Introduction

Type 2 diabetes (T2D) mellitus is a complex metabolic disorder with multiple metabolic and homeostatic disturbances that occur during the course of the disease and persist over time. About 537 million adults worldwide have diabetes, the majority of whom have T2D, and this number is projected to increase to 783 million by 2045 [1]. Diabetic microvascular complications, including diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy, lead to increased mortality, renal failure, blindness and overall reduced quality of life in people with diabetes mellitus [2]. Therefore, it is crucial to identify cost-effective strategies to prevent and slow the progression of microvascular complications in diabetic patients.

Glucosamine is a commonly used supplement for relieving osteoarthritis and joint pain [3]. About 20% of adults in the United States and Australia consume it daily [4, 5]. Although the efficacy of glucosamine for osteoarthritis and joint pain remains debated, several recent epidemiological studies have shown that glucosamine reduces the risk of a number of diseases, such as cardiovascular disease, type 2 diabetes and lung cancer [5,6,7]. A 3-year clinical trial of 212 participants showed a slight glucose-lowering effect in glucosamine users [8], and studies have shown a protective effect of glycaemia control on diabetic microvascular complications [9, 10]. In addition, previous studies have suggested that glucosamine may affect the inflammatory state [11,12,13], which has also been linked to the risk of microvascular complications in T2D [10]. However, the relationship between habitual glucosamine uses and microvascular complications in patients with T2D remains unclear.

To fill these knowledge gaps, in the current study we aimed to prospectively evaluate the association of habitual glucosamine use with risk of microvascular complications in individuals with T2D from the UK Biobank.

Methods

Study Population

The UK Biobank is a national health resource in the United Kingdom aimed at enhancing the prevention, diagnosis, and treatment of various illnesses and promoting public health [14, 15]. Between 2006 and 2010, the UK Biobank enrolled approximately 500,000 participants aged 40–69 from across the country. All participants provided informed consent, and the study was approved by the North West–Haydock Research Ethics Committee (16/NW/0274).

Individuals with T2D were identified using the Eastwood algorithm [16] and/or from measured HbA1c ≥ 48 mmol/mol (6.5%). The Eastwood algorithm combines hospital inpatient records, self-reported medical history, and medication, which is a reliable measurement with 96% accuracy. After excluding participants with prevalent diabetic microvascular complications (n = 2,985), reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2 [n = 1545]), or CVD (n = 4,573) at baseline, who had withdrawn from the UK Biobank (n = 57), or had incomplete data on the use of glucosamine (n = 399). Finally, 21,171 individuals with T2D were included in the present analysis (Fig. 1).

Fig. 1
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Flow chart of participant enrolment.

Exposure Assessment

Participants attended one of 22 assessment centers across the UK where they completed a touch screen questionnaire. One of the questions asked “Do you regularly take any of the following?”, and participants could choose their response from a list of supplements, including glucosamine. Based on this data, we defined glucosamine use as 0 = no and 1 = yes.

Individual baseline characteristics were identified from self-report and electronic hospital records. Variables of interest included age, sex, race, smoking status, drinking status, body mass index (BMI), physical activity, dietary intakes (fruit, vegetables, fish, processed meat and red meat), personal medical condition (including arthritis, hypertension and high cholesterol), use of aspirin and non-aspirin NSAIDs, supplementation of nutrients (vitamins, minerals and other dietary supplementation, including fish oil, zinc, calcium, iron and selenium), duration of T2D, measured HbA1c and drugs to treat high cholesterol, hypertension, and diabetes.

A healthy diet was defined based on the following criteria: total fruit and vegetable intake >4.5 pieces or servings/week, total fish intake >2 times/week, and processed meat intake ≤2 times per week and red meat intake <5 times per week. Meeting at least two of these criteria was considered indicative of a healthy diet [17].

According to global recommendations on physical activity for health [18], we categorized participants into two groups based on total moderate physical activity minutes each week (one vigorous physical activity minute equals two moderate physical activity minutes): <150 or ≥150 min/week. Hypertension was defined as a self-reported history of hypertension, systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or taking antihypertensive drugs [19, 20].

