Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus
Introduction
Although lifestyle modification combined with pharmacologic intervention is the primary strategy to meet glycemic targets in patients with type 2 diabetes mellitus (DM), alternative strategies, for example, nutritional supplementation with over-the-counter agents, continue to be extensively practiced by a large number of patients [1], [2]. There are more than 29 000 nutritional supplements available, and patients pay more than 12 billion dollars per year on these supplements [1], [2]. One supplement that remains controversial, particularly as it relates to improving glycemia, is chromium (Cr); and to date, routine clinical use has not been suggested [3]. However, several studies suggest that Cr may have more consistent effects in certain clinical states and conditions [4], [5], [6]. We reported that Cr supplementation, provided as 1000 μg/d as chromium picolinate (CrPic), improved glycemia, attenuated body weight gain, and enhanced insulin sensitivity in subjects with type 2 DM [6]. When compared with studies evaluating a similar dose and formulation of Cr, the data agreed with some, but not all, studies and suggested that subject characteristics may be important when assessing clinical response [6], [7], [8]. For example, Kleefstra et al [7] reported that Cr had no benefit in subjects with type 2 DM; but when compared with the studies suggesting a benefit, for example, Martin et al [6] and Wang et al [8], the subjects evaluated appeared to be more obese, were more advanced in their disease process, and were taking other medications, for example, metformin, in addition to high-dose insulin [7].
Given the recent observations, several questions regarding Cr remain. In particular, if Cr does improve glycemia, what are the mechanisms and which patient population is more likely to respond? In pilot studies, a major parameter predicting clinical response to Cr was the pretreatment insulin sensitivity; and additional studies suggest more consistent effects in the presence of insulin resistance and poorer glycemic control [5], [8]. Does Cr status of the patient determine who does or does not respond? What is the mechanism for the reported weight effects if indeed Cr modulates weight? In this regard, definitive energy balance studies, that is, dietary intake and energy expenditure (EE), using well-validated techniques have not been reported. As such, we sought to provide a comprehensive assessment of Cr supplementation by conducting randomized, double-blind, placebo-controlled evaluations in individuals with type 2 DM and representing a wide phenotype range and levels of insulin sensitivity. The overall effects of Cr were evaluated in addition to characterizing the specific differences in metabolic and physiologic parameters, that is, hepatic glucose production, Cr status, body weight/distribution, energy balance, and myocellular/intrahepatic lipid content, in those who did or did not respond clinically to Cr.
Section snippets
Study design
The design was double-blinded, randomized, and placebo-controlled. Type 2 DM subjects (age, 30-70 years) with a body mass index (BMI) range of 25 to 40 and with a fasting plasma glucose of at least 6.94 mmol/L (125 mg/dL) at the time of screening were evaluated. Exclusions were as follows: (1) medications known to affect glucose metabolism; (2) untreated thyroid or chronic liver, renal, or cardiovascular disease; and (3) a history of drug and/or alcohol abuse, or psychiatric disease prohibiting
Statistical analysis
The SAS (Cary, NC) mixed procedure was used for analysis of variance to detect the effects of Cr. The least square means were used to determine significance of all pairwise differences. Unpaired 2-tailed t test was used to determine statistical differences between treatments. Changes between pre- and posttreatment were also tested by t test with the hypothesis that change is null. Pearson correlation analysis was applied to analyze the relationships between assessments. Subjects randomized to
Results
A total of 137 subjects (70 Cr, 67 placebo) were evaluated for the entire cohort. As the overall goal was to evaluate a cohort of individuals with type 2 DM over a wide range of phenotypes, insulin sensitivity values were observed to range from extreme insulin resistance to clinically insulin sensitive. Specifically, insulin sensitivity in the entire cohort ranged from 0.96 to 10.7 mg/kg FFM per minute. There were no differences at baseline for clinical or biochemical characteristics of
Discussion
This study demonstrated that in a well-characterized cohort of type 2 DM subjects representing a wide phenotype, for example, lean to obese, and wide range of glycemic control, and including both insulin-sensitive and insulin-resistant subjects, there was not a consistent effect of Cr supplementation to improve insulin action or glycemic control. However, in subjects responding to Cr, the effect of Cr to improve glycemia was secondary to enhanced insulin sensitivity in muscle. There was no
Acknowledgment
Supported by R55 DK060126 and R01 DK060126 awarded to William T Cefalu, MD, and K23 DK068052 awarded to Corby K Martin, PhD. This work was partially supported by a Nutrition Obesity Research Center Grant 1P30 DK072476 entitled “Nutritional Programming: Environmental and Molecular Interactions” sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Chromium picolinate capsules and matching placebo were provided by Nutrition 21, Inc. Clinical trial registration no. NCT00398853
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Cited by (0)
All authors have made substantial contributions to the conception and design of the study, acquisition of data, and analysis and interpretation of data. In addition, all authors have reviewed the manuscript and provided important intellectual content and have approved the final submitted version. The manuscript is not under consideration elsewhere. There are no conflicts of interest with any of the authors and the submitted data. As the funding was from the National Institutes of Health, there is no problem with employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.