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Biochemical and Molecular Actions of Nutrients

Oral Chromium Picolinate Improves Carbohydrate and Lipid Metabolismand Enhances Skeletal Muscle Glut-4 Translocation in Obese,

Hyperinsulinemic (JCR-LA Corpulent) RatsWilliam T. Cefalu,1 Zhong Q. Wang, Xian H. Zhang, Linda C. Baldorand James C. Russell*

Department of Medicine, University of Vermont College of Medicine, Burlington, VT and *Department of Surgery, University of Alberta, Edmonton, AB, Canada

ABSTRACT Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improvesglucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of theinsulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male leanand obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 g/(kg d); n 5 or 6,respectively) in water or to control conditions (water, n 5). After 3 mo, a 120-min intraperitoneal glucose tolerance

test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantlylower fasting insulin levels (1848 102 vs. 2688 234 pmol/L; P 0.001; mean SEM ) and significantly improvedglucose disappearance ( P 0.001) compared with obese controls. Glucose and insulin areas under the curve forIPGTT were significantly less for obese CrPic-treated rats than in obese controls ( P 0.001). Obese CrPic-treatedrats had lower plasma total cholesterol (3.57 0.28 vs. 4.11 0.47 mmol/L, P 0.05) and higher HDL cholesterollevels (1.92 0.09 vs. 1.37 0.36 mmol/L, P 0.01) than obese controls. CrPic did not alter plasma glucose orcholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups;however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus,CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obesehyperinsulinemic JCR:LA-corpulent rats. J. Nutr. 132: 1107–1114, 2002.

KEY WORDS: ● insulin ● glucose ● chromium ● lipids ● rats

Insulin resistance is a key pathophysiologic feature of type

2 diabetes and is strongly associated with coexisting cardio-vascular risk factors and accelerated atherosclerosis (1). As aconsequence, one of the most desirable goals of treatment forpatients with type 2 diabetes is increasing insulin sensitivity invivo. Although energy restriction and exercise greatly improveinsulin resistance, the long-term success of dietary interven-tion in humans is poor (2). Therefore, strategies to improveinsulin resistance by pharmacologic means or nutritional sup-plementation represent a very attractive approach. Dietarysupplementation with chromium picolinate (CrPic)2 has beenproposed as one such nutritional intervention (3–6). How-ever, routine use of CrPic in subjects with diabetes is notcurrently recommended, and, indeed, the most recent clinicalpractice recommendations from the American Diabetes Asso-

ciation state that “chromium supplementation has no knownbenefit” (2). Further, the cellular and molecular mechanisms

by which chromium (Cr) supplementation affects insulin ac-

tion in vivo are currently unknown and an understanding of these mechanisms would be required before firm recommen-dations could be made regarding its routine use in the man-agement of type 2 diabetes.

Cr use by the general public, and in diabetic patients inparticular, has surpassed our ability as a scientific communityto provide evidence regarding its safety and efficacy. Part of the problem stems from the lack of definitive, randomizedtrials because many of the earlier studies evaluating Cr usewere open-label studies and, therefore, generated substantialbias. Additional concerns are the lack of “gold standard”techniques to assess glucose metabolism, the use of differingdoses 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 careproviders regarding use of Cr.Several lines of evidence in both rodent and human studies,

however, suggest that Cr may modulate intracellular pathwaysof glucose metabolism and improve comorbidities associatedwith insulin resistance (3–9). Thus, the overall objective of this study was to evaluate the role of CrPic in improving theclinical sequelae of the insulin resistance syndrome (e.g., dys-lipidemia, glucose intolerance, hyperinsulinemia) by use of arat model of insulin resistance.

1 To whom correspondence should be addressed. E-mail: [email protected].

2 Abbreviations used: AUC, area(s) under the curve; CrPic, chromium picoli-nate; ECL, enhanced chemiluminescence; Glut, glucose transporter; HbA1c,hemoglobin A1c; ITT, insulin tolerance test; IPGTT, intraperitoneal glucose toler-ance test; JCR, LA-cp; JCR, LA-corpulent; PMSF, phenylmethylsulfonyl fluoride;TPN, total parenteral nutrition.

