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Achilles tendons in people with type 2 diabetes show mildly compromised structure: an ultrasound tissue characterisation study
  1. Suzan de Jonge1,
  2. Robert Rozenberg2,
  3. Bruno Vieyra2,
  4. Henk J Stam2,
  5. Henk-Jan Aanstoot3,
  6. Harrie Weinans1,
  7. Hans T M van Schie1,4,
  8. Stephan F E Praet2
  1. 1Department of Orthopaedics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
  2. 2MOVEFIT-Sports Medicine, Department of Rehabilitation Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  3. 3Diabeter, Center for Pediatric and Adolescent Diabetes Care and -Research, Rotterdam, The Netherlands
  4. 4Department Scientific Research, UTC Imaging, Stein, The Netherlands
  1. Correspondence to Suzan de Jonge, Department Sports Medicine, Medical Center The Hague, Burg Banninglaan 1, Leidschendam 2262 BA, the Netherlands; s.dejonge{at}


Background Musculotendinous overuse injuries are prevalent in people with type 2 diabetes. Non-enzymatic glycosylation of collagen resulting in tendon stiffening may play a role. In this case–control study we determined whether patients with diabetes had poorer ultrasonographic structure in their Achilles tendons compared to age-matched controls.

Methods People with type 1 diabetes or type 2 diabetes, and age-matched controls, had computerised ultrasound tissue characterisation of both Achilles tendons. In contiguous ultrasonographic images of the tendon, echopatterns were quantified and categorised into four echo-types. Tendon abnormality was quantified as sum of echo-types III+IV. Furthermore, skin autofluorescence (AF) of the forearm (AF-value) was gathered.

Results Twenty four type 2 diabetes patients, 24 controls, 24 type 1 diabetes patients and 20 controls were included. AF-value was higher in type 1 diabetes (1.55±0.17) than in their controls (1.39±0.18, p<0.001) and in type 2 diabetes (2.28±0.38) compared to their controls (1.84±0.32, p<0.001) Achilles tendons of type 2 diabetes patients contained more echo-types III+IV (14.1±7.9%) than matched controls (8.0±5.4%, p<0.001). There was a trend towards a difference in echo-types III+IV between type 1 diabetes patients (9.5±5.3%) and their controls (6.5±3.7%, p=0.055). In a stepwise linear regression analysis, body mass index (BMI) was moderately associated with tendon abnormality in patients with diabetes and controls (β=0.393, p<0.001).

Conclusions Type 2, and possibly type 1, diabetes patients showed poorer ultrasonographic Achilles tendon structure that may be a risk factor for tendinopathy. Although markers for accumulation of advanced glycation end products were elevated in both diabetes populations, only BMI was associated with these abnormalities.

Trial registration number NTR2209.

  • Achilles
  • Ultrasound
  • Diabetes

Statistics from


Exercise is a cornerstone in the treatment of type 2 diabetes mellitus. However, patients with diabetes are vulnerable to overuse injuries.1–4 Although not significant, diabetes seemed more prevalent in people with Achilles tendinopathy than in asymptomatic people.5 These injuries may be due to overload because of obesity or altered moving patterns due to motor-sensory neuropathy, but tendons might also be directly affected by hyperglycaemia.6 Previous research shows that people with type 2 diabetes have thicker tendons7–9 and an increased level of ultrasonographic tendon disorganisation.10–12 Craig et al13 reported an association between plantar fascia thickness and complications in type 1 diabetes. Unfortunately, these studies were hampered by the fact that standard two-dimensional ultrasonography does not quantify tendon structure. Although Movin et al14 showed that hypoechoic areas seen on ultrasonography corresponded to histological collagen degeneration, a recent rodent study indicated that experimental induced diabetes resulted in structural, inflammatory and vascular changes in the Achilles tendon.15 Hyperglycaemia itself may also increase expression of matrix metalloproteinase-9 and metalloproteinase-13 in tendon cells and impair collagen synthesis.16 Nevertheless, the pathomechanics behind tendon degeneration in either type 1 or type 2 diabetes is most likely multifactorial and still largely unknown.12 ,17

