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Department of Medicine, University of Vermont College of Medicine, Burlington, VT and * Department of Surgery, University of Alberta, Edmonton, AB, Canada
1To whom correspondence should be addressed. E-mail: William.Cefalu{at}uvm.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • insulin • glucose • chromium • lipids • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). As a consequence, one of the most desirable goals of treatment for patients with type 2 diabetes is increasing insulin sensitivity in vivo. Although energy restriction and exercise greatly improve insulin resistance, the long-term success of dietary intervention in humans is poor (2
). Therefore, strategies to improve insulin resistance by pharmacologic means or nutritional supplementation represent a very attractive approach. Dietary supplementation with chromium picolinate (CrPic)2
has been proposed as one such nutritional intervention (3
–6
). However, routine use of CrPic in subjects with diabetes is not currently recommended, and, indeed, the most recent clinical practice recommendations from the American Diabetes Association state that "chromium supplementation has no known benefit" (2
). Further, the cellular and molecular mechanisms by which chromium (Cr) supplementation affects insulin action in vivo are currently unknown and an understanding of these mechanisms would be required before firm recommendations could be made regarding its routine use in the management of type 2 diabetes. Cr use by the general public, and in diabetic patients in particular, has surpassed our ability as a scientific community to provide evidence regarding its safety and efficacy. Part of the problem stems from the lack of definitive, randomized trials because many of the earlier studies evaluating Cr use were open-label studies and, therefore, generated substantial bias. Additional concerns are the lack of "gold standard" techniques to assess glucose metabolism, the use of differing doses and formulations, and heterogeneous study populations. As a result, a large body of conflicting data has been reported that contributes greatly to the confusion among health care providers regarding use of Cr.
Several lines of evidence in both rodent and human studies, however, suggest that Cr may modulate intracellular pathways of glucose metabolism and improve comorbidities associated with insulin resistance (3
–9
). Thus, the overall objective of this study was to evaluate the role of CrPic in improving the clinical sequelae of the insulin resistance syndrome (e.g., dyslipidemia, glucose intolerance, hyperinsulinemia) by use of a rat model of insulin resistance.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The effect of CrPic was assessed in the JCR:LA-corpulent (JCR:LA-cp) rat, a strain incorporating the autosomal recessive cp gene that induces obesity (10
,11
). The JCR:LA-cp rat, when homozygous for the autosomal recessive cp gene (cp/cp), lacks membrane-bound leptin receptors, leading to marked obesity (12
). The cp/cp rats are hyperphagic, become insulin resistant, hyperinsulinemic and hypertriglyceridemic, and develop advanced atherosclerotic disease as well as myocardial lesions consistent with an ischemic origin (13
,14
). The hyperinsulinemia develops rapidly after 4 wk of age, with an age at half-maximum of 5.5 wk. Breeding is done using heterozygous rats (cp/+) and yields 25% obese rats (cp/cp) and 75% lean rats [a 2:1 mix of cp/+ and +/+ referred to as +/?; for review see (15
)]. Hypertension does not develop in this strain, thus providing a rat model of spontaneous cardiovascular disease that exhibits all of the aspects seen in obese, insulin-resistant humans, including vasculopathy, but without the confounding effects of hypertension. In addition to the alterations in carbohydrate metabolism, a characteristic dyslipidemia associated with elevated triglycerides and increased LDL-cholesterol is observed (13
,16
).
Male cp/cp and +/? rats were bred in the established JCR:LA-cp colony at the University of Alberta as previously described (17
). The rats were maintained in a controlled environment at 20°C and 40–50% humidity, with 12 h of light per 24-h period. Nonpurified diet (Rodent Diet 5001, PMI Nutrition, St. Louis, MO) and tap water were consumed by rats ad libitum. At 6 wk of age, obese (cp/cp) insulin-resistant rats and lean normal (+/?) male rats were shipped to the University of Vermont by air freight, within a 24-h period.
All procedures involving rats were conducted in strict compliance with relevant state and federal laws, the Animal Welfare Act, Public Health Services Policy, and guidelines established by the Institutional Animal Care and Use Committee.