0022-3166/02 $3.00 © 2002 American Society for Nutritional Sciences.Manuscript received 18 September 2001. Initial review completed 1 October 2001. Revision accepted 20 February 2002.

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MATERIALS AND METHODS

Study design

The effect of CrPic was assessed in the JCR:LA-corpulent (JCR:LA-cp) rat, a strain incorporating the autosomal recessive cp genethat induces obesity (10,11). The JCR:LA-cp rat, when homozygousfor the autosomal recessive cp gene (cp/cp), lacks membrane-boundleptin receptors, leading to marked obesity (12). The cp/cp rats are

hyperphagic, become insulin resistant, hyperinsulinemic and hyper-triglyceridemic, and develop advanced atherosclerotic disease as wellas myocardial lesions consistent with an ischemic origin (13,14). Thehyperinsulinemia develops rapidly after 4 wk of age, with an age athalf-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 mixof cp/ and / referred to as /?; for review see (15)]. Hyperten-sion does not develop in this strain, thus providing a rat model of spontaneous cardiovascular disease that exhibits all of the aspectsseen in obese, insulin-resistant humans, including vasculopathy, butwithout the confounding effects of hypertension. In addition to thealterations in carbohydrate metabolism, a characteristic dyslipidemiaassociated with elevated triglycerides and increased LDL-cholesterolis observed (13,16).

Male cp/cp and /? rats were bred in the established JCR:LA-cpcolony at the University of Alberta as previously described (17). The

rats were maintained in a controlled environment at 20°C and40–50% humidity, with 12 h of light per 24-h period. Nonpurifieddiet (Rodent Diet 5001, PMI Nutrition, St. Louis, MO) and tap waterwere consumed by rats ad libitum. At 6 wk of age, obese (cp/cp)insulin-resistant rats and lean normal (/?) male rats were shipped tothe University of Vermont by air freight, within a 24-h period.

All procedures involving rats were conducted in strict compliancewith relevant state and federal laws, the Animal Welfare Act, PublicHealth Services Policy, and guidelines established by the InstitutionalAnimal Care and Use Committee.

The study consisted of a 4-wk baseline phase and a 12-wk treat-ment phase. During both the baseline and treatment phases, eachrat’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 pro-

tein, 5% crude fat, 5% crude fiber and 0.4 mg elemental Cr/kg. Aftercompletion of the baseline assessment, rats were randomly assigned toreceive 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, onthe basis of calculated water intake, was administered to provide anintake of 80 g/(kg body d), corresponding to 18 g elementalCr/(kg body d) during the treatment phase. The Cr concentration of the water provided the control group was negligible (1 g/L). Thewater provided the Cr-supplemented group was initially prepared as asolution containing 3000 g CrPic/L of water. The concentration of the initial solution was 7.1 mol/L, well below the reported solubilityof CrPic in water3 (0.6 mmol/L). The CrPic-supplemented water wasdiluted to achieve the target Cr intake per group on the basis of measured water intake. At the end of the treatment phase, a 120-minintraperitoneal glucose tolerance test and a 30-min insulin tolerancetest were performed 7 d apart to evaluate carbohydrate metabolism

and lipid levels. Skeletal muscle biopsies (vastus lateralis) were ob-tained at the end of insulin stimulation to assess glucose transporter(Glut)-4 levels.

Analytical methods

Intraperitoneal glucose tolerance test (IPGTT). One weekbefore necropsy, rats underwent an IPGTT, after overnight fooddeprivation (10 h). An intraperitoneal glucose injection was usedto provide a rapid glucose challenge with minimal stress and withoutthe possible confounding effects of gavage-related esophageal trauma.A D-glucose (500 g/L) solution was injected intraperitoneally using a27-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 weremeasured at each time point and the areas under the curve (AUC)were then determined.

Insulin tolerance test (ITT). An ITT was conducted before ratswere killed. After induction of anesthesia, a baseline tail cut wasobtained, followed by intraperitoneal injection of regular insulin (5U/kg) at time 0. Repeat tail cuts occurred at 5, 10, 15 and 30 min andthen 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 in100% 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 anesthesiaallows the rats to recover completely between tail cuts and has beenshown to have minimal effects on insulin and glucose levels (19,20).

