Epidemiological data

The first paper describing an association between OA and diabetes was published in 1961 (table 1).7 The authors looked at the occurrence of definite radiological OA in 6 anatomical areas of 30 patients with diabetes and 30 matched controls. The correlation was statistically significant for feet and knees. OA patterns were also studied in 809 patients with knee or hip joint replacement due to OA according to the presence of non-insulin-dependent diabetes.8 Patients with non-insulin-dependent diabetes more frequently had bilateral OA (adjusted OR 2.2; 95% CI 0.8 to 6.4). An association with generalised OA was not seen in this study maybe due to statistical considerations. The clinical, pathological and epidemiological relationships between fasting plasma glucose concentrations (FPG) and the sites of lesion in OA were evaluated in 1026 patients.9 The mean FPG (99±22.2 mg/dl) was significantly higher in OA (p<0.01) than in the normal controls (88±19.9 mg/dl). Interestingly, erythrocyte sedimentation rate (p<0.01) and pain at rest (p<0.02) were higher in patients with non-insulin-dependent diabetes. In all, 1003 women aged 45–64 from the Chingford population study completed risk factor questionnaires for CV events.10 For knee OA in either knee, the variables significantly associated were raised blood glucose OR 1.95 (95% CI 1.08 to 3.59) and moderately raised serum cholesterol OR 2.06 (95% CI 1.06 to 3.98). In a recent study testing the hypothesis that vascular cell adhesion molecule 1 could be a predictor of severe knee or hip OA, the authors compared patients who did (n=60) or who did not (n=852) undergo joint replacement surgery in 1990–2005 due to severe OA.11 Although not discussed in this paper, an increased prevalence of non-insulin-dependent diabetes was seen in the group of patients who had joint replacement (18.3% vs 6.3%) but this difference was not statistically significant (p=0.06). In contrast, one negative case-control study found no association between an impaired oral glucose tolerance test or non-insulin-dependent diabetes and another found a tendency but not a statistical difference.12 13

Based on these case-control studies, we cannot definitively conclude that diabetes/hyperglycaemia is an independent risk factor for OA since many potential confounders may interfere with the results, such as age, weight, level of activity etc. However, taken together, there may be a positive signal for an independent correlation between OA and diabetes.

In vitro data

Chondrocytes are glycolytic cells able to sense the concentration of glucose present in the cartilage matrix, the synovial fluid and in a less extent the subchondral bone being the sources for glucose.14 By sensing glucose, chondrocytes will then respond appropriately by adjusting their cellular metabolism. Chondrocytes express multiple isoforms of the glucose transporter (GLUT)/SLC2A family of glucose/polyol transporters which represent the first rate-limiting step in glucose use.15 Among them, GLUT-1 is especially important as it is regulated by anabolic and catabolic stimuli.16 However, there are very few studies assessing the role of high extracellular glucose concentrations in articular chondrocyte functions. Hyperglycaemia decreases dehydroascorbate transport into chondrocytes, which can compromise the synthesis of type II collagen, and hyperglycaemia increases reactive oxygen species (ROS) production, known to be major deleterious mediators for cartilage destruction.17 18 Interestingly, although normal chondrocytes can adjust their intracellular concentration to local glucose concentration, OA chondrocytes exposed to high glucose are unable to down regulate GLUT-1, accumulating more glucose and producing more ROS.19

Advanced glycation end products (AGEs), the products of non-enzymatic glycation and oxidation of proteins and lipids, accumulate in several diabetic tissues such as the vasculature due to hyperglycaemia.20 21 Similarly, AGEs accumulate in ageing and in OA cartilage leading to matrix stiffness, becoming more sensitive to mechanical stress.22 Along with their deleterious effects on cartilage matrix, AGEs can also bind to membrane receptors called RAGE (for ‘receptor for age glycation end products’) present on many cell types including chondrocytes.20 23 Once bound to RAGE, AGEs trigger the activation of different signalling pathways leading to the over expression of proinflammatory and prodegradative mediators and to some alterations in the chondrocyte differentiation phenotype.24,–,26 To the best of my knowledge, to date no experimental studies have assessed the level of AGEs formation in diabetic cartilage compared to normal cartilage, even in human or in animal cartilage. However, it seems realistic to consider that an increased concentration of glucose in the diabetic cartilage matrix environment would lead to the same deleterious result.

