As glucosamine is presently in wide use due to its purported beneficial effects in patients with osteoarthritis, it seemed important to consider its possible adverse effects on glucose metabolism. Many subjects who take glucosamine for osteoarthritis are obese, insulin resistant, diabetic, or at risk for the development of diabetes, and it is established that glucosamine induces insulin resistance in rats and mice. Hypotheses suggest that glucosamine causes insulin resistance by directly entering the hexosamine biosynthetic pathway. It has been proposed that this provides a model for glucotoxicity-induced defects in insulin action and secretion (1), since, under hyperglycemic conditions, a larger amount of glucose flux is metabolized through the hexosamine pathway. Therefore, we undertook this study to determine if glucosamine, taken at recommended doses for the treatment of osteoarthritis, had any detrimental effect on glucose metabolism.
Seven obese (BMI ≥27 kg/m2) and seven lean subjects (BMI ≤27) participated in the study. Three of the obese subjects and two of the lean subjects had impaired glucose tolerance (IGT). Each subject had a baseline 4-h meal tolerance test (MTT) and a frequently sampled intravenous glucose tolerance test, before and after 4 weeks of glucosamine sulfate (500 mg, three times/day).
At baseline, fasting plasma glucose and insulin levels were 5.4 ± 0.3 mmol/l and 14.4 ± 3.6 μU/ml in the obese subjects compared with 4.8 ± 0.3 and 10.8 ± 4.9 in the lean subjects, respectively. After 4 weeks of treatment with glucosamine sulfate, there were no changes in fasting plasma glucose, insulin, or lipoprotein levels.
After 4 weeks of treatment with glucosamine sulfate, there was no change in the area under the 4-h plasma glucose curve (AUCgluc) (1,551 ± 55 vs. 1,539 ± 55 mmol · l−1 · min−1) and the 4-h MTT plasma insulin curve (AUCins) (17,903 ± 8,745 vs. 17,861 ± 9,406 mU/l · min) in all subjects.
Insulin sensitivity was significantly reduced at baseline in the obese compared with the lean subjects (lean: 3.58 ± 0.6; obese: 1.2 ± 0.4 × 10−4 min−1 · μU−1 · ml−1; P < 0.01). After 4 weeks of treatment with glucosamine, there was no difference in insulin sensitivity in the combined group of subjects (2.37 ± 0.46 vs. 2.55 ± 0.58; P = 0.67), nor was there any difference when the subjects were analyzed according to BMI (obese or lean) or glucose tolerance (normal glucose tolerant or IGT).
Although there are many studies showing that acute or chronic administration of glucosamine and activation of the hexosamine pathway can cause insulin resistance, few studies on humans exist. Monauni et al. (2) reported that acute, short-term (6-h) intravenous glucosamine infusion had no detectable effects on glucose metabolism during a euglycemic clamp. Similarly, Pouwels et al. (3) reported that a 5-h infusion of glucosamine did not affect whole-body glucose uptake in human subjects. To date, there have been no studies on the chronic effects of oral glucosamine on insulin sensitivity.
We did not measure plasma glucosamine levels or metabolites of the hexosamine pathway, and, as such, it is possible that the glucosamine load given to our subjects may have been insufficient to produce insulin resistance. However that was not the intent of this study. We wanted to determine whether the recommended dose of glucosamine for treatment of osteoarthritis was detrimental to glucose metabolism in humans, and our data indicate that it is not. Given the common usage of glucosamine supplementation in insulin-resistant and other susceptible populations, these negative findings have significant clinical interest. Based on our results, we think it is unlikely that long-term treatment regimens or the use of glucosamine in diabetic subjects would lead to adverse effects on glucose metabolism. However, since we did not study these specific conditions, definitive conclusions on these issues warrant further study.
Address correspondence to Jerrold M. Olefsky, MD, University of California San Diego (0673), 9500 Gilman Dr., La Jolla, CA 92037. E-mail:.
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