Plasma was obtained at baseline, at wk 6 of treatment and at theend of the study (12 wk) for determination of glucose and insulinlevels. A lipid profile was obtained at baseline and at wk 12 (end of study). Glucose was determined by an enzymatic method using theCobs Mira autoanalyzer (Roche Biomedical, Nutley, NJ). The CV forthe glucose assay as determined within-run and day-to-day of glucosewere 1.2 and 1.5%, respectively. Plasma cholesterol, triglyceride, andHDL cholesterol were measured by kits (Sigma Chemical, St. Louis,MO). The inter- and intra-assay CV were 3.5 and 4.1% for choles-terol, 2.9 and 2.7% for triglyceride and 2.5 and 3.1% for HDL

cholesterol, respectively. Plasma insulin concentrations were ana-lyzed by RIA kit (Incstar, Stillwater, MN); the inter- and intra-assayCV were 3.8 and 4.5%.

Muscle biopsy. Rats were anesthetized with ventilated halo-thane and the skin covering the lateral portion of the vastus lateralismuscle was cleaned with alcohol. After incision, the subcutaneoustissues were dissected down to the muscle. A bundle of vastus lateralismuscle fibers (1 g) was dissected and clamped with a forked hemo-stat, cut, immediately put into a vial and frozen in liquid nitrogen.The incision was covered with a sterile dressing. The ITT was thenconducted and a repeat muscle biopsy was taken at 30 min postinsulinstimulation. Rats were killed by rapid decapitation.

Skeletal muscle fractionation and marker enzyme analyses. Theisolation of plasma and intracellular membranes from rat muscle wasperformed 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 mol/Lphenylmethylsulfonyl fluoride (PMSF). The tissue was then homog-enized by Polytron for 5 s. The homogenate was subjected to a seriesof differential centrifugation steps (1200 g for 10 min, followed by9000 g for 10 min and 190,000 for 60 min) to yield a crudemembrane pellet. The last step of purification was performed indiscontinuous sucrose gradients (25, 30 and 35% sucrose) at 100,000 g for 180 min. Membranes were collected atop each sucrose layer,washed by 10-fold dilution in 10 mmol/L NaHCO

3(pH 7.0) and

recovered by high speed centrifugation. A marker enzyme analysis of these membrane fractions showed that membranes obtained from the25% sucrose fraction and from the 35% sucrose fraction had 10-and 6-fold enrichments, respectively, in the plasma membranemarker 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 washomogenized in 3 mL extraction buffer (1% Triton X-100, 100mmol/L Tris (pH 7.4), 100 mmol/L sodium pyrophosphate, 100mmol/L sodium fluoride, 10 mmol/L EDTA, 10 mmol/L sodiumvanadate, 2 mmol/L PMSF and 0.1 g/L aprotinin) at 4°C. Theextracts were centrifuged at 100,000 g at 4°C for 45 min to removeinsoluble material and the supernatant used for the assay. Extracts,corresponding to 50 g of protein, were separated on 10% SDS-PAGE minigels. Proteins were transferred to a nitrocellulose sheetwith 500 mA for 2 h and then blocked with 5% nonfat dry milk inPBS for 1 h. The nitrocellulose sheets were incubated with anti-Glut-4 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) 1:200at 4°C overnight. After washing, the sheets were incubated withhorseradish peroxidase– conjugated rabbit anti-goat immunoglobulinG diluted 1:5000 at room temperature for 60 min. Antibody-antigen

complexes were detected by enhanced chemiluminescence and anexposure obtained on hyperfilm-enhanced chemiluminescence (ECL)3 The Merck Index, 12th edition.

CEFALU ET AL.1108

























film. Glut-4 content in skeletal muscle was quantified by densitomet-ric scanning as described previously (23).

Statistical analysis

Data were analyzed by repeated measures 2-way ANOVA usingthe Scheffe F-test for post-hoc analysis. AUC for glucose toleranceand insulin response were determined using the trapezoidal rule (24).

