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Considerable controversy exists regarding use of chromium (Cr) supplementation to modulate carbohydrate metabolism in subjects with diabetes. Recently, we reported that Cr supplementation, provided as 1000 ug/day as Cr picolinate, enhanced insulin sensitivity in subjects with Type 2 diabetes. Our data agreed with some, but not all, studies that evaluated a similar dose and formulation in Type 2 diabetes and suggested that subject selection and characteristics may be important considerations when assessing the clinical response. Thus, the goal of this study was to assess which metabolic or clinical characteristics, when obtained at baseline, best determine a clinical response to Cr when assessing changes in insulin sensitivity.
Seventy-three subjects with Type 2 diabetes were assessed in a double-blinded, randomized, placebo-controlled study. Subjects were assessed at baseline for glycemic control with HbA1c measures, oral glucose tolerance tests, and body weight and body fat measures (DEXA). After baseline, insulin sensitivity in vivo was assessed with use of hyperinsulinemic-euglycemic clamps. After the baseline clamp, subjects were randomized to receive Cr supplementation (1000 ug Cr/day provided as chromium picolinate) or placebo daily for 6 months. All study parameters were repeated after 6 months. The relationship of the baseline characteristics of the study subjects to the change in insulin sensitivity was determined.
63% of the subjects with Type 2 diabetes responded to the Cr treatment as compared to 30% with placebo. The only subject variable significantly associated with the clinical response to Cr was the baseline insulin sensitivity, as assessed with the hyperinsulinemic-euglycemic clamp (partial R2 = .4038) (p = .0004).
Subject phenotype appears to be very important when assessing the clinical response to Cr as baseline insulin sensitivity was found to account for nearly 40% of the variance in the clinical response to Cr
It is well observed in clinical trials that the measured response to an identical pharmacologic or lifestyle intervention will vary greatly among individuals. The reasons that explain a minimal as opposed to a very robust effect for subjects provided the same clinical intervention is not precisely known, but may be secondary to differences in genetic or physiologic makeup, in addition to differences in other subject characteristics. Such an observation may partially explain the considerable controversy that exists regarding use of chromium (Cr) supplementation to modulate carbohydrate metabolism in subjects with diabetes. In part, the controversy regarding the differences reported for Cr's effect in humans stems from the lack of definitive randomized trials, the lack of “gold standard” techniques to assess glucose metabolism, the use of differing doses and formulations, and the study of heterogeneous study populations (1). We recently reported that Cr supplementation, provided as 1000 ug/day as Cr picolinate, enhanced insulin sensitivity in subjects with Type 2 diabetes (2). However, our data agreed with some, but not all, studies that evaluated a similar dose and formulation in subjects with Type 2 diabetes (3,4). We concluded that patient selection may be an important consideration when assessing the clinical response to this nutritional supplement (2). If a specific patient phenotype is shown to be more responsive to Cr, or alternatively, that a particular characteristic suggests that a patient is not likely to respond, such information would prove clinically invaluable. Therefore, the goal of this study was to assess which metabolic or clinical patient factors, when obtained at baseline, appear to best determine the clinical response to Cr. In order to accomplish our goal, we assessed insulin sensitivity with use of hyperinsulinemic-euglycemic clamps before and after a specified period of Cr supplementation in subjects with Type 2 diabetes. We then determined which subject characteristic accounted for the greatest contribution to the change in insulin sensitivity.
Subjects were required to have Type 2 diabetes for more than six months, an age range of 25-70 years and a fasting glucose ≥ 125 mg/dl at time of screening. All procedures were approved and conducted in strict compliance with institutional human research guidelines.
The evaluations were double-blinded, randomized, and placebo-controlled. After entry criteria had been met, each subject met with the study nutritionist where instructions were provided for a weight maintenance diet. During the baseline period of 4 weeks, measures consisting of glycated hemoglobin, oral glucose tolerance testing (OGTT), body weight and % body fat were obtained. Forty-eight subjects had baseline measures assessed while on dietary therapy only. An additional twenty-five subjects had baseline measures assessed while on maintenance sulfonylurea therapy. Specifically, these subjects were evaluated only after a three month period during which all subjects received stable doses of glipizide gits at 5 mg/day. Subjects are part of an ongoing double-blinded, randomized clinical trial supported by the National Institute of Health that is evaluating the effect of chromium on insulin sensitivity and assessing the specific cellular mechanism of action. No subject was studied while maintained on agents known to affect insulin sensitivity, i.e. metformin or thiazolidinediones. After completing all baseline measures, subjects were then admitted to the inpatient unit for assessment of insulin sensitivity with use of hyperinsulinemic-euglycemic clamps. After completion of the clamp procedure and assessment of baseline insulin sensitivity, subjects were randomized to receive either two 500 ug capsules of chromium provided as chromium picolinate (CrPic) or two placebo capsules that were identical in physical characteristics. Subjects took assigned study capsules daily for 6 months. The chromium picolinate formulation was selected for these studies based on reports that it has a higher bioavailability compared to other formulations (1). Subjects returned to clinic monthly for assessment of compliance of study medication, to receive new monthly allotment of study capsules, vital sign recording and adverse event monitoring, and to ensure that no change was occurring in dietary intake or lifestyle. All parameters, including assessment of insulin sensitivity with hyperinsulinemic, euglycemic clamps, were repeated at the end of study, i.e. 6 months after randomization. The specific methodology for the hyperinsulinemic-euglycemic clamp, DEXA scan, OGTT and glycated hemoglobin has been described (2).
