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PubMed2004

Glucosamine-induced insulin resistance in L6 muscle cells.

BACKGROUND: Glucosamine increases flux through the hexosamine pathway, causing insulin resistance and disturbances similar to diabetic glucose toxicity. AIM: This study examines the effect of glucosamine on glucose uptake by cultured L6 muscle cells as a model of insulin resistance. METHODS: Glucose uptake by L6 myotubes was measured using the non-metabolized glucose analogue 2-deoxy-d-glucose after incubation with glucosamine for 4 and 24 h, with and without insulin and several other agents (metformin, peroxovanadium and d-pinitol) that improve glucose uptake in diabetic states. RESULTS: After 4 h, high concentrations of glucosamine (5 x 10(-3) and 10(-2) M) reduced basal and insulin-stimulated glucose uptake by up to 50%. After 24 h, the effect of insulin was completely abolished by 10(-2) M glucosamine and reduced over 50% by 5 x 10(-3) M glucosamine. Lower concentrations of glucosamine did not significantly alter glucose uptake. The effect of glucosamine could not be attributed to cytotoxicity assessed by the Trypan Blue test. Metformin, peroxovanadium and d-pinitol, each of which increased glucose uptake by L6 cells, did not prevent the decrease in glucose uptake with glucosamine. CONCLUSION: Glucosamine decreased insulin-stimulated glucose uptake by L6 muscle cells, providing a potential model of insulin resistance with similarities to glucose toxicity. Insulin resistance induced by glucosamine was not reversed by three agents (metformin, peroxovanadium and d-pinitol) known to enhance or partially mimic the effects of insulin.

Animals↗

PubMed2006

Mechanisms of glucosamine-induced suppression of the hepatic assembly and secretion of apolipoprotein B-100-containing lipoproteins.

Glucosamine-induced endoplasmic reticulum (ER) stress was recently shown to specifically reduce apolipoprotein B-100 (apoB-100) secretion by enhancing the proteasomal degradation of apoB-100. Here, we examined the mechanisms linking glucosamine-induced ER stress and apoB-lipoprotein biogenesis. Trypsin sensitivity studies suggested glucosamine-induced changes in apoB-100 conformation. Endoglycosidase H studies of newly synthesized apoB-100 revealed glucosamine induced N-linked glycosylation defects resulting in reduced apoB-100 secretion. We also examined glucosamine-induced changes in VLDL assembly and secretion. A dose-dependent (1-10 mM glucosamine) reduction was observed in VLDL-apoB-100 secretion in primary hepatocytes (24.2-67.3%) and rat McA-RH7777 cells (23.2-89.5%). Glucosamine also inhibited the assembly of larger VLDL-, LDL-, and intermediate density lipoprotein-apoB-100 but did not affect smaller HDL-sized apoB-100 particles. Glucosamine treatment during the chase period (posttranslational) led to a 24% reduction in apoB-100 secretion (P < 0.01; n = 4) and promoted post-ER apoB degradation. However, the contribution of post-ER apoB-100 degradation appeared to be quantitatively minor. Interestingly, the glucosamine-induced posttranslational reduction in apoB-100 secretion could be partially prevented by treatment with desferrioxamine or vitamin E. Together, these data suggest that cotranslational glucosamine treatment may cause defects in apoB-100 N-linked glycosylation and folding, resulting in enhanced proteasomal degradation. Posttranslationally, glucosamine may interfere with the assembly process of apoB lipoproteins, leading to post-ER degradation via nonproteasomal pathways.

Animals↗

PubMed2003

Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors.