RESULTS

There was no effect of CrPic on daily food and waterintakes or body weights over the 90-d treatment period (Table1). On the basis of the measured food and water intakes, thecontrol groups (both lean and obese) had daily elemental Crintakes ranging from 16 to 20 g/kg. The Cr-supplementedgroups had daily elemental Cr intakes ranging from 33 to 38g/kg.

There was also no difference between treatment groups infasting insulin levels obtained at study initiation. However, bywk 12, fasting insulin was lower in the CrPic-treated obese ratsthan in controls; there was no effect for CrPic in lean rats ( Fig.1 A). Further, there appeared to be no significant effect for

CrPic on glucose levels at wk 6 or 12 for either the lean orobese groups (Fig. 1B). Glucose disappearance during the ITTwas significantly improved in obese rats treated with CrPiccompared with obese controls [0.0933 0.0006 vs. 0.0717 0.0062 mmol/(L min)]. In addition, glucose and insulinAUC for the IPGTT were significantly less for obese ratstreated with CrPic compared with obese control rats (P 0.001) ( Figs. 2, 3). Lean rats treated with CrPic did notdiffer from lean controls in glucose disappearance or glucoseAUC (data not shown).

Total Glut-4 content, assessed in the vastus lateralis muscleat wk 12, did not differ between obese control or CrPic-treatedrats; however, membrane-associated Glut-4 was greater inCrPic-treated rats than controls after in vivo insulin stimula-

tion (Table 2). Obese-CrPic treated rats had lower plasmatotal cholesterol levels at the end of the study compared withobese controls ( Fig. 4). In addition, obese CrPic-treated ratshad higher HDL cholesterol levels (1.92 0.09 vs. 1.37 0.36 mmol/L, P 0.001) and improved cholesterol/HDLratio at wk 12 (Table 2) compared with obese controls.

DISCUSSION

This study demonstrated that CrPic enhances insulin sen-sitivity and glucose disappearance in a hyperinsulinemic, obeserat model, yet no difference was observed in lean controls.Further, CrPic improved lipid levels, as demonstrated by a

decrease in total cholesterol and a reduced total cholesterol/HDL cholesterol ratio at the end of the study in obese rats.CrPic did not alter total Glut-4 levels in muscle, but enhancedGlut-4 translocation in skeletal muscle after insulin stimula-tion. The cellular mechanism(s) responsible for these effectsare unknown but are being evaluated.

Although routine use of supplemental Cr remains contro-versial in clinical diabetes management, it has been estab-lished that Cr is an essential nutrient required for normalcarbohydrate metabolism, as demonstrated in early studies of total parenteral nutrition (TPN) in which Cr deficiency waswell documented (25–27). A Cr intake of 5 g/1000 kcal was

TABLE 1

Oral chromium picolinate (Cr-Pic) in JCR:LA corpulent rats that consumed water (control)

or Cr-Pic for 12 wk: weight, food, and water intake during study 1

n

Body weight, g Food intake, g/(rat d) Water intake, mL/(rat d)

Baseline 6 wk End of study Baseline 6 wk End of study Baseline 6 wk End of study

Lean RatsControl 5 368.8 9.8 379.0 8.1 393.2 7.1 21.0 1.6 20.8 0.9 20.0 0.6 25.3 1.4 26.6 1.0 23.5 0.9CrPic 5 374.2 9.5 392.0 10.1 413.6 6.8 21.5 1.3 21.1 0.6 20.0 0.3 26.1 0.5 27.7 1.0 26.0 0.6

Obese RatsControl 5 644.4 21.9 695.0 23.1 737.5 24.2 28.6 1.6 29.6 1.0 29.8 1.1 35.6 1.6 37.6 1.8 35.7 0.7CrPic 6 629.6 13.0 679.0 17.3 733.8 14.5 25.2 1.5 27.8 1.1 28.3 0.6 24.4 1.5 32.6 1.9 31.2 1.8

1 Values are mean SEM.

FIGURE 1 Fasting plasma insulin ( A ) and glucose ( B ) levels in leanand obese JCR:LA corpulent rats that consumed water (control) or

chromium picolinate (CrPic) for 12 wk. Values are means SEM, n

5– 6. *Different from obese control, P 0.001.