The study consisted of a 4-wk baseline phase and a 12-wk treatment phase. During both the baseline and treatment phases, each rat’s food and water intake and body weight were monitored weekly. The rats were fed a fixed formula diet (Harlan Teklad LM-485, Harlan Teklad, Madison, WI). The diet contained 19% crude protein, 5% crude fat, 5% crude fiber and 0.4 mg elemental Cr/kg. After completion of the baseline assessment, rats were randomly assigned to receive CrPic (n = 6 obese, n = 5 lean) or to the control group (n = 5 obese, n = 5 lean). The CrPic was provided in the water and, on the basis of calculated water intake, was administered to provide an intake of 80 µg/(kg body · d), corresponding to 
18 µg elemental Cr/(kg body · d) during the treatment phase. The Cr concentration of the water provided the control group was negligible (<1 µg/L). The water provided the Cr-supplemented group was initially prepared as a solution containing 3000 µg CrPic/L of water. The concentration of the initial solution was 7.1 µmol/L, well below the reported solubility of CrPic in water3
(0.6 mmol/L). The CrPic-supplemented water was diluted to achieve the target Cr intake per group on the basis of measured water intake. At the end of the treatment phase, a 120-min intraperitoneal glucose tolerance test and a 30-min insulin tolerance test were performed 7 d apart to evaluate carbohydrate metabolism and lipid levels. Skeletal muscle biopsies (vastus lateralis) were obtained at the end of insulin stimulation to assess glucose transporter (Glut)-4 levels.
Analytical methods
Intraperitoneal glucose tolerance test (IPGTT).
One week before necropsy, rats underwent an IPGTT, after overnight food deprivation (10 h). An intraperitoneal glucose injection was used to provide a rapid glucose challenge with minimal stress and without the possible confounding effects of gavage-related esophageal trauma. A D-glucose (500 g/L) solution was injected intraperitoneally using a 27-gauge needle at a dose of 1 g/kg body. Blood samples (0.5–0.6 mL) were taken at time 0 (before glucose injection) and at 30, 60, 90 and 120 min postglucose by tail cut (18
). Insulin and glucose levels were measured at each time point and the areas under the curve (AUC) were then determined.
Insulin tolerance test (ITT). An ITT was conducted before rats were killed. After induction of anesthesia, a baseline tail cut was obtained, followed by intraperitoneal injection of regular insulin (5 U/kg) at time 0. Repeat tail cuts occurred at 5, 10, 15 and 30 min and then the rat was killed. The rate of glucose disappearance [mmol/(L · min)] was determined.
For both the IPGTT and the ITT, rats inhaled 5% halothane in 100% oxygen via a facemask for 3–4 min at a flow rate of 1.25 L/min, then reduced to 2% in 100% oxygen. This method of anesthesia allows the rats to recover completely between tail cuts and has been shown to have minimal effects on insulin and glucose levels (19
,20
).
Plasma was obtained at baseline, at wk 6 of treatment and at the end of the study (12 wk) for determination of glucose and insulin levels. A lipid profile was obtained at baseline and at wk 12 (end of study). Glucose was determined by an enzymatic method using the Cobs Mira autoanalyzer (Roche Biomedical, Nutley, NJ). The CV for the glucose assay as determined within-run and day-to-day of glucose were 1.2 and 1.5%, respectively. Plasma cholesterol, triglyceride, and HDL cholesterol were measured by kits (Sigma Chemical, St. Louis, MO). The inter- and intra-assay CV were 3.5 and 4.1% for cholesterol, 2.9 and 2.7% for triglyceride and 2.5 and 3.1% for HDL cholesterol, respectively. Plasma insulin concentrations were analyzed by RIA kit (Incstar, Stillwater, MN); the inter- and intra-assay CV were 3.8 and 4.5%.
Muscle biopsy.
Rats were anesthetized with ventilated halothane and the skin covering the lateral portion of the vastus lateralis muscle was cleaned with alcohol. After incision, the subcutaneous tissues were dissected down to the muscle. A bundle of vastus lateralis muscle fibers (1 g) was dissected and clamped with a forked hemostat, cut, immediately put into a vial and frozen in liquid nitrogen. The incision was covered with a sterile dressing. The ITT was then conducted and a repeat muscle biopsy was taken at 30 min postinsulin stimulation. Rats were killed by rapid decapitation.