IGF-I stimulates insulin-like actions directly through its receptor, and it also enhances sensitivity to insulin-mediated effects in vivo. These studies were undertaken to analyze the role of IGF-I, insulin, and insulin/IGF-I hybrid receptors (HRs) in mediating IGF-I and insulin signaling in cells that had been made insulin-resistant by treatment with glucosamine. Human HepG2 cells, which express IGF-I receptors, insulin receptors (IRs), and IGF-I/insulin HRs, were exposed to 20 mM glucosamine; and the effects of IGF-I and insulin in stimulating glycogen synthesis were determined. An overnight exposure to glucosamine markedly attenuated the effects of insulin and IGF-I in stimulating glycogen synthesis. To determine which receptors were mediating this effect, the ability of insulin and IGF-I to stimulate phosphorylation of their respective receptors was analyzed. An 18-h exposure to glucosamine (20 mM) caused a 75% reduction in the ability of IGF-I to phosphorylate its receptor but no change in receptor abundance. Glucosamine also caused a major reduction in insulin-stimulated receptor phosphorylation, although, unlike IGF-I, there was also a 50% reduction in IR abundance. Exposure to glucosamine also resulted in a reduction in the ability of IGF-I or insulin to stimulate phosphorylation of insulin IGF-I/HRs. The combination of insulin plus IGF-I was a more potent stimulus of HR phosphorylation than either agent alone, and this combination was also more potent in partially reversing the inhibitory effect of glucosamine. Taken together, these findings indicate that glucosamine induces a loss of sensitivity to stimulation of insulin, IGF-I, or HR tyrosine kinase activity by insulin or IGF-I. Although insulin is able to partially reverse the effect of glucosamine on IR phosphorylation, it has a very minimal effect on glucosamine-induced inhibition of HR phosphorylation. However, the combination of IGF-I and insulin induces a major increase in HR phosphorylation, even in the presence of glucosamine, suggesting that it is improving the sensitivity of the HR to insulin activation.

Carcinoma, Hepatocellular↗

PubMed2001

Glucosamine therapy for treating osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis, and it is often associated with significant disability and an impaired quality of life. OBJECTIVES: To review all randomized controlled trials (RCTs) evaluating the effectiveness and toxicity of glucosamine in osteoarthritis (OA). SEARCH STRATEGY: We searched MEDLINE, Embase, and Current Contents up to November 1999, and the Cochrane Controlled Trials Register. We also wrote letters to content experts, and hand searched reference lists of identified RCTs and pertinent review articles. SELECTION CRITERIA: Relevant studies met the following criteria: 1) RCTs evaluating the effectiveness and safety of glucosamine in OA, 2) Both placebo based and comparative studies were eligible, 3) Both single blinded and double-blinded studies were eligible. DATA COLLECTION AND ANALYSIS: Data abstraction was performed independently by two investigators and the results were compared for degree of agreement. Gotzsche's method and a validated tool (Jadad 1995) were used to score the quality of the RCTs. Continuous outcome measures were pooled using standardized mean differences. Dichotomous outcome measures were pooled using Peto Odds Ratios. MAIN RESULTS: Collectively, the 16 identified RCTs provided evidence that glucosamine is both effective and safe in OA. In the 13 RCTs in which glucosamine was compared to placebo, glucosamine was found to be superior in all RCTs, except one. In the four RCTs in which glucosamine was compared to an NSAID, glucosamine was superior in two, and equivalent in two. REVIEWER'S CONCLUSIONS: Further research is necessary to confirm the long term effectiveness and toxicity of glucosamine therapy in OA. Most of the trials reviewed only evaluated the Rotta preparation of glucosamine sulfate. It is not known whether different glucosamine preparations prepared by different manufacturers are equally effective in the therapy of OA.

Double-Blind Method↗

PubMed2005

Inhibitory action of glucosamine on platelet activation in guinea pigs.

OBJECTIVE: Glucosamine, a naturally occurring amino monosaccharide, has been used to treat or prevent osteoarthritis in humans. Recently, we have revealed that glucosamine inhibits platelet activation in vitro. However, the effect of in vivo administration of glucosamine has not yet been clarified. In this study, we administered glucosamine orally to guinea pigs and examined its effects on platelet functions. MATERIALS AND METHODS: Glucosamine hydrochloride solution (0.5%, 5 mg/ml) was administered orally to guinea pigs ad libitum for 22 days, and platelet rich plasma was collected to evaluate platelet functions in vitro. Guinea pigs received an average of 400 mg glucosamine/animal/day. RESULTS: Glucosamine-administration suppressed platelet aggregation in response to ADP by 51% (p < 0.01), but not platelet aggregation induced by collagen. Furthermore, glucosamine-administration inhibited the ADP-induced extracellular release of ATP and production of thromboxane A(2) by 91% and 96%, respectively (p < 0.001). In contrast, glucosamine did not affect the body-weights, platelet counts and bleeding time in guinea pigs after the administration. CONCLUSIONS: These observations suggest that glucosamine is likely to exert an inhibitory action on platelets in vivo by suppressing platelet aggregation, ATP release, and thromboxane A(2) production. Thus, glucosamine could be expected as a novel and safe anti-platelet agent.

Adenosine Diphosphate↗

PubMed2005

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment.

