Journal of Nutrition

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tannock, L. R.
Right arrow Articles by Chait, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tannock, L. R.
Right arrow Articles by Chait, A.
© 2006 American Society for Nutrition J. Nutr. 136:2856-2861, November 2006

Nutrition and Disease

Glucosamine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor–Deficient Mice1

Lisa R. Tannock2,*, Elizabeth A. Kirk3, Victoria L. King2, Renee LeBoeuf4, Thomas N. Wight5 and Alan Chait4

2 Department of Internal Medicine, University of Kentucky, Lexington, KY 40536-0200; 3 Department of Pathobiology, and 4 Department of Medicine, University of Washington, Seattle, WA 98195; and 5 Hope Heart Institute, Seattle, WA 98101

* To whom correspondence should be addressed. E-mail: lisa.tannock{at}uky.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Glucosamine, commonly consumed for the treatment of osteoarthritis, is classified as a nutritional supplement; however, there are few data regarding its metabolic or vascular effects. Glucosamine is a component of the hexosamine pathway, which has been implicated in the development of insulin resistance. Anecdotal reports suggest that glucosamine consumption can increase circulating cholesterol concentrations. To investigate the metabolic and vascular effects of glucosamine supplementation, we studied male and female LDL receptor–deficient mice fed a Western diet (21% fat, 0.15% cholesterol). Three groups of 6–10 mice of each gender received either no supplement, 15 mg · kg–1 · d–1 glucosamine (equivalent to an average human dose), or 50 mg · kg–1 · d–1 glucosamine added to their drinking water for 5, 10, or 20 wk. Plasma cholesterol and triglyceride concentrations increased in all mice with the addition of the Western diet. However, after 20 wk of treatment, cholesterol and triglyceride concentrations increased further in male mice consuming glucosamine compared with control groups. Glucosamine-supplemented mice had increased initiation of atherosclerosis after 5 wk; however, there was no effect on progression of atherosclerosis in either gender after longer periods of glucosamine supplementation (10 or 20 wk). Although long-term glucosamine supplementation exacerbated the hyperlipidemia in male mice, no increase in atherosclerosis occurred. Thus, glucosamine supplementation appears to be safe, with no adverse vascular consequences.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Glucosamine is an aminosugar that plays a variety of roles in human health and metabolism. Glucosamine can be synthesized from glucose and is an essential component of glycosaminoglycans and mucopolysaccharides, which are components of connective tissue, skin, tendons, and cartilage. Although several trials suggest that glucosamine sulfate is efficacious in improving symptoms and reducing joint space narrowing of osteoarthritis of the knee (1–4), the recent glucosamine/chondroitin arthritis intervention trial using glucosamine HCl did not show significant benefits (5). However, glucosamine is available over-the-counter, is well tolerated, and is relatively inexpensive, resulting in widespread consumption by the American public. Because glucosamine is classified as a nutritional supplement, it is subject to minimal regulation by monitoring boards, and its effects on other chronic diseases as well as metabolic outcomes have not been well studied.

Endogenously synthesized glucosamine is a key component of the hexosamine pathway, which is thought to be a mechanism by which cells sense ambient glucose concentrations (6–9). In a variety of cell culture and animal models, administration of high doses of glucosamine has been shown to induce insulin resistance (10–12). However, doses commonly consumed by humans do not appear to increase insulin resistance (5,13). Another area of concern regarding glucosamine consumption is its potential effect on lipid metabolism; in the lay press, there are several reports of glucosamine supplementation leading to increased cholesterol concentrations (14–16). The Danish Medical Association has recently posted a concern regarding the effect of glucosamine in raising cholesterol concentrations and is gathering data (17). High cholesterol concentrations and insulin resistance are both recognized risk factors for the development of atherosclerosis and cardiovascular disease. Given that most people who choose to supplement glucosamine do so over long periods of time, the effects of glucosamine to raise insulin resistance and/or cholesterol could result in increased atherosclerosis development.