It can be hypothesised that the accumulation of non-enzymatic advanced glycation end products (AGEs) in the connective tissues cause tendon overuse injuries and increased matrix disorganisation.18 AGEs are the result of non-enzymatic glycosylation of proteins, induced by diabetes-related hyperglycaemia and hyperlipidaemia. AGEs create cross-links with short and long-lived proteins, and the formation of AGEs is one of the pathophysiological mechanisms that links hyperglycaemia and hyperlipidaemia to microvascular and macrovascular pathology. Since AGEs also form cross-links with collagen they might explain the predisposition to tendinopathy in people with diabetes.19 An autopsy study showed significantly higher levels of non-enzymatically bound glucose in tendons and other tissues of patients with type 2 diabetes.20 A validated non-invasive technique to estimate the level of glycated collagen in the skin is autofluorescence (AF).21 AGE levels based on skin biopsies22 and the skin AF measurement have been shown to be independent predictors for both the severity of long-term hyperglycaemia as well as the development of microvascular23 and macrovascular22 complications and cardiac death in type 1 diabetes and type 2 diabetes.24

Ultrasound tissue characterisation (UTC) was developed in equine tendons to detect and quantify more subtle tendon structural changes.25 ,26 In contiguous ultrasonographic images, dedicated algorithms quantified three-dimensional (3D)-stability of echo-patterns. Four echo-types can be discriminated: (I) intact and aligned tendon bundles; (II) discontinuous or waving tendon bundles; (III) fibrillar tissue; (IV) amorphous tissue with mainly cellular components and fluid. Greater levels of echo-types III+IV suggest poorer tendon structure. In previous human research symptomatic tendons showed significantly more echo-types III+IV than asymptomatic tendons.27

The primary aim of this study was to compare Achilles tendon structure in type 1 diabetes and type 2 diabetes patients with healthy age-matched controls. The secondary study aim was to correlate skin AF as a general indicator of AGEs with Achilles tendon structure. Furthermore, we investigated if age, body mass index (BMI), duration of diabetes, sports activity and glycated haemoglobin (HbA1c) levels were associated with Achilles tendon structure.



Patients and age-matched control participants were recruited in outpatient departments at the Erasmus MC University Medical Center in Rotterdam, The Netherlands, and a national expert centre for diabetes care (Diabeter, Rotterdam, the Netherlands). Inclusion criteria for the case group were type 1 diabetes (aged between 18 and 30 years) or type 2 diabetes (aged 35–60 years) diagnosed according to the WHO criteria. People with Achilles tendon pain and participants whose ultrasound scan was of poor quality were excluded. A written informed consent was obtained from all participants before participation in the study, approved by the ethical committee of the Erasmus University Medical Center in Rotterdam and listed in the Dutch Trial Register (number NTR2209).

Study measurements

Weight and height were measured to calculate the BMI. All participants recorded current sports and exercise activities (hours/week). Fasting venous blood samples were collected in a sodium fluoride tube and EDTA tube to, respectively, measure fasting glucose by a clinical chemistry analyser (Modular P Module, Roche Diagnostics, Almere, the Netherlands) and blood HbA1c content through high-performance liquid chromatography (ADAMS A1c HA-8160 analyser, Arkray Europe B.V., Amstelveen, the Netherlands).

Activity monitor

The participants received a preprogrammed accelerometer (GT1M; ActiGraph, LLC, Pensacola, Florida, USA) and wore it on the right hip for seven consecutive days while awake and not in the water. The activity levels assessed by the accelerometer are presented as mean counts per day.

Skin AF

Forearm skin AF was measured using the AGE-Reader (DiagnOptics Technologies BV, Groningen, the Netherlands). The AGE-Reader is a desktop device that uses the characteristic fluorescent properties of glycated collagen to estimate the level of AGE accumulation in the skin.24 The measurement is automated and obtained by placing the forearm on the device. Three measurements were taken and the mean AF-score of the three measurements was used in the analyses.