AIMS/HYPOTHESIS: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. MATERIALS AND METHODS: Glucosamine (6.48 mg kg(-1) min(-1) for 3 h) was infused with or without insulin (10 mU kg(-1) min(-1)) into anaesthetised rats under euglycaemic conditions. RESULTS: Glucosamine infusion alone increased blood glucosamine (1.9+/-0.1 mmol/l) and glucose (5.4+/-0.2 to 7.7+/-0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hind-leg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. CONCLUSION/INTERPRETATION: Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.

Algorithms↗

PubMed2006

Prevalence of and factors associated with glucosamine use in Canada.

OBJECTIVE: Glucosamine is commonly used for the treatment of osteoarthritis, and its use is increasing in the general population. The Canadian Multicentre Osteoporosis Study (CaMos) provided an opportunity to examine the prevalence of glucosamine use across age and gender groups, and to assess the factors associated with its use. METHOD: CaMos is a random, population-based sample of 9423 Canadians. Baseline assessments took place in 1996-1997 and the 5-year follow-up assessments in 2001-2002. The primary outcome of this analysis was glucosamine use at year 5. Prevalence estimates were age- and sex-standardized to the Canadian population. A number of factors potentially associated with glucosamine use were identified from the literature. Multivariable logistic regression was used to identify variables associated with glucosamine use. RESULTS: At 5 years, complete data were available for 7652 of the original 9423 participants (81.2%). For men, glucosamine use increased from 0.9% to 4.7% (weighted values), and for women, it increased from 1.3% to 8.2%. Glucosamine use was higher among older participants, those living in western Canada, and those with arthritis, back pain, higher calcium intake from supplements, physical activity and prior glucosamine use. CONCLUSIONS: Glucosamine use increased substantially over 5 years, and its use is associated with a number of factors. Some may use glucosamine to manage pain and symptoms of arthritis and back pain, while others use it as a preventive measure to maintain health.

Adult↗

PubMed2005

Metabolic engineering of Escherichia coli for industrial production of glucosamine and N-acetylglucosamine.

Glucosamine and N-acetylglucosamine are currently produced by extraction and acid hydrolysis of chitin from shellfish waste. Production could be limited by the amount of raw material available and the product potentially carries the risk of shellfish protein contamination. Escherichia coli was modified by metabolic engineering to develop a fermentation process. Over-expression of glucosamine synthase (GlmS) and inactivation of catabolic genes increased glucosamine production by 15 fold, reaching 60 mg l(-1). Since GlmS is strongly inhibited by glucosamine-6-P, GlmS variants were generated via error-prone PCR and screened. Over-expression of an improved enzyme led to a glucosamine titer of 17 g l(-1). Rapid degradation of glucosamine and inhibitory effects of glucosamine and its degradation products on host cells limited further improvement. An alternative fermentation product, N-acetylglucosamine, is stable, non-inhibitory to the host and readily hydrolyzed to glucosamine under acidic conditions. Therefore, the glucosamine pathway was extended to N-acetylglucosamine by over-expressing a heterologous glucosamine-6-P N-acetyltransferase. Using a simple and low-cost fermentation process developed for this strain, over 110 g l(-1) of N-acetylglucosamine was produced.

Acetylglucosamine↗

PubMed1998

Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus.

Sustained hyperglycemia can cause peripheral insulin resistance and pancreatic beta-cell dysfunction and has been termed glucose toxicity or glucose-induced desensitization. Glucosamine, a product of glucose flux through the hexosamine biosynthetic pathway (HBP), causes insulin resistance in peripheral tissues and has been shown to cause abnormal glucose-insulin secretion coupling, and thus has been implicated in the pathogenesis of glucose toxicity. Here, we investigate whether glucosamine-induced insulin secretory dysfunction is specific to glucose or also extends to nonglucose secretagogues such as arginine. Two groups of 12 weight-matched Sprague-Dawley rats underwent hyperglycemic clamp studies (steady-state blood glucose, approximately 220 mg x dL(-1)) during infusion of normal saline or glucosamine 3.5 mg x kg(-1) x min(-1) over a 100-minute period. Insulin levels were measured at baseline and between 90 and 100 minutes. One hundred minutes into the hyperglycemic clamp, subgroups of seven rats each (saline- and glucosamine-infused rats) received a bolus of arginine (100 mg x kg(-1)) while the glucose infusion rate was unaltered. Glucose and insulin levels were measured at 1, 3, 5, 10, 15, and 30 minutes after the arginine bolus. Both groups had similar fasting glucose and insulin levels. At steady state (60 to 100 minutes), glucose levels were almost identical in both groups (223.58+/-3.94 v 224.58+/-4.34 mg x dL(-1)), but the glucose infusion rate (26.55+/-1.60 v 8.83+/-1.35 mg x kg(-1) x min(-1), P < .0001) and insulin level (41.36+/-6.47 v 18.04+/-2.95 mU x mL(-1), P < .0001) were markedly reduced in animals receiving glucosamine. Peak insulin levels 1 minute after the arginine bolus were lower in rats infused with glucosamine versus saline (274.00+/-30.38 v 176.25+/-20.12 microU x ml(-1), P=.0319). Total insulin secretion in response to arginine was significantly lower in the glucosamine group as determined by the area under the curve (1,268.09+/-142.27 v 706.77+/-84.79 microU x mL(-1) x min, P=.0054). In conclusion, glucosamine causes severe impairment in glucose-induced insulin secretion. Further, glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine. This pattern of insulin secretory dysfunction is similar to that observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that glucosamine may participate in the pathogenesis of glucose toxicity at the level of the beta cell in NIDDM patients.