CHROMIUM AND INSULIN ACTION 1109

























shown to deplete subjects and was associated with hypergly-cemia, hyperinsulinemia, insulin resistance and increased ex-

ogenous insulin need. The addition of Cr to the TPN solutionsmarkedly improved glycemic status and greatly reduced insulinrequirements; therefore, Cr is now routinely added to TPNsolutions (26). Although Cr replacement in individuals sub-jected to TPN in early studies ameliorated specific symptomsthought to be representative of a Cr-deficient state, the role of Cr supplementation in enhancing glucose metabolism in sub-jects not likely to be Cr deficient is an area of great controversyin the clinical management of diabetic patients.

Several valence states exist for Cr; the most prevalentoxidation states are trivalent Cr, a stable and biologicallyactive form, and hexavalent Cr, the state associated withindustrial exposure and toxicity. Trivalent Cr is available inthe chloride or picolinate salt form or in an organic complex

with nicotinic acid and amino acids. Absorption of trivalentCr 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 excretionincreasing as a result of a glucose load (28,29). As a result, amajor limitation of assessing Cr status in biological tissues isanalytical, due to the extremely low levels of Cr in these

tissues. Other limitations include availability of techniques,cost, interference from sample matrix and specimen contam-ination (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 diminishwith age; in 40,800 patients aged 1 to 75 y, Cr levels inhair, sweat and blood diminished significantly with age, withvalues decreasing 25– 40% depending on the tissue of interest.In addition, it has been reported that diabetic subjects mayhave altered Cr metabolism because both absorption and ex-cretion were higher than in nondiabetic subjects (4,29). Hairand blood Cr levels are reported to be lower in diabeticsubjects; Morris et al. (5) reported that mean levels of plasma

Cr were 33% lower in 93 type 2 diabetic subjects comparedwith controls. Ding et al. (38) reported that Cr levels werereduced 50% in 57 diabetic subjects compared with 55control subjects. Ekmekcioglu et al. (39) confirmed the obser-vations of Ding et al. by evaluating Cr concentrations in

FIGURE 2 Insulin response of JCR:LA corpulent rats that con-

sumed water (control) or chromium picolinate (CrPic) for 12 wk tointraperitoneal glucose tolerance test (IPGTT) as assessed with area

under the curve (AUC). Values are means SEM, n 5– 6. *Different

from obese control, P 0.001.

FIGURE 3 Plasma glucose response of obese JCR:LA corpulent

rats that consumed water (control) or chromium picolinate (CrPic) for 12

wk to intraperitoneal glucose tolerance testing. Values are means

SEM, n

5– 6. Plasma glucose was lower in treated rats at each timepoint , P 0.0001.

TABLE 2

Oral chromium picolinate (Cr-Pic) in JCR:LA corpulent rats

that consumed water (control) or Cr-Pic for 12 wk: lipids and

membrane-associated glucose transporter (Glut)-41

n

Cholesterol/HDL cholesterol

ratio

Membrane-associated

Glut-42

Baseline End of st udy End of study

Lean ratsControl 5 1.76 0.04 1.88 0.02 137.2 7.6CrPic 5 1.70 0.05 1.76 0.10 132.8 3.9

Obese ratsControl 5 2.51 0.18 3.19 0.35 93.8 6.9CrPic 6 2.56 0.22 1.86 0.10* 142.4 6.0**

1 Values are means SEM; * P 0.05 vs. control; ** P 0.01 vs.control.

2 ASU (arbitrary scanning units), postinsulin stimulation.

FIGURE 4 Total plasma cholesterol levels in lean and obese

JCR:LA corpulent rats that consumed water (control) or chromium

picolinate (CrPic) for 12 wk for each treatment group over the course of

study. Values are means

SEM, n

5– 6. *Different from obese control,P 0.01.