Skeletal muscle fractionation and marker enzyme analyses.
The isolation of plasma and intracellular membranes from rat muscle was performed as described by Douen (21
) with minor modification. Briefly, 1 g rat muscle was minced in 250 mmol/L sucrose, 10 mmol/L NaHCO3, pH 7.0, containing 5 mmol/L NaN3 and 100 µmol/L phenylmethylsulfonyl fluoride (PMSF). The tissue was then homogenized by Polytron for 5 s. The homogenate was subjected to a series of differential centrifugation steps (1200 x g for 10 min, followed by 9000 x g for 10 min and 190,000 x for 60 min) to yield a crude membrane pellet. The last step of purification was performed in discontinuous sucrose gradients (25, 30 and 35% sucrose) at 100,000 x g for 180 min. Membranes were collected atop each sucrose layer, washed by 10-fold dilution in 10 mmol/L NaHCO3 (pH 7.0) and recovered by high speed centrifugation. A marker enzyme analysis of these membrane fractions showed that membranes obtained from the 25% sucrose fraction and from the 35% sucrose fraction had >10- and 6-fold enrichments, respectively, in the plasma membrane marker enzyme 5'-nucleotidase compared with muscle homogenates. 5'-Nucleotidase activity was assayed as described by Brake (22
).
Glut-4 content.
For analysis, an aliquot of the muscle biopsy was homogenized in 3 mL extraction buffer (1% Triton X-100, 100 mmol/L Tris (pH 7.4), 100 mmol/L sodium pyrophosphate, 100 mmol/L sodium fluoride, 10 mmol/L EDTA, 10 mmol/L sodium vanadate, 2 mmol/L PMSF and 0.1 g/L aprotinin) at 4°C. The extracts were centrifuged at 100,000 x g at 4°C for 45 min to remove insoluble material and the supernatant used for the assay. Extracts, corresponding to 50 µg of protein, were separated on 10% SDS-PAGE minigels. Proteins were transferred to a nitrocellulose sheet with 500 mA for 2 h and then blocked with 5% nonfat dry milk in PBS for 1 h. The nitrocellulose sheets were incubated with anti-Glut-4 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) 1:200 at 4°C overnight. After washing, the sheets were incubated with horseradish peroxidase–conjugated rabbit anti-goat immunoglobulin G diluted 1:5000 at room temperature for 60 min. Antibody-antigen complexes were detected by enhanced chemiluminescence and an exposure obtained on hyperfilm-enhanced chemiluminescence (ECL) film. Glut-4 content in skeletal muscle was quantified by densitometric scanning as described previously (23
).
Statistical analysis
Data were analyzed by repeated measures 2-way ANOVA using the Scheffé F-test for post-hoc analysis. AUC for glucose tolerance and insulin response were determined using the trapezoidal rule (24
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). On the basis of the measured food and water intakes, the control groups (both lean and obese) had daily elemental Cr intakes ranging from 16 to 20 µg/kg. The Cr-supplemented groups had daily elemental Cr intakes ranging from 33 to 38 µg/kg.
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). Further, there appeared to be no significant effect for CrPic on glucose levels at wk 6 or 12 for either the lean or obese groups (Fig. 1B
). Glucose disappearance during the ITT was significantly improved in obese rats treated with CrPic compared with obese controls [0.0933 ± 0.0006 vs. 0.0717 ± 0.0062 mmol/(L · min)]. In addition, glucose and insulin AUC for the IPGTT were significantly less for obese rats treated with CrPic compared with obese control rats (P < 0.001) (Figs. 2
, 3
). Lean rats treated with CrPic did not differ from lean controls in glucose disappearance or glucose AUC (data not shown).