Animals↗

PubMed1999

Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats.

Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by either potentiating or mimicking insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of glucosamine on insulin action that may play an important role in hyperglycemia-induced insulin resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp was performed during the last 120 minutes. Pretreatment with troglitazone or D-chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic insulin resistance. In contrast, HGO failed to increase during glucosamine infusion in rats pretreated with troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic insulin resistance. D-Chiroinositol pretreatment had no effect on the glucosamine-induced increase in HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR, indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats, glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D-chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol, partially blocked the glucosamine-induced hepatic insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to hexosamine-induced peripheral insulin resistance.

Animals↗

PubMed2001

Sulfate could mediate the therapeutic effect of glucosamine sulfate.

Glucosamine sulfate is a controversial osteoarthritis remedy that is presumed to stimulate articular cartilage glycosaminoglycan synthesis by increasing glucosamine concentrations in the joint space. However, this is not plausible because even large oral doses of the product have no effect on serum glucosamine concentrations. We propose instead that sulfate could mediate the clinical benefit attributed to this treatment. Sulfate is required for glycosaminoglycan synthesis, and unlike glucosamine, its serum level can be modified by dietary and other factors. In this study, we tested whether oral glucosamine sulfate increases serum sulfate concentrations and whether the sulfate concentration in the synovial fluid reflects that in the serum. The serum sulfate concentration of 7 normal subjects was 331 +/- 21 micromol/L before ingestion of 1.0 g glucosamine sulfate and 375 +/- 17 micromol/L 3 hours after (P <.05). Serum sulfate concentrations decreased from 325 +/- 19 to 290 +/- 19 micromol/L when the same dose of glucosamine sulfate was ingested with 1.0 g of the analgesic drug acetaminophen, which is largely metabolized by sulfation (P <.05). Unlike glucosamine sulfate, oral sodium sulfate did not significantly increase the serum sulfate concentration. Synovial fluid and serum sulfate concentrations were closely similar when measured in 15 patients undergoing diagnostic needle aspiration of a knee effusion (r =.99, slope =.97, P <.0001). These results do not prove that glucosamine sulfate improves osteoarthritis, but considered with other data, they do provide a plausible biochemical mechanism for its reported beneficial effects. This hypothesis is clinically relevant because it predicts that nonsulfate salts of glucosamine will be ineffective and that renal function, diet, and concurrent acetaminophen therapy could confound clinical trials of this therapy.

Acetaminophen↗

PubMed1970

The incorporation of D-glucosamine-14C into root tissues of higher plants.

d-Glucosamine-1-(14)C was rapidly taken up from aqueous solution by both excised bean (Phaseolus vulgaris) and corn (Zea mays) root tips. The labeled glucosamine did not accumulate in the tissues, however, but was metabolized to N-acetyl-d-glucosamine, N-acetyl-d-glucosamine phosphates, and uridine diphosphate N-acetyl-d-glucosamine. Little or no label was detected in respiratory CO(2), glycolytic intermediates, or d-glucosamine 6-phosphate. Between 5 and 10% of the (14)C was recovered in high molecular weight ethanol-insoluble materials which could be solubilized readily with alkali or by treatment with proteases, and which yielded labeled glucosamine upon complete hydrolysis with HCl. Milder hydrolytic conditions released quantities of N-acetylglucosamine-(14)C plus labeled fragments of higher molecular weight. It is concluded that d-glucosamine-(14)C may be used to label specifically the amino sugar residues of plant as well as animal macromolecules. N-Acetyl-d-glucosamine acts similarly as a precursor, except that it is taken up at only about 1/10 the rate of glucosamine and hence is utilized less efficiently.