Ascertainment of outcomes

The primary outcome of interest was overall incident diabetic microvascular complications, a composite indicator of the first occurrence of diabetic nephropathy, diabetic retinopathy, and/or diabetic neuropathy. Secondary outcomes included the incidence of three diabetic microvascular complications subtypes (diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy). Cases of nephropathy, retinopathy, and neuropathy were identified from hospital inpatient records coded according to the ICD-10 (Supplementary Table 1).

Statistical Analysis

The differences in baseline characteristics between individuals with and without glucosamine use were examined using the Student t-test for continuous variables and the χ² test for categorical variables. We compared event rates in participants who did and did not use glucosamine by using Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. The proportional hazards assumption was tested using Schoenfeld residuals. We adjusted for several potential confounders: age, sex, and race (white European, mixed, South Asian, black, others); body mass index; smoking status (never, former, current); drinking status (never, former, current); physical activity (<150 or ≥150 min/week); hypertension (yes or no), high cholesterol (yes or no), and arthritis (yes or no); aspirin use (yes or no), and non-aspirin non-steroidal anti-inflammatory drug use (yes or no); healthy diet (yes or no); vitamin supplement use (yes or no); and mineral and other dietary supplement use (yes or no; fish oil, zinc, calcium, iron, selenium); diabetes duration; measured HbA1c; use of diabetes medication (none, only oral medication, only insulin, or insulin and oral medication). To reduce the potential for inferential bias [21], we addressed missing values through multiple imputation with chained equations, resulting in five imputed datasets. The imputation methods were predictive mean matching (PMM) for numeric data, logistic regression (LogReg) for binary data, polytomous regression (PolyReg) for unordered categorical data (factor > 2 levels) and proportional odds model (Polr) for ordered categorical data (factor > 2 levels). We checked for convergence of our imputations with trace plots (Supplementary Fig. 1). The percentage of missing values are present in Supplementary Table 2.

We conducted a stratified analysis to assess potential modification effects by the following factors: sex (male or female), age (<55 or ≥55), body mass index (18.5-25.0, 25.0-29.9, or ≥30.0), smoking status (never, former, or current), drinking status (never, former, or current), physical activity (<150 or ≥150 min/week), diabetes duration (<5 or ≥5 years), HbA1c (<53 or ≥53 mmol/mol). We evaluated potential effect modification by modeling the cross-product term of the stratifying variable with glucosamine use.

We performed several sensitivity analyses. First, given that participants taking glucosamine were also more likely to use other supplements, we conducted a sensitivity analysis excluding participants who used any other supplements. Second, to reduce the impact of reverse causation, we conducted an analysis excluding participants who developed diabetic microvascular complications within one year of follow-up. Third, to assess the potential mediation by inflammation and lipids, we additionally adjusted for C-reactive protein (CRP) levels (continues, milligrams per liter) and lipid profiles, including HDL, LDL, and triglycerides (TG) (all continuous, millimoles per liter). We used R V.4.2.0 (R Development Core Team, Vienna, Austria) for all statistical analyses, and p < 0.05 (two-sided) were considered significant.

Results

Table 1 shows baseline characteristics of the study participants according to the use of glucosamine. Overall, 14.5% of the study population reported glucosamine use at baseline. Compared with non-users, glucosamine users were older, more likely to be women, more physically active, not current smokers, had a healthy diet, and had a higher prevalence of arthritis. Glucosamine users also tended to take more non-aspirin non-steroidal anti-inflammatory drugs, vitamins, minerals, and other dietary supplements than non-users. They were also more prone to have a shorter duration of diabetes, lower HbA1c levels, less likely to use diabetes medication at baseline.