Ultrasound tissue characterisation

Tendon integrity was evaluated quantitatively by one of two experienced examiners (HTMvS and SdJ) with the use of UTC (UTC2000, UTC imaging, Stein, the Netherlands). Participants were laying prone on an examination table with their feet hanging over the edge and with the ankle in approximately 5–10° dorsiflexion, to slightly pretension the Achilles tendon. A 10 MHz linear-array transducer (Smartprobe 10L5, Terason 2000, Teratech, USA) was moved automatically along and perpendicular to the Achilles tendon's long axis by means of a motor-drive. Transverse images were collected at regular distances of 0.2 mm and a 3D data block was reconstructed. The following UTC setting was used; Window Size=9. The stability of the echo pattern over contiguous images was analysed by means of custom-designed algorithms (UTC 2010 UTC imaging, resulting in discrimination of four echo-types. Previous research has shown that these echo-types are highly correlated to histomorphology of tendon tissue at various stages of integrity. Echotypes I and II represent more or less organised (secondary) tendon bundles. Echotypes III represent smaller, disorganised and more fibrillar tissue. Echotypes IV represent amorphous tissue.27 By one blinded researcher (SdJ), a point 4 cm from calcaneal insertion was determined in the sagittal plane. The tendon border was outlined at five equally spaced points from 3 to 5 cm proximal to the calcaneal insertion. The five outlines were interpolated to create a tendon volume of 2 cm length, making the region of interest for analysis. Proportions of the four echo-types were calculated within this volume. The sum of echo-types III and IV, representing poorer tendon structure, was used for statistical analyses. The interobserver reliability of this method appeared to be excellent with an intraclass correlation coefficient (ICC) of 0.89 and a mean difference of 0.9% in the sum of echo-types III+IV.28

Statistical analysis

Statistical analyses were performed using statistical software (PASW V.19.0). Values are presented as mean±SD for normally distributed parameters. For non-parametric parameters median and IQR are given. Differences in echo-types III+IV, AGE value and non-parametric baseline characteristics between the groups were tested using the Mann-Whitney U test. For differences in parametric baseline characteristics the unpaired t test was used. To calculate the association between the parameters age, BMI, AF-score, duration of diabetes, hours of sports participation, blood HbA1c level and tendon structure, a stepwise linear regression analysis was used. Standardised regression coefficients (β) were given. A p<0.05 level was chosen to indicate statistical significance.


Sixty two people with diabetes and 58 age-matched controls were screened for eligibility and resulted in 102 participants who met the inclusion criteria (figure 1). Ten people were excluded because of abnormal blood results (n=3), presence of Achilles tendon pain (n=3) or technical failure of ultrasound (n=4). Those with type 2 diabetes had a significantly higher BMI than their controls (table 1). Fewer people with type 1 diabetes were active in sports (75%), compared to their controls (95%). The self-reported hours of sport participation was significantly higher in the controls compared to the patients with diabetes.

Table 1

Baseline characteristics

Skin AF measurement

Mean AF-score for the type 1 diabetes group was 1.54 (0.16), which is 111% (12.0) of the predicted value for equally aged healthy individuals using the Koetsier et al21 regression model. The control group for type 1 diabetes had a mean AF-score of 1.38 (0.19): 98% (13.8) of predicted value. This was significantly lower than the patients with type 1 diabetes (p=0.008). The AF score of the type 2 diabetes patients was 2.31 (0.40), 114% (16.8) of the predicted value for healthy individuals. Their controls had significant lower value of 1.85 (0.31), which is 95% (16.1) of predicted value, p<0.001).

Ultrasound tissue characterisation

Tendons of people with type 1 diabetes contained 9.5% (5.3) echo-types III+IV (table 2). The tendons of matched controls contained 6.5% (3.7) echo-types III+IV (p=0.055). People with type 2 diabetes and matched controls had, respectively, 14.1% (7.9) and 8.0% (5.4) echo-types III+IV (p<0.001). In a stepwise multiple regression analysis BMI (β=0.393, p<0.001) and presence of diabetes (β=0.234, p=0.024) was associated with poorer tendon structure (echo-types III+IV). HbA1c (β=0.095, p=0.549), age (β=0.070, p=0.516), hours of sports participation (β=0.047, p=0.653) and AF score (β=0.003, p=0.978) did not contribute significantly to the model.