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). Obese-CrPic treated rats had lower plasma total cholesterol levels at the end of the study compared with obese controls (Fig. 4
). In addition, obese CrPic-treated rats had higher HDL cholesterol levels (1.92 ± 0.09 vs. 1.37 ± 0.36 mmol/L, P < 0.001) and improved cholesterol/HDL ratio at wk 12 (Table 2)
compared with obese controls.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Although routine use of supplemental Cr remains controversial in clinical diabetes management, it has been established that Cr is an essential nutrient required for normal carbohydrate metabolism, as demonstrated in early studies of total parenteral nutrition (TPN) in which Cr deficiency was well documented (25
–27
). A Cr intake of 5 µg/1000 kcal was shown to deplete subjects and was associated with hyperglycemia, hyperinsulinemia, insulin resistance and increased exogenous insulin need. The addition of Cr to the TPN solutions markedly improved glycemic status and greatly reduced insulin requirements; therefore, Cr is now routinely added to TPN solutions (26
). Although Cr replacement in individuals subjected to TPN in early studies ameliorated specific symptoms thought to be representative of a Cr-deficient state, the role of Cr supplementation in enhancing glucose metabolism in subjects not likely to be Cr deficient is an area of great controversy in the clinical management of diabetic patients.
Several valence states exist for Cr; the most prevalent oxidation states are trivalent Cr, a stable and biologically active form, and hexavalent Cr, the state associated with industrial exposure and toxicity. Trivalent Cr is available in the chloride or picolinate salt form or in an organic complex with nicotinic acid and amino acids. Absorption of trivalent Cr is low, and there appears to be little storage in tissues (although it concentrates in liver, spleen, kidney and bone) because most is rapidly excreted in the urine, with excretion increasing as a result of a glucose load (28
,29
). As a result, a major limitation of assessing Cr status in biological tissues is analytical, due to the extremely low levels of Cr in these tissues. Other limitations include availability of techniques, cost, interference from sample matrix and specimen contamination (30
–36
).
However, despite inherent problems with Cr assessment, recent studies have demonstrated successful determination of plasma Cr. Davies et al. (37
) reported that Cr levels diminish with age; in >40,800 patients aged 1 to >75 y, Cr levels in hair, sweat and blood diminished significantly with age, with values decreasing 25–40% depending on the tissue of interest. In addition, it has been reported that diabetic subjects may have altered Cr metabolism because both absorption and excretion were higher than in nondiabetic subjects (4
,29
). Hair and blood Cr levels are reported to be lower in diabetic subjects; Morris et al. (5
) reported that mean levels of plasma Cr were 33% lower in 93 type 2 diabetic subjects compared with controls. Ding et al. (38
) reported that Cr levels were reduced >50% in 57 diabetic subjects compared with 55 control subjects. Ekmekcioglu et al. (39
) confirmed the observations of Ding et al. by evaluating Cr concentrations in different hematological matrices in 53 subjects with type 2 diabetes compared with 50 controls; they reported significantly lower Cr levels in the plasma of the diabetic subjects compared with the nondiabetic healthy controls. In contrast, Zima et al. (40
) suggested no alteration of Cr levels in type 2 diabetes; however, only 11 subjects with type 2 diabetes were compared with 19 healthy controls. If clinical states such as diabetes are truly shown to be associated with diminished Cr levels, and if supplementation generally leads to an increase in Cr concentration, it is possible that diabetic patients may have inadequate dietary Cr intake. However, this area remains controversial because studies demonstrating an inadequate Cr intake in subjects with diabetes are not available.
