Shop
-1.png)
eStoreRx™
Online Supplement Dispensary
eStoreRx™ is an easy direct-to-patient ordering & fulfilment program for lifelong wellness.
The Journal of International Medical Research published a meta-analysis and Mendelian randomization (MR) evaluating the association between glucosamine supplementation and the risk for type 2 diabetes (T2D). Extremely high dose animal studies followed by one previously published human study suggested that glucosamine supplementation might exacerbate insulin resistance when used with osteoarthritis. However, it was too small to adequately evaluate this concern, and subsequent studies found no association between supplementation and fasting blood glucose levels, glucose metabolism, or insulin sensitivity, both among healthy people as well as those with impaired glycemic control. Nonetheless, a concern has persisted which this 2025 meta-analysis and MR was designed to address.
Briefly, because genetic single-nucleotide polymorphisms (SNPs) can be considered to be assigned randomly at birth, an MR is an attempt to determine causality (using data from large genome-wide association studies (GWAS)), similar to a randomized and controlled clinical trial. Additionally, MR analyses avoid misinterpreting reverse causality, given that SNPs precede any related diseases. This analysis used the databases from several GWAS for discovery and validation cohorts, including the FinnGen consortium (over 32,000 people with T2D and 183,000 controls), the MRC Integrative Epidemiology Unit (MRC-IEU) consortium (89,339 T2D and 372,045 controls), and the validation cohort, a previously published meta-analysis that evaluated SNPs potentially related to T2D, referred to as Xue’s meta-analysis (over 61,000 people with T2D). Between 4 and 5 SNPs that predict glucosamine status were used in this analysis. Notably, these variants were previously associated with life expectancy in an earlier published meta-analysis; each standard deviation increase in genetically predicted glucosamine levels was associated with a nearly 2-fold increase in likelihood for a higher maternal age at death, suggesting higher genetically predicted glucosamine levels may extend lifespan.
The results of this recent analysis suggest that not only does glucosamine supplementation not impair insulin sensitivity, but in contrast, it is associated with a lower risk for developing T2D. Quite remarkably, the reduction in T2D risk ranged from 87 to 92% (Odds ratio of 0.06 to 0.13). A multivariable MR that adjusted for a range of factors (e.g., HDL-C, LDL-C, triglycerides, body mass index, etc.) found an 88% reduction in risk. Although this was not a controlled trial evaluating glucosamine supplementation, MR does imply causality, i.e., that higher levels of glucosamine may directly reduce the risk for incident T2D.
This is roughly consistent with what has been observed in other trials with glucosamine supplementation. For example, a randomized and double-blind placebo-controlled trial that evaluated the use of 1500 mg per day of glucosamine sulfate for people with osteoarthritis found a slight glucose-lowering effect over a 3-year period (as well as benefit for osteoarthritis). A prospective analysis of data from the ongoing UK Biobank study found that over a median of 8.1 years, glucosamine use was associated with a significant 17% lower risk for developing T2D, after multivariate adjustment. This association was even stronger among participants with elevated C-reactive protein (CRP) levels. Glucosamine use was also associated with a reduction in microvascular complications and diabetic nephropathy in fully adjusted models. Also worth noting, another analysis of UK Biobank data also revealed a reduction in cardiovascular disease risk with glucosamine supplementation; a 15% lower risk for major cardiovascular events. These participants were not taking glucosamine to lower cardiovascular risk, but for its osteoarthritis benefits.
A number of mechanisms have been proposed to explain this potentially causal association between glucosamine levels and T2D risk. As mentioned above, inflammation may be a mediator (suggested by a greater benefit with elevated CRP levels). Very early studies with glucosamine sulfate did find inhibition of pro-inflammatory mediators via an NFkappaB-dependent mechanism, at least in chondrocytes (also a mechanism for osteoarthritis benefits). Glucosamine has also demonstrated an anti-inflammatory effect on epithelial cells of the GI tract, including inhibition of inflammatory/signaling molecules (IL-8, ICAM-1, p38MAPK and NF-kappaB). In 2015, a small but randomized and double-blind controlled trial found that glucosamine and chondroitin (often given with glucosamine) reduced CRP by 23%, marked by downregulated cytokine inflammatory pathways.
Lastly, glucosamine use or genetically determined levels of glucosamine also appear to impact cognition and influence dementia risk, at least in part mediated via a reduction in diabetes and/or inflammation. Glucosamine users in the UK Biobank study had a 13% lower risk for dementia, found to be mediated by a lower incidence T2D. Further evidence supporting this protective effect was published in 2024 in Frontiers in Endocrinology; this was an MR study evaluating the influence of glucosamine levels on both cognition and sarcopenia using data from a large GWAS (also taken from the UK Biobank study). Higher genetically predicted levels were associated with greater cognitive performance, as well as greater appendicular lean mass, whole-body fat-free mass, etc. A “postponing” of sarcopenia was also mediated via effects on body mass index and CRP.
While both genetically determined and supplemental glucosamine appear to reduce the risk of T2D, potentially causally, the risk reduction appears to be much greater with the former. It seems plausible that a lifetime of higher glucosamine levels would lead to more of a benefit than the limited and potentially brief exposure evaluated in relatively short clinical trials. Trials of very long-term use evaluating not only T2D risk, but also the risk for cardiovascular disease, and dementia would be quite valuable.
Submit your comment