Conversely, glucosamine consumption could alter the structure of the vascular wall in a manner that could decrease atherosclerosis. Glucosamine is a precursor for the synthesis of proteoglycans, a complex group of heterogeneous extracellular matrix molecules. Proteoglycans in the artery wall play a key role in the development of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins in the arterial wall (18). Proteoglycans bind lipoproteins via ionic interactions between the negatively charged sulfate and carboxyl groups on the glycosaminoglycans and positively charged amino acid residues on the lipoproteins. We previously found that proteoglycans synthesized by vascular smooth muscle cells in vitro in the presence of glucosamine are smaller, with shorter glycosaminoglycan chains, reduced sulfate incorporation, and decreased lipoprotein binding affinity (19). A recent study found that glucosamine stimulated increased heparan sulfate proteoglycan synthesis by endothelial cells and smooth muscle cells and also inhibited smooth muscle cell proliferation (20). If glucosamine has similar effects to modulate vascular proteoglycan synthesis in vivo, then it could be protective against atherosclerosis development, as suggested by a recent study that demonstrated decreased atherosclerosis in apoE-deficient mice given intraperitoneal glucosamine for 8 wk (20).

The purpose of this study was to determine whether chronic glucosamine supplementation altered atherosclerosis development in mice. A major focus was to characterize metabolic parameters in mice receiving chronic glucosamine supplementation. The LDL receptor–deficient (LDLR–/–) mouse was selected for this study, because similar to humans, it carries the majority of its cholesterol in LDL particles, is susceptible to diet-induced hyperlipidemia, and develops lesions of early atherosclerosis when fed an atherogenic (Western) diet (21,22).


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Animal model. LDLR–/– mice were purchased from Jackson Laboratories. Mice were separated into groups of 5 and were enrolled in the study at different times to ensure robust and reliable data. This project was approved by the Animal Care and Use Committees of the University of Washington and the University of Kentucky. Because gender-specific differences in atherosclerosis have been reported (23–25), we studied both genders and analyzed data in a gender-specific manner. Mice were housed in temperature controlled (25°C) vivarium facilities with 12-h light/dark cycles. Mice consumed normal mouse chow (18% protein, 5% fat; TD2018, Harlan Teklad) ad libitum until 8 wk of age, when they were switched to a Western diet [21.2% (by weight) fat, 0.15% cholesterol, 17.3% protein] (26) (TD88137, Harlan Teklad). Diets were stored in air-tight bags at –20°C and aliquots were removed as needed. Anesthetized mice were killed at the indicated intervals by cervical dislocation.

    Glucosamine supplementation. Supplemental glucosamine HCl (Sigma) was added to the drinking water at concentrations to achieve 3 doses: no added glucosamine (control), 15 mg · kg–1 · d–1 (comparable to the average human dose on a mg/kg basis) and 50 mg · kg–1 · d–1. Water consumption was determined every 2 d and mice were weighed weekly. Glucosamine supplementation began at the same time the Western diet started (age 8 wk) and continued for the duration of the study. To evaluate effects of glucosamine on various stages of lesion development, atherosclerosis was quantified after 5, 10, and 20 wk of diet treatment. To confirm proportional absorption of glucosamine, 12 female mice were gavaged with [14C]-glucosamine after 5 wk of diet/glucosamine supplementation. The [14C]-glucosamine was administered at constant specific activity: 6 mice on the 15 mg · kg–1 · d–1 dose received 74 kBq of [14C]-glucosamine carried in water with 15 mg/kg unlabeled glucosamine, and 6 mice on the 50 mg · kg–1 · d–1 dose received 246.4 kBq [14C]-glucosamine carried in water with 50 mg/kg unlabeled glucosamine, in the same total volume. Mice were bled 2 or 4 h after gavage for detection of radioactivity in plasma and were killed 24 h postgavage. Tissues were homogenized in a 1-mL volume and subject to liquid scintillation counting. Results are expressed as Bq/mg wet weight of tissue. Plasma radioactivity was determined by liquid scintillation counting of 25 µL of plasma.