The controversy surrounding Cr as an adjunctive treatment in diabetes stems in large part from conflicting data reported in previous studies of subjects with impaired glucose tolerance or diabetes in which the diets were supplemented with Cr in an effort to demonstrate an effect on carbohydrate metabolism. Table 3
provides an overview of many of the human studies reported and demonstrates that considerable differences in efficacy were noted, contributing greatly to the present day confusion among health care providers regarding routine use of Cr in patients with diabetes. Specifically, many of the reported studies were open label without adequate control groups (designated as "OL" in Table 3
) and thus generated substantial bias. Additional concerns were that overall nutritional status was not reported, nor was Cr intake from diet evaluated. For the latter concern, it may be difficult to assess dietary Cr intake because currently available software (e.g., Food Processor 7.5, ESHA Research, Salem, OR) may have Cr content values for <5% of foods. Therefore, Cr intake for these studies was assessed primarily with supplementation. Most of the studies did not use "gold standard" techniques to assess glucose metabolism; they used differing doses and formulations, evaluated heterogeneous study populations and had widely varying periods of observation. Indeed, one study by Ravina et al. (42
) suggested an effect that was observed after only 7 d of administration. Thus, the many confounders make these studies difficult to interpret when trying to suggest a consistent effect of supplemental Cr on human carbohydrate metabolism. It appears, however, that studies that specifically evaluated 
200 µg of Cr as Cr chloride (CrCl) did not elicit a clinical response in subjects with type 2 diabetes (Table 3
), whereas a more consistent clinical response was observed with daily supplementation of Cr >200 µg/d for a duration of at least 2 mo. In addition, other forms of Cr, especially CrPic, appeared to be more bioavailable and clinically more effective than CrCl in both human and rat studies (43
).
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) provided evidence for a dose effect of CrPic in a study of Chinese type 2 diabetic subjects. Short- (2 mo) and long-term (4 mo) efficacy were observed, as evidenced by reductions in fasting and 2-h glucose and insulin concentrations, and long-term reductions in hemoglobin A1c (HbA1c) concentrations utilizing varying doses of CrPic (200 or 1000 µg). The effectiveness of the 1000-µg dose in the Chinese study agrees with the effective dose observed in our human trial (3
). In a more recent study, Anderson et al. (44
) evaluated antioxidant and glycemic effects in Tunisian adults with type 2 diabetes. The amount of Cr given (400 µg/d), was similar to previous studies, but the formulation was different (Cr pidolate as opposed to CrPic). Although they reported a significant antioxidant effect, no statistically significant effect was seen on glycemia in either the zinc/Cr-supplemented group or the Cr-supplemented group, despite a drop in mean HbA1c of 0.9 and 1.0%, respectively. Anderson reported that the discrepancy in response to Cr may be dependent upon the form (pidolate vs. picolinate), duration of diabetes and status of subjects (44
).
Our data suggest a role for supplemental CrPic in obese, insulin-resistant states because CrPic improved glucose tolerance and insulin levels in obese rats but not in lean controls. It is not known whether the obese JCR:LA-cp rat is Cr deficient; thus, a limitation of this study is the lack of blood or urine Cr levels in the rats. A very important question would be whether blood Cr status could have explained the differences in the responses to Cr supplementation between lean and obese rats; if so, it would suggest an abnormality in the insulin signaling cascade in obesity that appears to be overcome with Cr supplementation. Whether hyperinsulinism, insulin resistance and/or obesity, therefore, play a role in Cr metabolism and/or excretion is an interesting question suggested by the present studies. Such an observation may also explain in part the reported discrepancies in response to CrPic in humans (see Table 3
).
Our observations in this rat model are in agreement with the limited human data, which suggest that Cr has a more predictable response in hyperinsulinemic or obese states (45
,46
) Wilson et al. (45
) reported that Cr had no effect in reducing insulin levels in healthy young subjects, but had a positive effect in those subjects with elevated fasting insulin levels. In addition, Morris et al. (46
) used insulin and glucose infusions to demonstrate an inverse relationship in humans between plasma insulin levels and plasma Cr levels under conditions in which plasma glucose was unchanged. These studies strengthen the association between Cr and insulin action and support our approach of characterizing both the phenotype and metabolic conditions when assessing the role of adjunctive use of Cr.
Thus, subject phenotype, i.e., body fat distribution, may be an important parameter in predicting a consistent effect of Cr and is a very relevant area of human investigation. In human studies, it has been clearly demonstrated that central obesity and, in particular, an increase in visceral or intra-abdominal fat is related to insulin resistance (3
,47
,48
) and interventions that reduce visceral fat, i.e., energy restriction, markedly improve resistance (49
). However, we have evidence in humans that demonstrates an effectiveness of Cr at 1000 µg/d provided as CrPic in improving insulin sensitivity without a change in body fat distribution (3
). Although no effect on total body weight was observed in the present study of the JCR rat, the effect on body fat distribution was not addressed.