Linear multiple regression was used to analyze the data on SAS. All the investigated variables were involved in the model as independent variables. Dependent variable was defined as the response to Cr, defined as the change in insulin sensitivity (assessed with clamp studies) at end of study as compared to the baseline value. Model selection was based on F test.
A total of 73 subjects (38M/35F) completed the protocol for which 38 were randomized to chromium. The subjects had an average (± SD) age of 57.8 ± 8.7 years, GHb of 7.4 ± 2.4 %, fasting glucose of 145.7 ± 46.5 mg/dl, BMI of 30.4 ± 4.2, body weight of 87.4 + 12.7 kg, and whole body glucose disposal (by clamp) of 287 ± 144 mg/min.
The response rate (defined by an increase in insulin sensitivity from baseline clamp to end of study clamp) was 63% of the subjects randomized to Cr as opposed to 30% for placebo. Table 1 summarizes the contribution of the study variables to the prediction model for change in insulin sensitivity. The only subject variable significantly associated with the clinical response to Cr was the baseline whole-body insulin-mediated glucose disposal, i.e. insulin sensitivity, as assessed with the hyperinsulinemic clamp (p = .0004). This parameter accounted for nearly 40% (partial R2 = .4038) of the variance in the clinical response to Cr (Table 1).
This preliminary report suggests that a major determinant for assessing clinical response to Cr in subjects with Type 2 diabetes is the presence of insulin resistance prior to intervention. As described, variables assessed in this report included demographic parameters such as age, race, and gender, metabolic parameters which included assessment of glycated hemoglobin, glucose disposal obtained during clamp, insulin and glucose response to OGTT, and phenotype parameters, as assessed by BMI, percent body fat, and body weight. With a statistical model that included all the other parameters, no other demographic or biochemical parameter other than the baseline insulin sensitivity was determined to be significant in the modeling used.
It has been well documented that concerns with past studies evaluating Cr have been the lack of definitive randomized trials and the lack of “gold standard” techniques to assess glucose metabolism (1). For this study, we used the most precise measure of assessing insulin action, i.e. hyperinsulinemic-euglycemic clamps. An additional strength of the study was the fact that we evaluated response in a randomized, double blinded fashion. As described, all subjects received the same lifestyle instructions and the groups consisted of being randomized to daily chromium or placebo. As observed, at end of study, the chromium group had a response rate of 63% whereas the response rate observed for the placebo group, i.e. 30%, would not be unexpected given the study design. Due in large measure to the labor intensity of the clamp technique, the cohort of subjects reported represent the largest database of individuals with Type 2 diabetes evaluated to date with use of hyperinsulinemic clamps after a specific period of Cr supplementation.
The observation that baseline insulin resistance is important in predicting clinical response was also suggested in animal studies (5,6). Specifically, Cr supplementation did not increase insulin sensitivity in lean, insulin sensitive animals whereas improved insulin action and enhanced cellular signaling were observed in obese insulin resistant rats (5,6). Other studies that evaluated different formulations of chromium have also suggested improved insulin sensitivity in different animal models (7,8). Thus, it would appear that in clinical states such as obesity and insulin resistance, alterations in Cr metabolism may contribute to the attenuation in insulin action which may be improved with high dose Cr supplementation. Such an observation, if validated, may partially explain the reported discrepancies in response to Cr in the human population and why Cr supplementation appears to have a more predictable response in hyperinsulinemic or obese states (1,9,10). The precise molecular mechanism by which Cr improves insulin action in these states is the focus of the ongoing NIH supported clinical trial. But, it is noteworthy that the supplement had its major effect in individuals who were observed to be insulin resistant prior to the intervention. This observation, if confirmed once the study is completed, is an important public health finding given that insulin resistance was chosen as a primary endpoint because it is a key pathophysiologic feature of type 2 diabetes, obesity and the “metabolic syndrome” and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis (11).
In conclusion, this study is the first to report that baseline insulin resistance is a major factor in determining whether a patient may respond on a clinical level to supplemental Cr. Insulin resistance was shown to account for approx. 40% of the variance in the insulin sensitivity response to Cr after the treatment period. Although the presence of insulin resistance appears to be the largest contributor to clinical response, it is important to note that over 60% of the response was not explained, which suggests that other factors, including genetic, may also play a major role.
Funding: Supported in part by R55 DK060126 and R01 DK060126 awarded to William T. Cefalu, M.D. and M01RR00109
Authors and Contribution to Study:Zhong Q. Wang: Study design, manuscript preparation
Jianhua Qin: Data analysis, manuscript review
Julie Martin: Study Coordination, subject recruitment, manuscript review
Xian H. Zhang: Study conduct, manuscript review
Olga Sereda: Study conduct, performance of clamp procedures, manuscript review
Richard Anderson: Study design, data review and analysis, manuscipt review
Patricia Pinsonat: Study coordination, subject recruitment, manuscript review
William T. Cefalu: Study design, data review and analysis, manuscript preparation.
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