Table 2

Mean proportions of four echo-types measured with UTC

In a subanalysis on the predictive value of diabetes-associated parameters in the patients with diabetes, only BMI was associated with Achilles tendon structure. Duration of diabetes (β=−0.013, p=0.933), HbA1c (β=−0.055, p=0.715) and AF score (β=0.075, p=0.683) did not contribute to the regression model.


This study shows that asymptomatic Achilles tendons of people with type 2 diabetes had worse structure than age-matched controls. The observed difference in tendon disorganisation between type 1 diabetes patients and healthy matched controls did not reach statistical significance and requires replication. Nevertheless, it is an interesting finding that can be regarded as a hint that the hyperglycaemic state in young, but otherwise healthy, type 1 diabetes patients may lead to an impaired Achilles tendon structure. These ultrasonographic tendon structure irregularities suggest tendon disintegration, which may lead to clinical symptoms of tendinopathy.25–27 This finding might explain previous study results showing tendinomuscular overuse injury as a frequent cause for early termination of exercise programmes in type 2 diabetes.29 ,30 In accordance, our study results extend on a recent qualitative ultrasound study by Abate et al12 and are consistent with epidemiological data providing a hint that diabetes mellitus is more prevalent in patients with Achilles tendinopathy than in asymptomatic persons.5 We are not sure whether the ultrasonographic differences between diabetes and control groups are caused by measurement errors. Nevertheless, our cross-sectional comparison suggests that overweight and obese patients with diabetes participating in weight-bearing exercise, should be controlled regularly on Achilles tendon pain or stiffness to avoid premature drop-out due to Achilles tendinopathy. Since we only measured asymptomatic people, we can only speculate at which level of echo-type III and IV asymptomatic people with type 1 or type 2 diabetes may develop or experience tendon pain or stiffness. Furthermore, the observed difference in echo-types III+IV between people with type 1 diabetes and their aged-matched controls was only borderline significant. Owing to limited power, a type 2 statistical error cannot be excluded. Therefore, our findings in people with type 1 diabetes should be taken cautiously and warrant further investigations.

At this stage, we can only speculate on the underlying causal relation between diabetes and the observed ultrasonographic tendon irregularities in our asymptomatic populations. In the present study, BMI shows the strongest association with poorer ultrasonographic tendon structure (echo-types III+IV). The group with patients with type 1 diabetes had a mean BMI in the healthy 20–25 kg/m2 range. This may partly explain the borderline association with an increased percentage of ultrasonographic tendon abnormalities, as BMI has been shown to be an important risk factor for tendinopathy in previous research.31 However, its association with ultrasonographic tendon disintegration was not examined previously. The deleterious effect of BMI on tendon disintegration could be mediated by increased mechanical loading, suggesting that not only body weight, but also increased physical activity might be associated with ultrasonographic tendon abnormalities. However, our results could not confirm an association or interaction between objectively determined physical activity level, body weight and ultrasonographic tendon structure irregularities. In a previous publication, Gaida et al32 have suggested that cytokines released by visceral fat may play a role in the pathogenesis of tendinopathy. In addition, they noted that a large proportion of their tendinopathy population have signs of metabolic obesity with a normal weight.32 Since we excluded participants with clinical tendinopathy, the present study design is not well suited to study the long-term effects of metabolic syndrome on Achilles tendon complaints. Nevertheless, our results do support the notion that biomarkers for hyperlipidaemia, insulin resistance and visceral fat deposition should be integrated in future studies on diabetes and tendinopathy risk.31