Glucosamine↗

PubMed2003

Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice.

Glucosamine (2-amino-2-deoxy-d-glucose) and glucosamine-containing products have been reported to have efficacy in the treatment of various musculoskeletal disorders. Glucosamine's efficacy, including reduction of pain, is attributed to disease-modifying properties, specifically to cartilage-rebuilding associated with modulation of interleukin-1-induced activation of chondrocytes and to inhibition of proinflammatory effects of the nuclear factor-kappaB pathway. However, glucosamine has not been shown to have direct analgesic activity. We report here that commercial glucosamine (90.4% glucosamine sulfate + 9.6% excipients) administered as the sole agent (up to 500 mg/kg p.o.) was inactive in the mouse abdominal irritant test but that certain combinations of glucosamine with nonopioid analgesics at the oral doses and ratios tested resulted in a synergistic (ibuprofen and ketoprofen), additive (diclofenac, indomethacin, naproxen, and piroxicam), or subadditive (aspirin and acetaminophen) antinociceptive interaction. In the specific case of ibuprofen, the racemate (standard ibuprofen) produced dose-related antinociception with ED50 = 26.1 +/- 3.4 mg/kg. Combinations containing racemic ibuprofen and glucosamine in greater than 1:1 ratio (glucosamine/ibuprofen) were synergistic in the test (e.g., ED50 = 11.0 +/- 2.1 for the 9:1 ratio; p < 0.01, analysis of variance). Combinations containing glucosamine and ibuprofen (2:1 and 9:1) yielded plasma levels of ibuprofen that were no different from administration of ibuprofen alone. The possibility that combinations containing certain fixed ratios of glucosamine and certain nonsteroidal anti-inflammatory drugs (NSAIDs) might enhance pain relief in patients with pain or might achieve acceptable levels of pain relief with lower doses of NSAIDs (reduced adverse effects) is presently being pursued in clinical trials.

Acetaminophen↗

PubMed2006

Exogenous glucosamine globally protects chondrocytes from the arthritogenic effects of IL-1beta.

The effects of exogenous glucosamine on the biology of articular chondrocytes were determined by examining global transcription patterns under normal culture conditions and following challenge with IL-1beta. Chondrocytes isolated from the cartilage of rats were cultured in several flasks either alone or in the presence of 20 mM glucosamine. Six hours later, one-half of the cultures of each group were challenged with 10 ng/ml IL-1beta. Fourteen hours after this challenge, RNA was extracted from each culture individually and used to probe microarray chips corresponding to the entire rat genome. Glucosamine alone had no observable stimulatory effect on the transcription of primary cartilage matrix genes, such as aggrecan, collagen type II, or genes involved in glycosaminoglycan synthesis; however, glucosamine proved to be a potent, broad-spectrum inhibitor of IL-1beta. Of the 2,813 genes whose transcription was altered by IL-1beta stimulation (P < 0.0001), glucosamine significantly blocked the response in 2,055 (approximately 73%). Glucosamine fully protected the chondrocytes from IL-1-induced expression of inflammatory cytokines, chemokines, and growth factors as well as proteins involved in prostaglandin E2 and nitric oxide synthesis. It also blocked the IL-1-induced expression of matrix-specific proteases such as MMP-3, MMP-9, MMP-10, MMP-12, and ADAMTS-1. The concentrations of IL-1 and glucosamine used in these assays were supraphysiological and were not representative of the arthritic joint following oral consumption of glucosamine. They suggest, however, that the potential benefit of glucosamine in osteoarthritis is not related to cartilage matrix biosynthesis, but is more probably related to its ability to globally inhibit the deleterious effects of IL-1beta signaling. These results suggest that glucosamine, if administered effectively, may indeed have anti-arthritic properties, but primarily as an anti-inflammatory agent.

Animals↗

PubMed1999

Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects.

Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reduction of basal and insulin-stimulated glucose uptake activities in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Insulin responsiveness of uptake was also reduced. There was no change in total membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While glucosamine treatment had no significant effects on hexokinase activity measured in cell extracts, glucose phosphorylation in intact cells was impaired after treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucosamine treatment. These effects were similar in nondiabetic and type 2 cells. In summary: 1) Chronic treatment with glucosamine reduces glucose transport/phosphorylation and storage into glycogen in skeletal muscle cells in culture and impairs insulin responsiveness as well. 2) Down-regulation of glucose transport/phosphorylation occurs at a posttranslational level of GLUTs. 3) Glycogen synthase activity increases with glucosamine treatment. 4) Nondiabetic and type 2 muscle cells display equal sensitivity and responsiveness to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucose metabolism at multiple sites and can contribute to insulin resistance in this tissue.

Adult↗

PubMed2006

Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects.

Glucosamine is a popular nutritional supplement used to treat osteoarthritis. Intravenous administration of glucosamine causes insulin resistance and endothelial dysfunction. However, rigorous clinical studies evaluating the safety of oral glucosamine with respect to metabolic and cardiovascular pathophysiology are lacking. Therefore, we conducted a randomized, placebo-controlled, double-blind, crossover trial of oral glucosamine at standard doses (500 mg p.o. t.i.d.) in lean (n = 20) and obese (n = 20) subjects. Glucosamine or placebo treatment for 6 weeks was followed by a 1-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by hyperinsulinemic-isoglycemic glucose clamp (SI(Clamp)) and endothelial function evaluated by brachial artery blood flow (BAF; Doppler ultrasound) and forearm skeletal muscle microvascular recruitment (ultrasound with microbubble contrast) before and during steady-state hyperinsulinemia. Plasma glucosamine pharmacokinetics after oral dosing were determined in each subject using a high-performance liquid chromatography method. As expected, at baseline, obese subjects had insulin resistance and endothelial dysfunction when compared with lean subjects (SI(Clamp) [median {25th-75th percentile}] = 4.3 [2.9-5.3] vs. 7.3 [5.7-11.3], P < 0.0001; insulin-stimulated changes in BAF [% over basal] = 12 [-6 to 84] vs. 39 [2-108], P < 0.04). When compared with placebo, glucosamine did not cause insulin resistance or endothelial dysfunction in lean subjects or significantly worsen these findings in obese subjects. The half-life of plasma glucosamine after oral dosing was approximately 150 min, with no significant changes in steady-state glucosamine levels detectable after 6 weeks of therapy. We conclude that oral glucosamine at standard doses for 6 weeks does not cause or significantly worsen insulin resistance or endothelial dysfunction in lean or obese subjects.

Administration, Oral↗

PubMed1993

Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor.

Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed alpha-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.

Animals↗

PubMed2003

Influence of glucosamine on matrix metalloproteinase expression and activity in lipopolysaccharide-stimulated equine chondrocytes.

OBJECTIVE: To characterize potential mechanisms of action of glucosamine inhibition of matrix metalloproteinase (MMP) expression and activity in lipopolysaccharide (LPS)-stimulated equine chondrocytes. SAMPLE POPULATION: Chondrocytes cultured from samples of metacarpophalangeal articular cartilage collected from cadaveric limbs of horses. PROCEDURE: The effect of glucosamine on MMP activity in conditioned medium from LPS-stimulated cartilage explants was determined by a colorimetric assay with azocoll substrate. Treatments consisted of negative and positive controls, glucose (50 mM), and glucosamine (50, 25, 6.25, 3, and 1.5 mM). The influence of glucosamine on MMP synthesis was determined in chondrocytes in pellet culture incubated with LPS (20 microg/mL). Concentration of MMP-13 was quantified in spent medium via ELISA; nonspecific MMP activity was determined via azocoll digestion in organomercurial-activated medium. Effects of glucosamine on MMP mRNA concentration in similarly treated chondrocytes were determined by northern blot hybridization with MMP-1, -3, and -13 probes. Statistical analyses were performed with 2-way ANOVA. RESULTS: Glucosamine had no effect on activated MMP activity but inhibited MMP protein expression, as determined by azocoll digestion (glucosamine, 3 to 50 mM) and MMP-13 ELISA (glucosamine, 1.5 to 50 mM). Resting mRNA concentrations for MMP-1, -3, and -13 mRNA were significantly lower in cultures exposed to glucosamine at concentrations of 50 and 25 mM than those of positive controls. CONCLUSIONS AND CLINICAL RELEVANCE: Glucosamine appears capable of pretranslational, and possibly also translational, regulation of MMP expression; data suggest a potential mechanism of action for chondroprotective effects of this aminomonosaccharide.

Animals↗