CEFALU ET AL.1110

























different hematological matrices in 53 subjects with type 2diabetes compared with 50 controls; they reported significantlylower Cr levels in the plasma of the diabetic subjects comparedwith 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 comparedwith 19 healthy controls. If clinical states such as diabetes aretruly shown to be associated with diminished Cr levels, and if supplementation generally leads to an increase in Cr concen-tration, it is possible that diabetic patients may have inade-quate dietary Cr intake. However, this area remains contro-versial because studies demonstrating an inadequate Cr intakein subjects with diabetes are not available.

The controversy surrounding Cr as an adjunctive treatmentin diabetes stems in large part from conflicting data reported inprevious studies of subjects with impaired glucose tolerance ordiabetes in which the diets were supplemented with Cr in aneffort to demonstrate an effect on carbohydrate metabolism.Table 3 provides an overview of many of the human studiesreported and demonstrates that considerable differences inef ficacy were noted, contributing greatly to the present dayconfusion among health care providers regarding routine use of

Cr in patients with diabetes. Specifically, many of the reportedstudies were open label without adequate control groups (des-ignated as “OL” in Table 3) and thus generated substantialbias. Additional concerns were that overall nutritional statuswas not reported, nor was Cr intake from diet evaluated. Forthe latter concern, it may be dif ficult to assess dietary Crintake because currently available software (e.g., Food Proces-sor 7.5, ESHA Research, Salem, OR) may have Cr contentvalues for 5% of foods. Therefore, Cr intake for these studieswas assessed primarily with supplementation. Most of thestudies did not use “gold standard” techniques to assess glucose

metabolism; they used differing doses and formulations, eval-uated heterogeneous study populations and had widely varyingperiods of observation. Indeed, one study by Ravina et al. (42)suggested an effect that was observed after only 7 d of admin-istration. Thus, the many confounders make these studiesdif ficult to interpret when trying to suggest a consistent effectof supplemental Cr on human carbohydrate metabolism. Itappears, however, that studies that specifically evaluated200g of Cr as Cr chloride (CrCl) did not elicit a clinical responsein subjects with type 2 diabetes (Table 3), whereas a moreconsistent clinical response was observed with daily supple-mentation of Cr 200 g/d for a duration of at least 2 mo. Inaddition, other forms of Cr, especially CrPic, appeared to bemore bioavailable and clinically more effective than CrCl inboth human and rat studies (43).

Anderson et al. (4) provided evidence for a dose effect of CrPic in a study of Chinese type 2 diabetic subjects. Short- (2mo) and long-term (4 mo) ef ficacy were observed, as evi-denced by reductions in fasting and 2-h glucose and insulinconcentrations, and long-term reductions in hemoglobin A1c(HbA1c) concentrations utilizing varying doses of CrPic (200or 1000 g). The effectiveness of the 1000-g dose in the

Chinese study agrees with the effective dose observed in ourhuman trial (3). In a more recent study, Anderson et al. (44)evaluated antioxidant and glycemic effects in Tunisian adultswith type 2 diabetes. The amount of Cr given (400 g/d), wassimilar to previous studies, but the formulation was different(Cr pidolate as opposed to CrPic). Although they reported asignificant antioxidant effect, no statistically significant effectwas seen on glycemia in either the zinc/Cr-supplementedgroup or the Cr-supplemented group, despite a drop in meanHbA1c of 0.9 and 1.0%, respectively. Anderson reported thatthe discrepancy in response to Cr may be dependent upon the

TABLE 3

Effect of chromium supplementation on carbohydrate metabolism in humans1

ReferenceStudytype

Studyduration Dose ( g) Subjects n Technique assessed

Results

Glucose Ins ul in HbA1c IS

Studies using CrCl formulationTrow (56) OL 2 mo 100 Type 2 12 OGTT — — NA NASherman (57) DB 4 mo 150 Type 2; 1; NonDM 14 OGTT — NA NA NARabinowitz (41) DB 4 mo 150 Type 1; Type 2 43 Meal challenge — — NA NAUusitupa (58) DB 6 mo 160 IGT, Elderly 26 OGTT — — — NAUusitupa (59) DB 6 wk 200 Type 2 DM 10 OGTT, HbA1c — 2 — NAPotter (60) OL 3 mo 200 IGT 5 Hyperglycemic clamp — — — 12