The dose of supplemental Cr used in this rat study should be put in perspective.
For example, recently established adequate intake of Cr for men was suggested to be 35 µg/d (50
). Assuming an average 75 kg body mass, this would relate to an intake of 0.47 µg/kg. In our recent human trial, we demonstrated improved insulin sensitivity with 1000 µg/d of Cr as CrPic (3
) and, given the range of body weights of subjects, intake of Cr ranged from 10 to 13 µg/kg. Other human trials have demonstrated a response at much lower Cr intakes (4
). On the basis of the measured food and water intakes, rats treated with Cr in this study were receiving twice as much elemental Cr from the water as from the diet and had a total approximate daily intake of >30 µg/kg. Thus, the rats in this study received supplemental Cr at levels greater than those observed to be effective in our human trials and that could be considered a pharmacologic dose.
Our data also demonstrate that supplemental CrPic may improve lipid levels because we observed decreased plasma total cholesterol, increased HDL cholesterol and an improved cholesterol/HDL cholesterol ratio in obese rats treated with CrPic. This observation has been noted in some, but not all human trials with supplemental Cr (4
,51
–53
), i.e., in studies of type 2 diabetic subjects, Anderson et al. (4
) noted a significant drop in cholesterol levels, and Lee et al. (51
) observed a 17% drop in triglyceride levels. Other reported human studies showed no significant effects on lipids with Cr nicotinic acid (200 µg) or CrPic (1000 µg) supplementation (53
,54
). Beneficial effects on lipids were also demonstrated in rats given a synthetic, functional biomimetic Cr compound parenterally (52
). Whether the improvement in lipid levels is secondary to improvements in insulin levels per se or a direct effect of Cr on lipid metabolism, is currently unknown. However, there remain interspecies differences in response to dietary changes between rodent and human studies, and this effect on lipids, before being extrapolated to human studies, will have to be evaluated specifically in human trials.
Despite recognition of a specific Cr-deficient state, Cr remains the only essential transition metal whose mechanism of action is not known. Recent studies, however, have shed light on the potential mechanism by which Cr may help to maintain proper carbohydrate metabolism at a molecular level. It has been demonstrated that a naturally occurring oligopeptide, low-molecular-weight Cr-binding substance (termed "chromodulin"), binds chromic ions in response to an insulin-mediated chromic ion flux, and the metal-saturated oligopeptide then binds to an insulin-stimulated insulin receptor, activating the receptor’s tyrosine kinase activity as much as eightfold in the presence of insulin (8
,9
,55
). Thus, chromodulin appears to play a role in an autoamplification mechanism in insulin signaling and provides new insights into how insulin action can be enhanced with Cr supplementation (55
). Increased insulin signaling would be expected to enhance the regulated movement of Glut-4 and, subsequently, enhance glucose disposal. Thus, we evaluated for changes in Glut-4 content and translocation in this rat study. Although skeletal muscle Glut-4 content was not affected, an enhanced Glut-4 translocation was observed in the obese rats, as demonstrated by an increase in membrane-associated Glut-4 content after insulin stimulation. The upstream cellular signals responsible for the enhanced translocation (i.e., enhanced insulin receptor substrate phosphorylation, increased phosphatidyl inositol-3, Akt activity) are currently being evaluated.
In summary, this study has confirmed previous reports demonstrating a favorable effect of supplemental Cr in humans and suggests that Cr supplementation in obese insulin-resistant states may improve insulin action. Further, the improvement in insulin sensitivity resulted in significant improvement in lipid levels. These physiologic improvements occurred without differences in body weight between treatment groups, suggesting a direct effect of CrPic on insulin action. Although insulin signaling was not assessed in this study, improvement in cellular insulin signaling was suggested by enhanced Glut-4 translocation after insulin stimulation. These findings will have to be confirmed in human trials with mechanistic aims before definitive recommendations can be made.
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FOOTNOTES |
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3 The Merck Index, 12th edition.
Manuscript received 18 September 2001. Initial review completed 1 October 2001. Revision accepted 20 February 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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