    Metabolic analyses. All food was removed 4 h prior to collection of blood from the retro-orbital sinus and samples were obtained in all mice at baseline and study end. Mice in the 20-wk group also had a sample obtained after 10 wk. Plasma cholesterol concentrations were determined by using a colorimetric kit (kit 234–99, Diagnostic Chemicals) and cholesterol standards (Boehringer Mannheim). Plasma triglyceride concentrations were determined colorimetrically after removal of free glycerol (kit 450032). The lipoprotein cholesterol profile was determined for 3–6 mice per group on mouse plasma separated by FPLC (27). Glycated hemoglobin was quantified using a commercial kit (kit G7540, Pointe Scientific). Plasma glucose concentrations were determined by the Trinder method (kit G7521, Pointe Scientific) and insulin concentrations were measured by ELISA (kit 10–1149, Mercodia). To estimate insulin resistance, the HOMA index (the homeostasis model assessment for insulin resistance) was calculated using the equation [glucose (mg/dL) · insulin (µIU/mL)/405] (28, 29).

    Atherosclerosis analysis. Fatty streaks were quantified by evaluation of oil red O stained lesions in the aortic sinus, as described previously (22). Briefly, 9 sections (10 µm thick) per mouse obtained throughout the aortic sinus (400µm) were stained with oil red O, counterstained with Harris' hematoxylin, and the lesion area was quantified using computer assisted morphometry (Image-Pro software, Media Cybernetics). Aortic surface lesions were analyzed on aortas cleaned of fat and adventitia and cut open along the greater curvature (30). Lesion area was determined by computer assisted morphometry and quantified using ImagePro software (31).

    Evaluation of proteoglycan synthesis ex vivo. To determine the effects of oral glucosamine on vascular proteoglycan synthesis, the aortas were removed from 5 female mice per group after 5 wk of glucosamine, and 3 female mice per group after 20 wk of glucosamine (0 mg · kg–1 · d–1 and 50 mg · kg–1 · d–1 groups only) supplementation. The aortas were cleaned of fat and adventitia, cut into 2-mm rings, then placed in separate dishes in 1 mL of low sulfate Dulbecco's Modified Eagle's medium containing 3.7 MBq [35S]-SO4. After 24 h, the culture medium were collected in the presence of protease inhibitors, as previously described (19). Aortic rings were washed with saline then homogenized in 1 mL of 4 mol/L guanidine-HCl buffer. Proteoglycan synthesis was evaluated by determination of [35S]-SO4 incorporation by cetyl pyridinium chloride incorporation (32). Secreted proteoglycans were purified on DEAE-Sephacel minicolumns and proteoglycan size and distribution was evaluated by SDS-PAGE, as previously described (19).

    Statistical analysis. Data are reported as mean ± SEM. Absorption of [14C]-glucosamine was compared by t test. Other data were tested using 2-way ANOVA (glucosamine supplementation group and time) within each gender, with multiple pairwise comparisons performed using the Holm-Sidak method. We tested variances for homogeneity and performed analyses as suggested by the statistical package (SigmaStat). Differences with <0.05 were regarded as significant. The 5-wk atherosclerosis studies were performed first at the University of Washington then repeated at the University of Kentucky. Data from the 2 institutions were compared by 2-way ANOVA (glucosamine supplementation and institution) and were found not to differ; thus, all 5-wk data were pooled.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Tolerance of glucosamine. Glucosamine was well tolerated. Water intake did not differ between mice receiving glucosamine or control mice (data not shown). Body wt and hepatic weight did not differ between the mice receiving glucosamine and control mice of the same gender at any time (data not shown). No adverse effects from glucosamine supplementation were seen. Glucosamine absorption was proportionally increased in the group receiving 50 mg · kg–1 · d–1 compared with 15 mg · kg–1 · d–1 as tested by administration of [14C]-glucosamine. Glucosamine appeared to be mainly distributed to kidney and liver, with lower concentrations in heart and aorta, by 24 h after administration (Table 1). The amount of [14C]-glucosamine entering the aorta did not increase with the higher dose; however, other tissues did show a proportional increase in [14C]-glucosamine distribution (P < 0.05; Table 1).