Although presence of diabetes was associated with poorer tendon structure on ultrasound, diabetes associated parameters, like duration of diabetes, HbA1c and skin AF, lack to clarify an association with percentage of ultrasonographic tendon abnormalities. Hyperglycaemia could be a determinant for ultrasonographic tendon structure abnormalities, but our study does not support the hypothesis that skin AF predicts tendon disintegration.33 ,34 The lack of a significant association does not exclude a role of AGEs in tendon pathology, since skin AF has not been validated as a predictor of AGE accumulation in the tendon. Skin AF is an indicator of general glycation products and known to predict the severity of long-term hyperglycaemia in diabetes.22 ,23 The higher levels of non-enzymatically bound glucose found in tendons of patients with diabetes in an autopsy study20 suggest there is a missing link between skin measured AGEs and AGEs in tendons. Different ex vivo studies demonstrated that elevated glycation caused increased tendon stiffness.35 ,36 Possibly this is caused by supraphysiological concentrations of AGE forming metabolites such as methylglyoxal and ribose. Also, other factors like pentosidine concentration or altered gait might play a role. Abate et al17 concluded in their review that many complex pathogenetic mechanisms are involved in rheumatological manifestations of diabetes.

One limitation to this study was that, in terms of BMI, our diabetes patients were not perfectly matched with the controls. It was particularly difficult to find controls for type 2 diabetes patients with an equal BMI. Possibly the metabolic syndrome is a risk factor on itself and should not be split up. Type 1 diabetes patients were recruited from a national expert centre for diabetes care and can be considered a random sample. We cannot be certain that the type 2 diabetes patients represent a random sample. Although patients were referred by general practitioners and medical specialists and presence of diabetes related diseases was comparable with the prevalence in diabetes type 2 patients in the Netherlands, patients were not specifically tested for diabetic polyneuropathy. Nevertheless, clinical polyneuropathy was documented in none of the available medical files and was also not reported by the patients.

This study noticed that people with type 2 diabetes have poorer tendon structure measured with ultrasound which may make them vulnerable for tendon overuse injuries. For a good outcome of exercise programmes it is necessary to reduce the risk of myotendinous overuse injuries in patients with type 2 diabetes. It might be advisable to implement an adapted exercise protocol for the patients at risk for tendinopathy.29 However, more research is needed to identify these risk factors.


This study showed that people with type 2, and potentially also type 1 diabetes, have compromised structure of the mid-portion of the Achilles tendon. Although diabetes patients have elevated AGE skin AF scores compared with their controls, the difference in ultrasonographic tendon disintegration seems to be based mainly on the BMI.

What are the new findings

  • Type 2, and possibly type 1 diabetes patients showed poorer Achilles tendon structure than healthy controls.

  • In both healthy controls and patients with diabetes, body mass index was moderately associated with the level of ultrasonographic Achilles tendon abnormalities.

  • Skin autofluorescense based advanced glycation end products was not associated with poorer ultrasonographic tendon structure.

How might it impact on clinical practice in the near future

  • Clinicians should consider the potential for diabetes to increase the risk of Achilles tendon injuries.

  • To avoid premature drop-out due to Achilles tendinopathy, overweight and obese patients with diabetes participating in weight bearing exercise should be controlled regularly on Achilles tendon pain or stiffness.


The authors thank Daniëlle Visser and Serieta Mohkamsing of the department of Rehabilitation Medicine at Erasmus University Medical, for their logistic assistance in this study. The authors also thank all participants for their participation.



  • Contributors SdJ primarily was responsible for carrying out the study, including performing all ultrasonographic scans, and she was the major author of the manuscript. RR contributed to study design, data analysis and interpretation and contributed to the manuscript. BV contributed to the data collection. SFEP contributed to study conception and design, data analysis and interpretation and contributed to the manuscript. HJS, H-JA, HW and HTMvS contributed to study conception and design, data collection and analysis and reviewed and edited the manuscript.

  • Funding This work was supported by Dutch Diabetes Research Foundation (research grant no #2010.11.1387.

  • Competing interests HTMvS is founder and shareholder of UTC imaging,

  • Patient consent Obtained.

  • Ethics approval Ethical committee of the Erasmus University Medical Center in Rotterdam.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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