Subchronic toxicity evaluation of glucosamine and glucosamine in combination with chondroitin sulfate in obese Zucker rats

Toxicol Appl Pharmacol. 2021 Feb 1;412:115371. doi: 10.1016/j.taap.2020.115371. Epub 2020 Dec 17.


D-glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor β1 (TGFβ1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (leprfa/leprfa) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced CmaxD-glucosamine concentrations of up to 24 μM in tail vein serum concurrent with a transient 30% increase in blood glucose concentration in the 600 mg/kg/day dose group. D-Glucosamine did not significantly alter body weight, blood glucose or serum insulin levels at any dose tested after 13 weeks exposure, but did increase urinary TGFβ1 concentrations. The Zucker rats developed nephropathy and scrotal sores that were related to their hyperglycemia and obesity, and D-glucosamine exposure exacerbated these conditions to a small extent. The incidence of pulmonary osseous metaplasia was increased in rats exposed to D-glucosamine and a single incidence of adrenal osseous metaplasia was noted in one animal exposed to 600/480 mg D-glucosamine HCl/chondroitin sulfate. These lesions may have been treatment related. These studies suggest that the risk of adverse effects of oral D-glucosamine is small compared to that of hyperglycemia in these animals, but the potential for TGFβ1-mediated pathologies, such as osseous metaplasia and renal nephropathy may be increased.

Keywords: Chondroitin sulfate; Diabetes; Glucosamine; Subchronic study; TGFbeta; Zucker rat.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Biomarkers / urine
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Chondroitin Sulfates / toxicity*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Glucosamine / toxicity*
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Metaplasia
  • Obesity / blood
  • Obesity / complications*
  • Obesity / pathology
  • Rats, Zucker
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Toxicity Tests, Subchronic
  • Transforming Growth Factor beta1 / urine


  • Biomarkers
  • Blood Glucose
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • Chondroitin Sulfates
  • Glucosamine