View this table:
[in this window]
[in a new window]
  		TABLE 1 Absorption of [14C]-glucosamine after 5 wk of glucosamine supplementation in female LDLR–/– mice1

 
    Metabolic effects of glucosamine. Initiation of the Western diet caused significant elevations in plasma cholesterol (P < 0.001) and triglyceride concentrations (P < 0.001) in both female and male mice compared with baseline concentrations (Table 2). However, in male mice only, plasma cholesterol concentrations were higher (P < 0.01) in mice receiving glucosamine compared with control mice after 20 wk, with a similar trend for an increase in plasma triglyceride concentrations (P = 0.06), suggesting that prolonged glucosamine consumption exacerbated the dyslipidemia. Analysis of the lipoprotein cholesterol distribution profile of male mice after 20 wk of diet and glucosamine treatments demonstrated that this increase in cholesterol and triglycerides was primarily due to an increase in the VLDL fraction in mice receiving glucosamine compared with control mice (data not shown). In female mice, there were no differences in total cholesterol or triglyceride concentrations between mice receiving glucosamine and control mice at any point (Table 2). The lipoprotein distribution profile did not vary between groups at any time in female mice, nor in male mice at the earlier time points (data not shown).


View this table:
[in this window]
[in a new window]
  		TABLE 2 Plasma cholesterol and triglyceride concentrations increased after 20 wk of glucosamine supplementation in male but not female LDLR–/– mice1

 
Similar to the effect of the Western diet on circulating lipids, the initiation of the Western diet increased glucose, insulin, and glycated hemoglobin concentrations and the HOMA index (all P < 0.002) in both female and male mice compared with baseline (Table 3). Glucose, insulin, or glycated hemoglobin concentrations and the HOMA index did not differ between mice receiving glucosamine and control mice at any point.


View this table:
[in this window]
[in a new window]
  		TABLE 3 Circulating glucose, insulin, and glycated hemoglobin concentrations and the HOMA index are increased by the initiation of a Western diet but not by glucosamine supplementation in male or female LDLR–/– mice1

 
    Effect of glucosamine on atherosclerosis. There was a progressive increase in atherosclerosis lesion area over time in both female and male mice (P < 0.001 for both genders). In female mice receiving glucosamine for 5 wk, there was a considerable and reproducible increase in extent of fatty streak lesion area compared with the control group (Fig. 1A; P = 0.005). The control group differed significantly from the other 2 groups, but the glucosamine groups did not differ from one another. A similar effect was observed in male mice (Fig. 1B; P < 0.05); the control group differed significantly from the 50 mg · kg–1 · d–1 group). This outcome was reproduced in 2 separate groups of mice enrolled at different times in different institutions (graphs show all mice). In contrast, lesion areas did not differ between groups receiving glucosamine or controls in either gender after 10 or 20 wk of treatment (Fig. 1A,B). Similarly, en face analysis of the aortic lesion area revealed no differences between mice receiving glucosamine or controls after 10 and 20 wk of diet (data not shown). In particular, there was no increase in atherosclerosis in male mice after 20 wk of glucosamine, despite the exacerbation of dyslipidemia induced by glucosamine at that time.


Figure 1
View larger version (13K):
[in this window]
[in a new window]
  		Figure 1  Glucosamine supplementation increased atherosclerosis development in female (A) and male (B) LDLR–/– mice at 5 wk, but not at later time points. Points shown are for individual mice with means shown by the horizontal lines in each cluster of symbols. Means without a common letter differ, P < 0.05.

 
    Effect of glucosamine on aortic proteoglycan synthesis. In female mice that received glucosamine for 5 (data not shown) or 20 wk (Fig. 2A), sulfate incorporation did not differ between glucosamine and control groups for either secreted or tissue-associated proteoglycans. The proteoglycans secreted by mouse aortic rings ex vivo have similar migration patterns to those seen with proteoglycans synthesized by cultured vascular smooth muscle cells (19); however, the size of secreted proteoglycans did not differ between glucosamine or control groups after 5 (data not shown) or 20 wk (Fig. 2B).


