpret.
Grade A Studies. The 1997 study from China that was included in the meta-analysis merits further comment.9 Significant differences in HbA1c, fasting blood sugar, and fasting insulin levels were observed with the low- and high-dose chromium groups compared with placebo at four months. What is noteworthy is the fact that this study used very high doses of total elemental chromium compared with other studies (200 μg and 1,000 μg of elemental chromium). This correlates approximately to dosages of 1,600 μg and 8,000 μg of chromium picolinate.
One other factor that makes this study difficult to generalize is the fact that it was performed in a Chinese population that may have unique levels of chromium deficiency due to dietary variations. In addition, due to the relative genetic homogeneity found in many regions of China, such a study may only represent a narrow perspective of the interactions between genes, diet, and disease. Because baseline chromium levels in this Chinese population were not measured, it is impossible to say that the degree of chromium deficiency in this diabetic population is the same as it would be in an American population. If this Chinese population had a greater degree of baseline chromium deficiency, supplementation would have had a greater effect.
Another study included in the meta-analysis but worth mentioning on its own was an eight-month randomized, double-blind, placebo-controlled trial of 29 subjects with insulin resistance (pre-diabetes) given 1,000 μg chromium picolinate per day (yielding at least 100 μg of elemental chromium).10 Significant improvements were seen in insulin sensitivity at four and eight months. Most noteworthy is the fact that the FDA issued a qualified health claim for chromium picolinate and insulin resistance based solely on this study.11 All other claims and all other studies related to any other claims for chromium picolinate were rejected by the FDA.
The only randomized clinical trial published after the meta-analysis included 40 subjects with impaired glucose tolerance who received either 400 μg twice a day (800 μg/d) of chromium picolinate or placebo for three months.12 No differences were seen in insulin or cholesterol between the two groups.
Grade B Studies. The same research group in China performed another study—a 10-month open-label study of 833 diabetics who received 500 μg elemental chromium (as 4,000 μg chromium picolinate approximately).13 According to the authors, study subjects experienced significant reductions in fasting and post-prandial glucose. Statistical P values were not provided. This study was not included in the meta-analysis.
A prospective open-label test of the glycemic index-lowering properties of chromium was published in 2004.14 In this study, 13 healthy subjects were given white bread alone or white bread with chromium picolinate (400 or 800 μg) taken 30 minutes before the meal. The glucose area under the curve was determined to calculate the glycemic index. The addition of chromium did lower the glycemic index of white bread in a non-dose dependent fashion by 23% with 400 μg (P = 0.053) and by 20% with 800 μg (P = 0.054). These values approached, but did not achieve, statistical significance.
Another 2004 study compared 1,000 μg of high-chromium yeast with placebo in reducing the oxidative stress of diabetic subjects as measured by thiobarbituric acid (TBARS) and by total antioxidant status (TAS) of three subgroups stratified by HbA1c.15 The abstract offers incomplete information and does not include the number of subjects enrolled, and the full text article was not available at the time of writing. TBARS was decreased in diabetic subjects and TAS level was increased in the most out-of-control diabetics (HbA1c > 8.5%), which the authors indicate correlates with improved overall antioxidant status in diabetics. This is a poorly reported trial that uses nonstandard measurements for antioxidant status; it should not be relied upon.
Weight Loss and Body Fat Loss
Grade M Study. A meta-analysis of chromium picolinate studies for weight loss was published in 2003.16 Although the authors identified 31 weight-loss studies, only 17 met the criteria for inclusion and of those, only 10 provided sufficient data for inclusion in the meta-analysis. When the data from the 10 trials were pooled, the result was a small but significant difference in favor of chromium picolinate (weight loss of 1.1 kg compared with placebo). Secondary analysis of data for body composition was available from seven of the pooled studies and showed a significant reduction in percentage of body fat (-1.2% in favor of chromium picolinate). There were no significant differences seen for lean body mass.
Grade A Studies. The majority of the effect found in the meta-analysis came from one trial, the 1996 trial of 154 patients.17 The allocation of dosage of chromium picolinate in this study was difficult to ascertain because subjects were allowed to consume a drink base containing 0, 100, and 200 μg of chromium picolinate and were asked to drink at least two servings of the drink base each day. Then they were asked to report how many servings of the drink base they consumed each day. The amount of chromium picolinate each subject consumed was calculated from their self-report of product usage. The results of this study showed a significant difference between the active and placebo groups regarding weight loss, percent body fat, and fat weight. Although these differences were statistically significant, they were not clinically significant, except for the fat weight reduction at the 400 μg dose (see Table 1).
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The methodology employed in the aforementioned study does not provide a standardized assessment of the dose of active product and could allow subjects to consume more than the assigned dosage. This study also does not address the possibility that if participants drank a great deal of liquid every day, they may have taken in less solid food and fewer calories, which would have obscured the real effect of chromium on weight loss.
The second largest randomized controlled study in the meta-analysis was performed by the same authors and included 122 subjects receiving 400 μg chromium picolinate (amounting to 50 μg of elemental chromium) or placebo for 90 days.18 The only statistically significant difference between the placebo and active group was the reduction in fat mass (-2.81 kg for chromium picolinate and -1.53 kg for placebo, P = 0.023). Body fat percentage and weight were not significantly different. A secondary analysis was performed in which estimated caloric intake and energy expenditure were taken into account. In this analysis, the differences between the active and placebo group all became statistically significant (see Table 2). This is certainly interesting; however, it was not the primary analysis and should be considered in the context of the fact that the primary analysis failed to show such changes.