In vivo data

In the well known streptozotocin-induced diabetes rat model which mimics type I diabetes, cartilage becomes resistant to the anabolic action of insulin-like growth factor 1 (IGF-1), a condition that is correctable by hypophysectomy, suggesting a metabolic impairment at the tissue level.27 In this model, it is noteworthy that after 70 days, there are intense remodelling and collagen deposition in the synovium.28

Human experimental data

Motor and sensory dysfunction of muscle may be important factors in the pathogenesis of articular damage.29 It is well accepted that patients with OA have muscle weaknesses and a vibratory sense loss in the regional OA joint.30 Interestingly, this neurological dysfunction is present locally and throughout the body, at least in patients with hip OA, suggesting a generalised alteration of the peripheral nervous system.31 Two main neurological syndromes have been described in diabetes. The first is the Charcot neuroarthropathy, a rare but devastating complication leading to joint deformity and eventually amputation or secondary OA. The second is a symmetric, mainly sensory polyneuropathy often accompanied by autonomic neuropathy.32 This latter diabetic neuropathy could be one of the suggested alteration of the peripheral nervous system seen in patients with OA leading to muscle weaknesses and joint laxity. I speculate that such peripheral nerve impairment induced by diabetes could be an added risk factor for OA in patients with diabetes.

Diabetes was first considered as a non-inflammatory disease. However, we now know that hyperglycaemia can trigger a low-grade systemic inflammation which would explain the increased risk of CV events seen in patients with diabetes.33,–,36 Low-grade systemic inflammation is associated with cartilage loss.37 Although MetS is a well known association with mild systemic inflammation, I propose that an independent hyperglycaemia-induced systemic inflammation may also have an impact on the progression of OA.

Based on these strong signals for a correlation between diabetes and OA (see figure 1), it is time to encourage the scientific community to perform prospective studies devoted to confirm or invalidate this hypothesis. In vitro and in vivo experimental studies should now be designed in order to have a better understanding of the mechanisms underlying the potential interactions between both diseases. These clinical and experimental studies would also help to decipher the respective roles of type 1 and type 2 diabetes in this suspicion of increased risk for OA. Finally, a better knowledge of the specificities of a diabetes-induced OA phenotype compared to the others should lead to a personalised approach of preventive and curative treatments for OA.

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Figure 1

A general paradigm for a diabetes-induced OA phenotype. Hypothesis: hyperglycaemia is the main trigger of joint degradation in OA. Local increased concentration of glucose alters the cartilage matrix by increasing the formation of AGEs that can, in turn, activate chondrocytes and synoviocytes to produce prodegradative and proinflammatory mediators and modify the quality of the subchondral bone. Alterations in the function of the glucose transporters at the surface of chondrocytes participate in the perpetuation of the deleterious process. Moreover, hyperglycaemia induces a low-grade systemic inflammation state that aggravates the OA process. Finally, the neurotoxicity of hyperglycaemia leads to a neuromuscular deficiency, which will also worsen OA by destabilising the joint. AGEs, advanced glycation end products; OA, osteoarthritis.

Research agenda

• ▶  What is the prevalence of OA in patients with non-insulin-dependent and insulin-dependent diabetes?

• ▶  Is insulin a potential protector against cartilage degradation?

• ▶  What are the characteristics of a diabetes-induced OA phenotype?

• ▶  Are antidiabetic drugs active for counteracting the OA process? (Such as peroxisome proliferator-activated receptor γ agonists, etc.)