Can J Physiol Pharmacol. 2014 Apr;92(4):285-91.

Oral glucosamine sulfate supplementation does not induce endoplasmic reticulum stress or activate the unfolded protein response in circulating leukocytes of human subjects.

McAlpine CS, Beriault DR, Behdinan T, Shi Y, Werstuck GH.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.



Background: Glucosamine sulphate is a dietary supplement that is marketed as a treatment for osteoarthritis. Recent evidence from animal and cell culture models, suggests glucosamine treatment can promote the misfolding of proteins and the activation of the unfolded protein response (UPR). We investigated whether glucosamine sulphate supplementation activates the UPR in circulating leukocytes of human subjects.

Methods and Results: Cultured Thp1 human monocytes were exposed to increasing concentrations of glucosamine (0, 0.25, 1, 4mmol/L) for 18 hours. We observed a dose depended increase in intracellular glucosamine levels as well as the activation of the UPR. To test the effect of glucosamine sulphate supplementation in humans, 14 healthy human subjects took 1500mg/day glucosamine sulphate for 14 days. Metabolic parameters and blood samples were collected before and after supplementation. In humans, glucosamine sulphate supplementation did not alter metabolic parameters including lipid levels and glucose tolerance. Further, glucosamine sulphate supplementation did not affect intracellular glucosamine levels or activate the UPR in leukocytes of human subjects.

Conclusions: Our results indicate that in healthy human subjects, recommended doses of glucosamine sulphate (1500mg/day) for 14 days does not significantly alter intracellular glucosamine levels and does not activate the UPR in circulating leukocytes.

PMID: 24708210



Glucosamine is marketed as a dietary supplement and is commonly used as a treatment for osteoarthritis. Although their effectiveness is controversial, glucosamine supplements are generally considered to be safe (1).

f12In previous studies performed in mouse models, we have found that high levels of glucosamine can induce a cellular stress (endoplasmic reticulum (ER) stress) that is associated with the development of diseases including diabetes and atherosclerosis (2-4). In fact, we have shown that mice given high doses of glucosamine develop accelerated atherosclerosis – the underlying cause of most heart attacks and strokes (5).

In this study we investigate the potential for glucosamine supplements to induce ER stress in cultured cells and in healthy human subjects (6). Fourteen healthy volunteers took the recommended daily dose of glucosamine sulphate (1500 mg/day) for two weeks. Blood samples were taken before and after the supplementation and ER stress levels were measured in isolated leukocytes. No significant changes were observed in ER stress levels or in any other measured parameter in this study.

Our results suggest that the concentration of glucosamine in a supplement, when taken as directed, is insufficient to increase plasma glucosamine levels to the threshold required to induce ER stress in the circulating blood cells of a healthy human. These findings are consistent with the perceived safety of glucosamine supplements in humans.



1. Reginster JY et al (2001) Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 357, 251-256.
2. Khan MI, Werstuck GH et al (2009) Evidence supporting a role for endoplasmic reticulum stress in the development of atherosclerosis in a hyperglycaemic mouse model. Antioxid Redox Signal 11, 2289-2298.
3. Sage AT, Werstuck GH et al (2010) Hexosamine biosynthesis pathway (HBP) flux promotes endoplasmic reticulum (ER) stress, lipid accumulation, and inflammatory gene expression in hepatic cells. Am J Physiol Endocrinol Metab 298, E499-E511.
4. McAlpine C, Werstuck GH et al (2012) Endoplasmic reticulum stress and glycogen synthase kinase-3β activation in apolipoprotein E-deficient mouse models of accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 32, 82-91.
5. Beriault DR, Werstuck GH et al (2011) Glucosamine-supplementation promotes endoplasmic reticulum stress, hepatic steatosis and accelerated atherogenesis in apoE-deficient mice. Atherosclerosis 219, 134-140.
6. McAlpine CS, Werstuck GH et al (2014) Glucosamine-supplementation does not activate the unfolded protein response in circulating leukocytes. Can J Physiol Pharmacol 92, 285-291.



This research was funded by operating grants from the Heart and Stroke Foundation of Ontario (000031) and the Canadian Institutes for Health Research (MOP62910).


Geoff Werstuck, PhD
Associate Professor
Thrombosis and Atherosclerosis Research Institute and the
Department of Medicine, McMaster University
237 Barton Street East
Hamilton, Ontario, Canada
L8L 2X2



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