Diabetes and Rheumatic Diseases

Todd W. Burner; Ann K. Rosenthal


Curr Opin Rheumatol. 2009;21(1):50-54. 

Abstract and Introduction


Purpose of Review: This review summarizes recent advances in the field of diabetes and rheumatic disease. These conditions exert a significant healthcare burden on our society and much remains to be learned regarding their pathophysiology and treatment.
Recent Findings: We summarize new insights into diabetes and its association with osteoarthritis, rheumatoid arthritis, carpal tunnel syndrome, osteoporosis, diffuse idiopathic skeletal hyperostosis, crystalline arthropathy, neuropathic arthropathy, and tendinopathy. Diabetes has major effects on connective tissues, which have significant impact on both the development and outcome of these diseases of cartilage, bone, ligament, and tendon. An improved understanding of the mechanisms through which diabetes alters connective tissue metabolism should lead to better preventive and therapeutic interventions.
Summary: Incremental progress has been made in understanding the interactions between diabetes and common musculoskeletal syndromes. Although this review highlights exciting areas of future interest, more work in this field is certainly warranted.

Abstract and Introduction


According to the American Diabetes Association website (http://www.ADA.org), over 23 million Americans suffer from diabetes. Estimated annual cost of this disease burden is in the range of $174 billion. Diabetic patients suffer disproportionately from common musculoskeletal conditions in terms of increased prevalence, severity, and morbidity.[1]

The high glucose, high insulin milieu of diabetic tissues affects many of the key cells and matrix components of connective tissues. For example, reactive oxygen species are increased in diabetes and certainly may mediate tissue damage. Nonenzymatic cross-links, known as advanced glycation end-products (AGEs), tend to accumulate in the long-lived proteins of connective tissues,[2] and may alter both extracellular matrix structure and function as well as cell viability.[3] A role for other mediators such as changes in aldose reductase and the polysorbital pathway are less well characterized in connective tissues, but may also contribute to end-organ damage.[4] One wonders if these factors also play a role in the increased infection risk and diminished wound healing known to affect diabetic patients.

Although changes in connective tissue physiology in diabetes are well documented, the clinical impact of these changes remains poorly studied. In this review, we attempt to highlight what we feel are some of the more interesting and important recent advances in the area of diabetes and rheumatic disease.


Osteoarthritis is the most common form of arthritis in adults and as such would frequently co-occur with diabetes by chance alone. Although there are some fascinating studies suggesting that AGEs may play a role in the cartilage degeneration that characterizes osteoarthritis,[5] clear clinical evidence that diabetes predisposes to premature or severe osteoarthritis is lacking. The fact that obesity is a common risk factor for both osteoarthritis and diabetes makes epidemiologic studies difficult. Dahaghin et al.[6] sought to explore the role of certain metabolic factors including diabetes in the development of hand osteoarthritis (HOA) in overweight patients. An association with diabetes and HOA was only noted in people aged 55-62 years, and was absent in other age groups. However, a significantly higher prevalence of HOA was noted in the subset of patients with a combination of overweight status, diabetes, and hypertension. Further, this increased disease burden was noted in a relatively younger patient population.

Peripheral neuropathy, a common complication of diabetes, may also adversely affect joints and increase the risk of advanced, aggressive forms of osteoarthritis. Recent research by Shakoor et al.[7] looks specifically at this association, and describes a clear link between knee osteoarthritis and diminished lower extremity vibratory perception thresholds.

Diabetes may also affect the outcomes of therapy in osteoarthritis. Recent work by Meding et al.[8] examined the effect of diabetes on outcomes of total knee replacement (TKR) surgery. They noted a propensity for diabetic patients to have more severe pain and radiographic changes both preoperatively and postoperatively, an increased risk of deep tissue infection as well as an increased revision rate compared with nondiabetic controls. Insulin-dependent diabetic patients, in particular, had worse functional outcomes postoperatively, and were noted to comprise the majority of those patients who developed deep tissue infections.

Diabetes may also affect the risks of common pharmacologic therapies used for osteoarthritis. Recent work by Pham et al.[9] suggests that insulin resistance worsens when therapeutic doses of oral glucosamine are used to treat osteoarthritis. Several other studies[10,11] have suggested otherwise, including a recent one by Muniyappa et al.[12] that found no relationship between oral glucosamine and worsened insulin resistance. Further studies need to be done before clear recommendations regarding glucosamine use in diabetic patients can be made.

Rheumatoid Arthritis

Although diabetes is not recognized as an independent risk factor for the development of rheumatoid arthritis (RA), many patients suffer from both conditions. As a result, much thought has been given to the possibility of unique sensitivity of diabetic patients to the side effects of standard pharmacologic RA therapy. Two recent studies investigate the safety profiles of medical therapies widely used in the treatment of RA. The first, by Martin et al.,[13] examines the problem of peripheral neuropathy associated with leflunomide use. Generally thought to be a rare side effect of leflunomide, peripheral neuropathy was noted to occur more frequently in diabetic patients. It was also noted to be increased in older patients and those who were taking other potentially neurotoxic medications. Weisman et al.[14] rigorously examined the side effects of etanercept in patients with RA and concomitant diseases including diabetes. Their primary endpoint was the incidence of medically important infections (MIIs) resulting in hospitalization or treatment with intravenous antibiotics. Employing a placebo-controlled, randomized, double-blinded approach, the authors failed to note any etanercept-related increase in the incidence of MIIs in diabetic patients.