Figure 2
View larger version (38K):
[in this window]
[in a new window]
  		Figure 2  Aortas from female LDLR–/– mice supplemented with glucosamine for 20 wk did not have altered proteoglycan sulfate incorporation (A) or size (B). Values are means ± SEM, n = 3 (A). In B, each lane represents proteoglycans secreted from individual aortae.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The purpose of this study was to determine whether glucosamine supplementation, at doses similar to the average human dose (on a mg · kg–1 · d–1 basis), affected atherosclerosis development and metabolic indices. We report 2 main findings from our studies. First, in both male and female LDLR–/– mice, short term glucosamine supplementation (5 wk) significantly increased atherosclerosis initiation, but this early difference in atherosclerosis did not persist, and ultimately there was no difference in atherosclerosis progression between glucosamine and control groups. Glucosamine groups and the control group did not differ in any lipid or glycemic variable after 5 wk of glucosamine supplementation to account for this increased atherosclerosis, nor were there differences in vascular proteoglycan synthesis. Thus, the mechanism(s) by which glucosamine increases atherosclerosis initiation are not clear. Second, long-term glucosamine supplementation (20 wk) in male, but not female, mice exacerbated the diet-induced hyperlipidemia. In this study, we have confirmed previous reports that the Western diet can induce a type 2 diabetes–like phenotype in male LDLR–/–mice (26,33) but also demonstrate increases in glucose, insulin, and glycated hemoglobin concentrations and the HOMA index in female LDLR–/– mice. The effect of glucosamine supplementation to exacerbate the dyslipidemia in male mice but not female mice may indicate gender differences in susceptibility to adverse effects of glucosamine or may indicate an effect of glucosamine to exacerbate hyperlipidemia in the setting of insulin resistance. There is a paucity of human data examining the effects of glucosamine supplementation on lipid variables, despite several anecdotal reports in the lay press (14,15,17). The importance of this exaggerated hyperlipidemia induced by glucosamine is not clear, because despite this increase in cholesterol and triglyceride concentrations, we did not observe any differences between groups in the extent of atherosclerosis. One limitation of this interpretation may be the duration of investigation. We did not evaluate metabolic indices between 10 and 20 wk of glucosamine supplementation; thus, the duration of the increased dyslipidemia is unknown. It is possible that continued glucosamine supplementation, with continued exacerbation of dyslipidemia, may lead to increased progression of atherosclerotic lesions.

The mechanism leading to increased early atherosclerosis in glucosamine-supplemented mice compared with control mice is not clear. Our data are in opposition to a recent study that demonstrated decreased atherosclerosis after 8 wk of intraperitoneal glucosamine administration in apoE-deficient mice (20). There are numerous differences between the studies that could account for the discrepant results, including different mice (LDLR–/– vs. apoE–/–), different formulation of glucosamine (our study used glucosamine HCl, whereas the other study used glucosamine sulfate), dose, duration, and route of administration of glucosamine. However, our finding of increased atherosclerosis after 5 wk of supplementation was robust and reproduced in separate groups of mice enrolled at different times and in different institutions. Although we observed a robust increase in atherosclerosis initiation, this likely has low clinical impact, because human studies have shown initiation of atherosclerosis occurs at very young ages (34,35); thus, most humans consuming glucosamine would already have early atherosclerotic lesions. We found no effect of glucosamine on atherosclerosis progression.

We previously reported that glucosamine supplementation (at millimolar concentrations) of vascular smooth muscle cells in vitro led to the synthesis of smaller, less sulfated proteoglycans, with reduced LDL binding affinity (19). We hypothesized that if this effect of glucosamine to alter vascular proteoglycan synthesis existed in vivo, it would result in decreased atherosclerosis secondary to reduced retention of LDL in the arterial wall. However, when we examined the synthesis of proteoglycans ex vivo by aortic rings obtained from mice after 5 or 20 wk of glucosamine supplementation, we found no effect of glucosamine on the size of or the amount of sulfate incorporated into secreted proteoglycans. Thus, either the arterial wall concentrations of glucosamine were insufficient to induce alterations in vascular proteoglycan synthesis, or the effect of glucosamine to decrease proteoglycan size that we observed in vitro does not occur in vivo. To address this, we estimated glucosamine distribution by administering to mice proportional doses of radioactive glucosamine. We found that whereas glucosamine concentrations in the plasma, liver, kidney, and heart were proportionally increased after administration of the higher dose of [14C]-glucosamine compared with the lower dose, the radioactivity localized to the aorta was not different between the doses. The concentrations of glucosamine achieved in plasma after administration of these doses could not be determined due to technological limitations in assaying the small plasma volumes obtainable in mice. However, the plasma concentrations of glucosamine achieved after oral ingestion of glucosamine have been estimated to be <60 µmol/L (13), and in 1 study examining concentrations in 18 subjects, the highest plasma concentration was 11.5 µmol/L (36). In our previous in vitro studies, we did not observe effects on proteoglycan synthesis in vascular smooth muscle cells exposed to micromolar concentrations of glucosamine (19). Thus, the local vascular wall concentrations of glucosamine were likely too low to affect proteoglycan synthesis in vivo, accounting for the difference between our observed results and our hypothesis that glucosamine-induced alterations in vascular proteoglycans would result in decreased atherosclerosis.