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Grade C Study. A retrospective questionnaire-based study of 18,995 people between ages 53 and 57 looked at weight gain and chromium supplementation.19 Among respondents who were overweight or obese, those who took the most (the highest third) chromium supplementation (in any form) gained less weight over 10 years than those who took less chromium. There were several limitations to this study including reliance upon self-reported weights (both current and from 10 years ago). In addition, the study did not account for dietary chromium intake, nor did it quantify the dosage range of chromium that appeared to be effective.
Safety
Chromium occurs in both trivalent, Cr(III), and hexavalent, Cr(VI), forms. The debates over chromium toxicity almost exclusively concern Cr(VI), because ingestion of Cr(VI) is 10-100 times more toxic than ingestion of Cr(III) compounds.20
The Estimated Safe and Adequate Daily Dietary Intake of elemental Cr(III) has been set at 50-200 μg.21 Most diets contain less than 60% of the minimum suggested intake of 50 μg, suggesting dietary intake may not be sufficient.22 There have been several case reports and in vitro studies stipulating cytotoxicity and chromosomal damage associated with chromium picolinate, inferring that the safety of Cr(III) may be largely dependent on the ligand,1 and that chromium nicotinate, chromium citrate, and chromium chloride may be safer products than chromium picolinate; however, in animal models the latter seems to have a substantially higher absorption rate than other chromium compounds.23
Dosage
Dosage of the elemental Cr(III) is one of the most important considerations in the review of the literature.
Chromium picolinate (formula: Cr(C6H4NO2)3; molecular weight: 418.33 amu) contains 12.4% elemental Cr(III).24 Common dosages used, reported with one significant figure, are provided in Table 3.
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Efficacy Summary
When considering dosage and efficacy, it is worthwhile to separate glucose/insulin efficacy from weight-loss/fat-loss efficacy as structured above.
Glucose/Insulin Efficacy and Dosage. Although mechanistic data seem to support the fact that chromium is deficient in the serum of many people with diabetes, controversy exists as to whether this represents a true tissue deficiency of chromium. The data on improving control of glucose and insulin by using chromium in the treatment of diabetes are inconclusive and seem to be derived exclusively from a single and limited study in a Chinese population sample. It is unclear whether the sample has a greater degree of chromium deficiency in general, given its dietary restrictions and/or its nutritional genomics. This study used the highest dosage of elemental chromium (200-1,000 μg of elemental chromium derived from approximately 2,000 to 8,000 μg of chromium picolinate) and found a significant effect.9
Based on the significant effect obtained using a high dosage of chromium picolinate, when Gunton et al published a negative study on the use of chromium in diabetes using 800 μg chromium picolinate (100 μg of elemental chromium approximately),12 Nutrition 21 scientists published a response criticizing the study for using an insufficient dosage.24 When this same company applied to the FDA for a qualified health claim,11 the only claim allowed was related to reducing insulin resistance based on a study utilizing 500 μg per day of elemental chromium (4,000 μg chromium picolinate).
The ability to significantly impact glucose and insulin levels appears to require high amounts of elemental chromium in dosages ranging from 200 μg to 1,000 μg per day, which correlates approximately to chromium picolinate dosages of 2,000 μg to 8,000 μg.
Weight-Loss and Fat-Loss Efficacy Summary. The weight-loss data are even less robust than the glucose/insulin data. A meta-analysis by Pittler et al did show a significant difference when compared with placebo, but the amount of weight lost was too small to be clinically significant (1.1 kg difference). The percent body fat reduction reported by Pittler et al was statistically significant (1.2% difference between groups), but in reality such a small difference remains clinically insignificant.16 More importantly, the comparison between studies was not entirely accurate because it indiscriminately combined dosages of chromium picolinate and elemental chromium without taking into consideration the fact that chromium picolinate contains only 12.4% Cr(III), and that some studies have reported dosages of chromium picolinate when others have specified the amount elemental chromium used.
It is important to note that all weight-reduction studies have used dosages of total elemental chromium lower than those used in diabetes studies. The studies included in the meta-analysis used chromium picolinate in dosages ranging from 20 μg to 200 μg of elemental chromium. The two largest studies showed the largest effects, and both used a 400 μg dose of chromium picolinate when statistical significance was reached compared with placebo.17,18
Conclusion
The current research support is at best equivocal for the use of chromium as an aid in the treatment of diabetes and in weight and/or fat reduction. It would take a dosage of at least 4,800 μg chromium picolinate to improve insulin sensitivity and 8,000 μg chromium picolinate to reduce HbA1c and improve glucose levels. Small amounts of weight loss and fat loss may be possible at dosages of 400 μg chromium picolinate.
Replacing chromium in a known chromium-deficient population appears to have merit, but would require individual testing prior to initiating therapy to identify appropriate recipients of this treatment. Providing chromium supplementation to a population that is not chromium-deficient is unlikely to provide any specific benefit according to published literature to date.
Recommendation
In a diabetic population, there may be a role for chromium replacement as it may be depleted at faster rates compared with non-diabetics. In this population, the dose required for efficacy is at least 5,000 μg chromium picolinate, not the commonly used dose of 400 μg. Because the safety of chromium picolinate, specifically, has not been firmly established, it is recommended that other forms of chromium be employed. For weight loss, there are pooled data to support a statistically significant reduction in weight with chromium picolinate. However, the amount of weight loss is too small to be clinically significant; patients should focus instead on diet and lifestyle changes.
References
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24. Komorowski J, Juturu V. Chromium supplementation does not improve glucose tolerance, insulin sensitivity, or lipid profile: A randomized, placebo-controlled, double-blind trial of supplementation in subjects with impaired glucose tolerance: Response to Gunton et al. Diabetes Care 2005;28:1841-1842; author reply 1842-1843.
Udani J, et al. Chromium for Type 2 diabetes mellitus and weight loss. Altern Med Alert 2006;9(7):78-83.Subscribe Now for Access
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