Carpal Tunnel Syndrome

Carpal Tunnel Syndrome (CTS) is a common compression neuropathy of the median nerve associated with many conditions including diabetes. A role for diabetes in the development or severity of CTS has been proposed. Diabetes may induce structural alterations of tendon, increase obesity, and produce metabolic abnormalities that result in proliferation or fibrosis of the connective tissues surrounding the nerve.

In two recent studies, investigators sought to quantify various risk factors for CTS in hopes of better understanding the causes of this condition. Geoghegan et al.[15] applied a case-control approach to identify significant risk factors for CTS. In addition to wrist fracture, RA, osteoarthritis, and obesity, the authors noted statistically significant increased risk in patients with diabetes [odds ratio (OR) = 1.51, 95% confidence interval (CI): 1.24-1.84]. They also noted increased risk in patients taking specific medications for diabetes including insulin (OR = 1.52, 95% CI: 1.06-2.18), sulphonylureas (OR = 1.45, 95% CI: 1.07-1.97), and metformin (OR = 1.20, 95% CI: 0.84-1.72). Similarly, van Dijk et al.[16] explored the prevalence of specific conditions in CTS patients. They demonstrated an increased prevalence of diabetes (OR = 2.2, 95% CI: 1.5-3.1), hypothyroidism (OR = 1.4, 95% CI: 1.0-2.0), and RA (OR = 2.2, 95% CI: 1.4-3.4) in CTS patients. However, information regarding time of diagnosis of these conditions was unavailable, and routine screening for these specific conditions in CTS patients could not be recommended.

Metabolic conditions including diabetes are thought to impair bone homeostasis. Type 1 diabetes has been associated with abnormal bone formation or bone turnover, or both possibly leading to decreased bone mineral density (BMD) and increased marrow adiposity.[17] Three recent studies contribute to our understanding of this relationship.

Liu et al.[18] developed a diabetic rat model of bone regeneration/repair. Using Zucker Diabetic Fatty (ZDF) rats, investigators performed tibial osteotomies with distraction gaps that were subsequently analyzed for new bone formation. They found a reproducible reduction in new bone formation as well as an increased adipose volume in adjacent bone marrow in the ZDF rats compared with control rats. They suggest that this model might be used by others in studying bone repair and remodeling in diabetes.

In two separate publications, Altan et al.[19,20] examined the therapeutic role of Nigella sativa (a plant extract) as a supplement to human parathyroid hormone (hPTH) in the treatment of diabetic rats with low bone mass. N. sativa is thought to function as both a natural antioxidant as well as an antidiabetic agent. These data suggest that addition of N. sativa to hPTH therapy enhances the desired anabolic effect when used in a streptozotocin-induced diabetic rat model.

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by ossification of spinal ligaments associated with large bridging osteophytes between vertebral bodies. Although the pathophysiology of DISH remains largely unknown, several conditions are thought to be associated with DISH. These include obesity, hyperlipidemia, hyperuricemia, hypertension, hyperinsulinemia, and diabetes. Sencan et al.[21] specifically examined the prevalence of DISH in a diabetic group compared with a nondiabetic control group. While noting higher prevalence of DISH in the diabetic group, this increase did not reach statistical significance. Mader et al.[22] noted a trend towards more diabetes, hypertension, and elevated BMI in the DISH patients compared with the controls, but were cautious to note atypical characteristics of their control group. Clearly, larger studies need to be done in order to better address this issue.

The pathophysiology of DISH is unknown, but much attention has been given to serum concentrations of glucose sensitive factors with bone-promoting effects such as insulin-like growth factor (IGF-1), growth hormone (GH), and insulin. Denko and Malemud[23] discovered that DISH patients with BMI more than 28 kg/m2 had higher serum levels of insulin, but interestingly did not have elevated serum GH or IGF-1 levels.

Atzeni et al.[24] published a wonderful overview of pathologic calcification that suggests DISH may also be a function of decreased levels of protective matrix proteins such as matrix Gla protein (MGP). Sarzi-Puttini and Atzeni[25] recently reviewed DISH and also noted an association with higher BMI, hyperuricemia, and diabetes. They also suggest a role for altered serum levels of matrix proteins including MGP.

Gout is an acute and chronic arthritis caused by monosodium urate (MSU) crystals. Hyperuricemia is a necessary condition for gout and is part of the constellation of lipid and nonlipid cardiovascular risk factors typically defined as the metabolic syndrome. Type II diabetes is also a part of this syndrome and as such, an association of gout and type II diabetes would be expected. Renal insufficiency, a common complication of diabetes, also predisposes to gout. Whether the onset of diabetes or its complications exacerbates existent gout or affects outcomes has not been well studied.