Glucosamine is classified as a supplement and is thus subject to minimal regulation by most regulatory boards. Glucosamine is widely consumed and has been for many years; thus, it is unlikely that significant toxicity results from long-term consumption. However, there are several anecdotal reports in the lay press indicating that some individuals do develop adverse metabolic effects when consuming glucosamine (14,15,17). The currently available data do not rule out an adverse effect of chronic glucosamine consumption on lipid concentrations in humans. The long-term ramifications of even a subtle increase in dyslipidemia are important. Although we found that long-term glucosamine consumption increased cholesterol and triglyceride concentrations in male mice, we did not find any adverse effect on atherosclerosis progression. Thus, the data from this study suggest that glucosamine supplementation is safe, with no long-term adverse vascular consequences. However, we caution that these data are observed in mouse atherosclerosis, and we propose that clinical trials evaluating glucosamine should include measurements of cholesterol and triglycerides, as well as evaluation of cardiovascular outcomes.


   ACKNOWLEDGMENTS
 
The authors thank Tim McMillen for expert technical assistance.


   FOOTNOTES
 
1 Supported by grants AT00555, DK02456, and HL52848, and a grant from the Juvenile Diabetes Research Foundation. The facilities of the Clinical Nutrition Research Unit (CNRU; DK35816) nutrient-gene core and the Diabetes Endocrinology Research Center (DERC; DK17047) cell and tissue core were used. We gratefully acknowledge support by the University of Kentucky Hospital under the Physician Scientist Program. Back

Manuscript received 10 August 2006. Initial review completed 31 August 2006. Revision accepted 12 September 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162:2113–23.[Abstract/Free Full Text]

2. Bruyere O, Pavelka K, Rovati LC, Deroisy R, Olejarova M, Gatterova J, Giacovelli G, Reginster JY. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause. 2004;11:138–43.[Medline]

3. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000;283:1469–75.[Abstract/Free Full Text]

4. Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G, Henrotin Y, Dacre JE, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251–6.[Medline]

5. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO III, Weisman MH, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795–808.[Abstract/Free Full Text]

6. Zraika S, Dunlop M, Proietto J, Andrikopoulos S. The hexosamine biosynthesis pathway regulates insulin secretion via protein glycosylation in mouse islets. Arch Biochem Biophys. 2002;405:275–9.[Medline]

7. Wells L, Vosseller K, Hart GW. A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance. Cell Mol Life Sci. 2003;60:222–8.[Medline]

8. Parker GJ, Lund KC, Taylor RP, McClain DA. Insulin resistance of glycogen synthase mediated by o-linked N-acetylglucosamine. J Biol Chem. 2003;278:10022–7.[Abstract/Free Full Text]

9. McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA. Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci USA. 2002;99:10695–9.[Abstract/Free Full Text]

10. Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC. Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J Biol Chem. 2001;276:31099–104.[Abstract/Free Full Text]

11. Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes. 1999;48:1562–71.[Abstract]

12. Spampinato D, Giaccari A, Trischitta V, Costanzo BV, Morviducci L, Buongiorno A, Di Mario U, Vigneri R, Frittitta L. Rats that are made insulin resistant by glucosamine treatment have impaired skeletal muscle insulin receptor phosphorylation. Metabolism. 2003;52:1092–5.[Medline]

13. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol. 2005;43:187–201.[Medline]

14. healthandage.com [homepage on the Internet]. Dr. Irene's Tidbits. c2002 [cited 2002 Mar 13]. Available from http://drirene.healthandage.com/qa3/qa30013.htm.