Mossop (61) DB 3 mo 600 Type 1; Type 2 26 FBG 2 NA NA NANath (62) OL 2 mo 500 Type 2 12 OGTT 2 2 NA NAGlinsmann (63) OL 18–133 d 180–3000 Type 1; Type 2 6 IVGTT, OGTT 2 NA NA NA

Amato (54) DB 2 mo 1000 NonDM, Elderly 19 Minimal model — — NA —Wilson (45) DB 3 mo 220 NonDM, Young 26 FBG/insulin — 23 NA NA

Studies using CrPic formulationEvans (64) DB 42 d 200 Type 2 11 FBG, HbA1c 2 NA 2 NALee (51) DB 2 mo 200 Type 2 30 FBG, HbA1c — NA — NARavina (65) OL 10 d 200 Type 1; Type 2 48/114 Insulin tolerance, HbA1c NA NA 2 1 Anderson (4) DB 4 mo 200, 1000 Type 2 180 OGTT, HbA1c 2 2 2 NACefalu (3) DB 4, 8 mo 1000 Obese, NonDM 29 Minimal model — 2 NA 1Jovanovic (66) DB 2 mo 320, 640 Gest DM 20 OGTT, HbA1c 2 2 — NARavina (42) OL 1–7 d 600 DM 3 FBG 2 NA NA NAMorris (67) OL 3 mo 400 Type 2 5 Insulin tolerance, HOMA — 2 NA 1Cheng (68) OL 1–10 mo 500 Type 2 833 Fasting, postmeal 2 NA NA NA

1 Abbreviations used: DB, double blind; DM, Diabetes Mellitus; FBG, fasting plasma glucose; HbA1c, hemoglobin A1c; HOMA, homeostasis modelassessment; IGT, impaired glucose tolerant; IS, insulin sensitivity; IVGTT, intravenous glucose tolerance test; NA, not assessed; OGTT, oral glucosetolerance test; OL, open label; 2, decreased; 1, increased; —, no change.

2 -cell sensitivity to glucose.3 In hyperinsulinemic patients only.


























form (pidolate vs. picolinate), duration of diabetes and statusof subjects (44).

Our data suggest a role for supplemental CrPic in obese,insulin-resistant states because CrPic improved glucose toler-ance and insulin levels in obese rats but not in lean controls.It is not known whether the obese JCR:LA-cp rat is Crdeficient; thus, a limitation of this study is the lack of blood orurine Cr levels in the rats. A very important question would bewhether blood Cr status could have explained the differencesin the responses to Cr supplementation between lean andobese rats; if so, it would suggest an abnormality in the insulinsignaling cascade in obesity that appears to be overcome withCr supplementation. Whether hyperinsulinism, insulin resis-tance and/or obesity, therefore, play a role in Cr metabolismand/or excretion is an interesting question suggested by thepresent studies. Such an observation may also explain in partthe reported discrepancies in response to CrPic in humans (seeTable 3).

Our observations in this rat model are in agreement withthe limited human data, which suggest that Cr has a morepredictable 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 apositive effect in those subjects with elevated fasting insulinlevels. In addition, Morris et al. (46) used insulin and glucoseinfusions to demonstrate an inverse relationship in humansbetween plasma insulin levels and plasma Cr levels underconditions in which plasma glucose was unchanged. Thesestudies strengthen the association between Cr and insulinaction and support our approach of characterizing both thephenotype and metabolic conditions when assessing the role of adjunctive use of Cr.

Thus, subject phenotype, i.e., body fat distribution, may bean important parameter in predicting a consistent effect of Crand is a very relevant area of human investigation. In humanstudies, it has been clearly demonstrated that central obesity

and, in particular, an increase in visceral or intra-abdominalfat is related to insulin resistance (3,47,48) and interventionsthat reduce visceral fat, i.e., energy restriction, markedly im-prove resistance (49). However, we have evidence in humansthat demonstrates an effectiveness of Cr at 1000 g/d providedas CrPic in improving insulin sensitivity without a change inbody fat distribution (3). Although no effect on total bodyweight was observed in the present study of the JCR rat, theeffect on body fat distribution was not addressed.