Table 1 Baseline characteristics of UK biobank participants with type 2 diabetes by glucosamine use.
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Table 2 shows the associations between glucosamine use and incident diabetic microvascular complications. During a median of 12.3 years of follow-up, 4,399 people developed diabetic microvascular complications, including 2,084 cases of incident diabetic nephropathy, 2,401 incident diabetic retinopathy, and 831 incident diabetic neuropathy. In the multivariable adjusted analyses, the hazard ratios associated with glucosamine use were 0.89 (95% CI: 0.81, 0.97) for composite diabetic microvascular complications; and 0.87 (95% CI: 0.76, 0.98) for diabetic nephropathy, but there was no significant inverse association between glucosamine use and risk of diabetic retinopathy 0.94 (95% CI: 0.83, 1.06) or diabetic neuropathy 0.88 (95% CI: 0.71, 1.08).

Table 2 Association of glucosamine supplement use with risk of microvascular complications among individuals with type 2 diabetes.
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In stratified analyses, the association between glucosamine supplement use and incident diabetic microvascular complications was not significantly modified by any of the subgroup factors (Supplementary Figs. 2–5). In our sensitivity analyses, the associations between glucosamine use and diabetic microvascular complications remained stable: first, when we excluded participants who used any other supplements (Supplementary Table 3); second, when we excluded participants who developed diabetic microvascular complications within one year of follow-up (Supplementary Table 4); and third, after further adjustment for CRP and lipid profiles (Supplementary Table 5).

Discussion

In this large prospective study, habitual glucosamine use was associated with a 11% lower risk of composite microvascular complications and a 13% lower risk of diabetic nephropathy. These associations were independent of other potential confounders, such as sociodemographic factors, lifestyle behaviors, health status, drug use and other supplements use. Results from sensitivity analyses further supported the robustness of the main findings.

To the best of our knowledge, this is the first prospective cohort study to explore the association between glucosamine use and the risk of diabetic microvascular complications. It is notable that previous studies have indicated that short-term, high-dose glucosamine administration can negatively impact glucose tolerance and insulin sensitivity, causing endothelial dysfunction in both animals and humans [22,23,24,25,26,27,28]. However, several clinical trials have found that long-term administration of glucosamine at oral dose levels does not adversely affect glucose metabolism and endothelial function in both healthy individuals and diabetics [29,30,31,32]. In contrast, a long-term controlled trial involving 212 arthritis patients reported a mild glucose-lowering effect after a 3-year glucosamine intervention [8]. In another prospective cohort study, glucosamine administration was found to reduce the risk of developing type 2 diabetes [7], and a meta-analysis of clinical trials reported similar results [33]. Consistent with these findings, our current study observed a slight association between habitual glucosamine use and lower baseline blood glucose levels. The inconsistency between animal and human results may partly stem from the substantially higher glucosamine doses used in animal research (100-200 times higher) compared to typical oral doses in humans [33].

There are several potential mechanisms that may explain the observed protective effect of glucosamine use on diabetic microvascular complications. First, glucosamine use may influence inflammation by inhibiting the translocation of the transcription factor NF-κB into the nucleus [12, 34], with the activation of its p65 subunit considered a key factor in the development of diabetic complications [10, 35, 36]. In experimental studies, NF-κB inhibitors have shown nephroprotective effects in both diabetic and nondiabetic nephropathy models [37, 38]. Additionally, findings from the National Health and Nutrition Examination Survey (NHANES) indicate that regular glucosamine use is associated with significantly reduced levels of C-reactive protein, a marker indicating systemic inflammation [39]. Clinical studies also reveal that individuals with type 2 diabetes exhibit elevated levels of circulating inflammatory markers, which seem to predict the onset and progression of diabetic complications [10]. In addition, Moreover, glucosamine’s antioxidant and free radical scavenging effects are well-documented [40,41,42,43]. At a concentration of 0.8 mg/ml, glucosamine demonstrated scavenging activity of 84% against superoxide radicals and 55% against hydroxyl radicals [43]. Superoxide, generated due to mitochondrial dysfunction in diabetes, is thought to play a significant role in the development of diabetic complications [44]; Thus, the antioxidant capabilities of glucosamine may partly elucidate its potential protective mechanism against diabetic microvascular complications. Furthermore, an earlier animal study indicated that glucosamine imitates the effects of a low-carbohydrate diet by decreasing glycolysis and enhancing amino acid catabolism in mice [45]. Low-carbohydrate diets have been linked to improved metabolic profiles in patients with type 2 diabetes [46, 47]. While other mechanisms may also play a role, further prospective studies and intervention trials are essential to clarify the potential benefits of glucosamine in preventing microvascular complications in type 2 diabetes.