15. askwaltstoll.md [homepage on the Internet]. c1998 [cited 1999 Jan 27]. Available from http://askwaltstollmd.com/archives/gluc.html.

16. Andersen GD. Commonly asked questions of 2000: glucosamine and chondroitin. Dynamic Chiropractic [serial on the Internet]. 2001 [cited 2001 Jan 1];19(1):[about 4 p.]. Available from http://chiroweb.com/archives/19/01/01.html.

17. Danish Medical Association. Glucosamine and an elevated cholesterol level. c2004 [cited 2004 Oct 23]. Available from http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=4221.

18. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002;417:750–4.[Medline]

19. Tannock LR, Little PJ, Wight TN, Chait A. Arterial smooth muscle cell proteoglycans synthesized in the presence of glucosamine demonstrate reduced binding to LDL. J Lipid Res. 2002;43:149–57.[Abstract/Free Full Text]

20. Duan W, Paka L, Pillarisetti S. Distinct effects of glucose and glucosamine on vascular endothelial and smooth muscle cells: evidence for a protective role for glucosamine in atherosclerosis. Cardiovasc Diabetol. 2005;4:16.[Medline]

21. Breslow JL. Mouse models of atherosclerosis. Science. 1996;272:685–8.[Abstract]

22. Crawford RS, Kirk EA, Rosenfeld ME, LeBoeuf RC, Chait A. Dietary antioxidants inhibit development of fatty streak lesions in the LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol. 1998;18:1506–13.[Abstract/Free Full Text]

23. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci USA. 1995;92:8264–8.[Abstract/Free Full Text]

24. Whitman SC, Ravisankar P, Daugherty A. IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E–/– mice. J Interferon Cytokine Res. 2002;22:661–70.[Medline]

25. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000;106:523–31.[Medline]

26. Merat S, Casanada F, Sutphin M, Palinski W, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol. 1999;19:1223–30.[Abstract/Free Full Text]

27. Ordovas JM, Osgood D. Preparative isolation of plasma lipoproteins using fast protein liquid chromatography (FPLC). Methods Mol Biol. 1998;110:105–11.[Medline]

28. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.[Medline]

29. Xia Z, Sniderman AD, Cianflone K. Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice. J Biol Chem. 2002;277:45874–9.[Abstract/Free Full Text]

30. Daugherty A, Whitman SC. Quantification of atherosclerosis in mice. Methods Mol Biol. 2003;209:293–309.[Medline]

31. Whitman SC, Rateri DL, Szilvassy SJ, Yokoyama W, Daugherty A. Depletion of natural killer cell function decreases atherosclerosis in low-density lipoprotein receptor null mice. Arterioscler Thromb Vasc Biol. 2004;24:1049–54.[Abstract/Free Full Text]

32. Schonherr E, Jarvelainen HT, Sandell LJ, Wight TN. Effects of platelet-derived growth factor and transforming growth factor, beta1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem. 1991;266:17640–7.[Abstract/Free Full Text]

33. Schreyer SA, Vick C, Lystig TC, Mystkowski P, LeBoeuf RC. LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice. Am J Physiol Endocrinol Metab. 2002;282:E207–14.[Abstract/Free Full Text]

34. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Natural history of aortic and coronary atherosclerotic lesions in youth. Findings from the PDAY Study. Arterioscler Thromb. 1993;13:1291–8.[Abstract/Free Full Text]

35. Jarvisalo MJ, Jartti L, Nanto-Salonen K, Irjala K, Ronnemaa T, Hartiala JJ, Celermajer DS, Raitakari OT. Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation. 2001;104:2943–7.[Abstract/Free Full Text]

36. Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE. Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness. Ann Rheum Dis. 2006;65:222–6.[Abstract/Free Full Text]





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tannock, L. R.
Right arrow Articles by Chait, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tannock, L. R.
Right arrow Articles by Chait, A.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Copyright © 2006 by American Society for Nutrition