Diabetes is also occasionally included as a possible risk factor for calcium pyrophosphate dihydrate (CPPD) deposition disease. This is based on a handful of small case collections.[26] Clearly, larger population-based studies are needed to address this issue.

In contrast, several of the musculoskeletal syndromes associated with the hydroxyapatite-like basic calcium phosphate (BCP) crystals such as calcific tendinitis are clearly associated with diabetes.[27] The mechanisms through which diabetes contributes to calcific tendinitis are not known. Similar calcific processes certainly occur in blood vessels of diabetic patients as well as in spinal ligaments in DISH. Metabolic changes, consequent to chronic high glucose and insulin levels, may produce important changes in connective tissues that might predispose to pathologic calcification. Historically, calcific tendinopathy was attributed to dystrophic calcification at sites of tissue necrosis or ischemia. More recent evidence, however, suggests that tendinitis is more degenerative than inflammatory.[28] Interestingly, in diabetes, there is even less inflammation after tendon injury than in nondiabetic patients.[29] A recent model of calcific tendinitis, based on the isolation of matrix vesicles from adult tendon, may shed light on the factors contributing to tendon calcification in vivo.[30] This work suggested an important role for extracellular matrix changes in calcific tendinitis. Although AGEs may be involved, increased reactive oxygen species, undersulfation of proteoglycans, and increased activity of the mineralization-promoting transglutaminase enzymes may also predispose to tissue calcification.

Charcot arthropathy, which is also called neuropathic arthritis, is a serious complication of diabetes. It is characterized by fracture, dislocation, and subluxation of the affected joint in the presence of a significant sensory deficit. Charcot arthropathy typically affects the foot in diabetic patients with peripheral neuropathy. It can present early on as an acute inflammatory process, which is frequently mistaken for osteomyelitis, gout, or injury, and then develops into a chronic arthritis with severe deformities. Late stages are often complicated by refractory skin ulcers and may culminate in amputation. Whether Charcot arthropathy results from repetitive microtrauma without a protective sensory response or it is associated with bone deficits from microangiopathy or altered sympathetic tone, remains unclear. Charcot arthropathy may be a marker for a subset of patients with higher morbidity and mortality from their diabetes.[31]

Treatment options for Charcot arthropathy are limited. Nonweight bearing and immobilization of the affected limb have been the mainstays of therapy. Recently, a weight-bearing total contact cast was evaluated in patients with Charcot arthropathy. In this retrospective, single center case collection, these casts were well tolerated and did not appear to increase the risk of skin ulcerations or worsen bony destruction.[32] Bisphosphonates have also been reported to be useful for the acute phase of Charcot arthropathy. Naqvi et al.[33] recently reported the successful use of pamidronate in three patients with Charcot arthropathy. While two had acute disease, one was in the subacute phase at the time of treatment. These patients were given one to three injections of 90 mg of pamidronate intravenously and all had a beneficial response at 4 weeks to 14 months of follow up.

Tendinopathies occur frequently in patients with diabetes. The shoulder and hand are particularly commonly involved. Painful tendinopathies, including shoulder tendinitis, limited hand mobility (cheiropathy), tendon ruptures, and adhesive capsulitis affect 30-60% of diabetic patients, and cause considerable disability among affected patients.[34] Diabetic tendons are increased in stiffness and are thicker than their normal counterparts.[35] Although most work in diabetes has concentrated on the upper extremity, a recent study[36] showed increased buckling of the patellar tendon in knees of patients with osteoarthritis and diabetes compared with those with osteoarthritis alone. These findings imply altered tendon biomechanics in these patients and reinforce the findings of previous studies. For example, reduced length and increased thickness of the Achilles tendon may predispose to the development of Charcot arthropathy of the foot, ulceration, and subsequent amputation.[37]

Shoulder tendinitis is a particular problem in diabetic patients. Correct anatomic diagnosis of shoulder syndromes can be challenging. Many of these syndromes fall into the category of rotator cuff tendinitis. A recent population-based study from Finland confirmed that insulin-dependent diabetes was a significant risk factor for rotator cuff tendinitis, increasing the relative risk 8.8 fold (CI: 1.9-40.3).[38] Flexor tenosynovitis in the hand is also quite common in diabetic patients with a prevalence estimated at 10-20% of diabetic patients.[39] It is caused by excess fibrous connective tissue deposition in the tendon sheath. Interestingly, diabetes and its control may also affect therapy. Although inter-sheath injections are typically very successful for flexor tenosynovitis in the hand, high hemoglobin A1C levels, reflecting poor diabetic control, adversely affect results from this intervention.[39]

Tendon rupture may also be associated with diabetes, although good quality epidemiologic studies are lacking. In addition, diabetes may be an additional risk factor for tendon ruptures associated with the use of fluoroquinolones.[40]

The above studies represent small, but significant advances in the effort to understand the complex interplay between diabetes and rheumatic disease. As a society, we have much to gain from this advancing field of medicine, as it no doubt causes significant morbidity. To that end, it is important that more research be conducted in this exciting and evolving field.


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