Our study indicates that glucosamine use may help prevent nephropathy, although its effects on retinopathy and neuropathy appear less pronounced. This can be explained by inherent differences in the etiology of each microvascular complication that may influence the range of mechanisms potentially targeted by glucosamine. For instance, hyperglycemia plays a primary role in the onset of diabetic retinopathy [48,49,50], while nephropathy risk is influenced by hyperglycemia in combination with other metabolic factors such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension [51]. Glucosamine has been shown to improve several of these metabolic risk factors [12, 34, 39], which may explain the more substantial risk reduction observed for kidney disease. The absence of a statistically significant association between glucosamine use and neuropathy may be result from the small number of participants who developed neuropathy.

The main strengths of this study are its use of prospective cohort data with a substantial sample size, the extensive information available on covariates, and the robust, consistent results across multiple sensitivity analyses. However, there are some limitations in our study. First, the UK Biobank did not collect comprehensive information regarding glucosamine use, such as dose and duration of use [14]. And differences in nutrient intake doses can produce very different or even conflicting results. Therefore, further studies are needed to investigate this association. Second, the UK Biobank did not collect data on the side effects associated with glucosamine use. Nonetheless, glucosamine is considered one of the safest supplements for osteoarthritis, with only minimal side effects reported, including rare allergic reactions, diarrhea, constipation, nausea, and heartburn [3]. While some earlier studies suggested that glucosamine might impair glucose tolerance in those at high risk for diabetes [52, 53], clinical trials have demonstrated that glucosamine does not affect glucose metabolism or lipid profiles at any oral dose in either healthy individuals or diabetes patients [29, 30]. Third, in an observational study, distinguishing the impact of a healthy lifestyle from the habitual use of supplements can be challenging. In this context, regular glucosamine use may serve as an indicator of a healthier lifestyle among participants. Consequently, we cannot rule out the possibility that the observed inverse associations may be influenced by healthy lifestyle factors among those using glucosamine, despite our thorough adjustments for potential confounders, including obesity, physical activity, smoking, and diet, in the analyses. In addition, microvascular complications were diagnosed based on cumulative hospital records and linkage to national death registries using ICD codes. Consequently, any misclassification of patients with these complications could dilute the study results, potentially underestimating the true strength of the association. Furthermore, due to the observational study design, residual or unknown confounders could not be excluded, although we endeavored to adjust for potential confounders. Finally, the UK Biobank study is known to have a selection bias toward healthy volunteers with healthy lifestyles and lower rates of diabetes [14]; therefore, the findings may not be generalizable to other populations. Future research could strengthen these findings through randomized controlled trials to better assess the associations in more diverse and representative cohorts.

In this large prospective study of patients with type 2 diabetes, we found that habitual use of glucosamine, a commonly used supplement for the treatment of osteoarthritis and joint pain, was associated with lower risks of composite microvascular complications and diabetic nephropathy in patients with type 2 diabetes. These findings suggest that glucosamine could be considered as part of a comprehensive management strategy for patients with type 2 diabetes. Integrating glucosamine into patient care may help reduce the risk of microvascular complications, thereby improving overall health outcomes. However, further research is needed to explore the biological mechanisms underlying these associations and to establish causality through randomized controlled trials. Additionally, examining the long-term effects of glucosamine in diverse populations will provide a robust evidence base for clinical guidelines and public health policies aimed at managing diabetes and its complications effectively.