The dose of supplemental Cr used in this rat study shouldbe put in perspective. For example, recently establishedadequate intake of Cr for men was suggested to be 35 g/d(50). Assuming an average 75 kg body mass, this would relateto an intake of 0.47 g/kg. In our recent human trial, we

demonstrated improved insulin sensitivity with 1000 g/d of Cr as CrPic (3) and, given the range of body weights of subjects, intake of Cr ranged from 10 to 13 g/kg. Otherhuman trials have demonstrated a response at much lower Crintakes (4). On the basis of the measured food and waterintakes, rats treated with Cr in this study were receiving twiceas much elemental Cr from the water as from the diet and hada total approximate daily intake of 30 g/kg. Thus, the ratsin this study received supplemental Cr at levels greater thanthose observed to be effective in our human trials and thatcould be considered a pharmacologic dose.

Our data also demonstrate that supplemental CrPic mayimprove lipid levels because we observed decreased plasmatotal cholesterol, increased HDL cholesterol and an improved

cholesterol/HDL cholesterol ratio in obese rats treated withCrPic. 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 significantdrop in cholesterol levels, and Lee et al. (51) observed a 17%drop in triglyceride levels. Other reported human studiesshowed no significant effects on lipids with Cr nicotinic acid(200 g) or CrPic (1000 g) supplementation (53,54). Ben-eficial effects on lipids were also demonstrated in rats given asynthetic, functional biomimetic Cr compound parenterally(52). Whether the improvement in lipid levels is secondary toimprovements in insulin levels per se or a direct effect of Cr onlipid metabolism, is currently unknown. However, there re-main interspecies differences in response to dietary changesbetween rodent and human studies, and this effect on lipids,before being extrapolated to human studies, will have to beevaluated specifically in human trials.

Despite recognition of a specific Cr-deficient state, Cr re-mains the only essential transition metal whose mechanism of action is not known. Recent studies, however, have shed lighton the potential mechanism by which Cr may help to main-tain proper carbohydrate metabolism at a molecular level. Ithas been demonstrated that a naturally occurring oligopeptide,low-molecular-weight Cr-binding substance (termed “chro-

modulin”), binds chromic ions in response to an insulin-mediated chromic ion flux, and the metal-saturated oligopep-tide then binds to an insulin-stimulated insulin receptor,activating the receptor’s tyrosine kinase activity as much aseightfold in the presence of insulin (8,9,55). Thus, chromodu-lin appears to play a role in an autoamplification mechanism ininsulin signaling and provides new insights into how insulinaction can be enhanced with Cr supplementation (55). In-creased insulin signaling would be expected to enhance theregulated movement of Glut-4 and, subsequently, enhanceglucose disposal. Thus, we evaluated for changes in Glut-4content and translocation in this rat study. Although skeletalmuscle Glut-4 content was not affected, an enhanced Glut-4translocation was observed in the obese rats, as demonstrated

by an increase in membrane-associated Glut-4 content afterinsulin stimulation. The upstream cellular signals responsiblefor the enhanced translocation (i.e., enhanced insulin receptorsubstrate phosphorylation, increased phosphatidyl inositol-3,Akt activity) are currently being evaluated.

In summary, this study has confirmed previous reports dem-onstrating a favorable effect of supplemental Cr in humans andsuggests that Cr supplementation in obese insulin-resistantstates may improve insulin action. Further, the improvementin insulin sensitivity resulted in significant improvement inlipid levels. These physiologic improvements occurred withoutdifferences in body weight between treatment groups, suggest-ing a direct effect of CrPic on insulin action. Although insulinsignaling was not assessed in this study, improvement in cel-

lular insulin signaling was suggested by enhanced Glut-4 trans-location after insulin stimulation. These findings will have tobe confirmed in human trials with mechanistic aims beforedefinitive recommendations can be made.

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