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CLINICAL SCIENCES

Dyslipidemia in Achilles Tendinopathy Is Characteristic of Insulin Resistance

GAIDA, JAMES EDMUND1; ALFREDSON, LOTTA2; KISS, ZOLTAN STEVEN3; WILSON, ANDREW MICHAEL4; ALFREDSON, HÅKAN2; COOK, JILL LEIGH5

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Medicine & Science in Sports & Exercise: June 2009 - Volume 41 - Issue 6 - p 1194-1197
doi: 10.1249/MSS.0b013e31819794c3
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Abstract

The etiology and the pathogenesis of chronic tendinopathy are not well understood (2). Although overuse is considered a major causative factor for midportion Achilles tendinopathy (15), up to one third of cases occur among completely nonactive individuals (26). Furthermore, midportion Achilles tendinopathy is often seen among overweight individuals (6,7,10) who are often taking medication to treat aspects of the metabolic syndrome (3,10). Even among elite level athletes, a slightly elevated waist circumference (83 cm) dramatically increases the risk of tendon abnormality (18).

Although increased body weight directly affects Achilles tendon loading, it is unlikely that increased tendon loading adequately explains these relationships (8,18,23). Alternate mechanisms linking obesity and tendinopathy may be found by examining systemic factors that become increasingly common in the presence of obesity. These include dyslipidemia, hypertension, glucose intolerance, and insulin resistance (5,25,28). Because lipid deposition is known to occur in tendons (1,11), high cholesterol levels have been observed among individuals with Achilles tendon rupture (19,22), and the esterified fraction of cholesterol is elevated in biopsies from Achilles tendinopathy subjects (29) we chose to focus on serum lipid profiles.

Thus, the aim of this study was to compare fasting lipid profile in subjects with chronic painful midportion Achilles tendinopathy and a group of gender-, age-, and BMI-matched controls with normal tendons.

MATERIAL AND METHODS

Ethics

This project was approved by the human research ethics committee at La Trobe University and was conducted according to the principles of the Declaration of Helsinki. All participants gave written, informed consent.

Participants

Sixty individuals (32 men [53%]) referred to the Sports Medicine Unit, Umeå University, Sweden, for chronic Achilles tendon pain and diagnosed with midportion Achilles tendinopathy were included in this study. The participants were mainly middle-aged (mean ± SD age = 48 ± 9 yr [men = 47 ± 10 yr, women = 49 ± 8 yr]) and tending toward overweight (body mass index [BMI] = 25± 3 kg·m−2 [men = 26 ± 3 kg·m−2, women = 25 ± 3 kg·m−2]). Each participant had the diagnosis established by an experienced orthopedic surgeon (HA), which was confirmed with ultrasound (details below). Participants were excluded if they had an established diagnosis of familial hypercholesterolemia (FH) or insertional Achilles tendinopathy.

Sixty control participants (32 men [53%]) without a history of tendon injury were recruited from the general community. Each control participant was matched to onepatient based on gender, age (±10 yr), and BMI (±2kg·m−2). Thus, the control participants were of similar age (47 ± 10 yr [men = 45 ± 11 yr, women = 49 ± 8 yr]) and BMI (25 ± 3 kg·m−2 [men = 26 ± 2 kg·m−2, women = 25 ± 3 kg·m−2]). Twenty-nine controls were recruited in the Umeå region of Sweden whereas 31 were recruited from the Melbourne region of Australia. As with the patient group, a diagnosis of FH was an exclusion criterion.

Ultrasound

All participants (cases and controls) had both Achilles tendons investigated with gray-scale and color Doppler ultrasound. All Swedish participants (60 cases, 29 controls) had imaging performed by an experienced orthopedic surgeon (HA) using an Acuson Sequoia 512 (Siemens AG, Munich, Germany). All Australian participants (31 controls) had imaging performed by an experienced musculoskeletal radiologist (ZSK) using an Acuson Aspen Advanced (Siemens AG).

All subjects had the diagnosis of midportion Achilles tendinopathy confirmed by characteristic ultrasonographic changes. These included a widening of the anterior-posterior (AP) diameter of the Achilles midportion, hypoechoic regions, and structural changes such as a loss of definition of the anterior tendon margin. Color Doppler showed neovascularization in the structurally abnormal regions of the Achilles tendon. In contrast, all control subjects had normal Achilles tendon structure and no changes on color Doppler ultrasound.

Anthropometry

Height was recorded to the nearest centimeter using a wall-mounted stadiometer. Weight was measured to the nearest 0.1 kg while wearing light clothing on a digital scale. Body mass index (BMI) was then expressed as weight (kg) divided by the square of height (m).

Blood collection

Blood samples were collected between 0700 and 0900 after a 12-h fast. Blood was drawn from the antecubital vein using sterile equipment and aseptic technique into a 3.5-mL serum separating tube. Blood was allowed to clot at room temperature for 30 min before centrifugation. Two participants in the tendinopathy group who were taking statins were asked for a copy of a lipid analysis conducted before commencing medication.

Lipid profile analysis

Samples were sent to a chemical pathology laboratory in either Umeå University Hospital or Melbourne for routine analysis. Laboratory staff were blind to study data except patient name, age, and gender. The analysis included measurement of total cholesterol, triglycerides (TG), HDL-C, %HDL-C, LDL-C, LDL-C/HDL-C ratio, TG/HDL-C ratio, lipoprotein (a), apolipoprotein B, apolipoprotein A1, and apolipoprotein B/apolipoprotein A1 ratio. Apolipoprotein A1 was only measured in Swedish subjects (patient group n = 28, control n = 29).

Statistical analysis

Differences between the two groups were determined using independent sample t-tests for continuous variables with normal distribution. Variables with skewed distributions (Kolmogorov-Smirnov test, P < 0.05) were tested with the nonparametric Mann-Whitney U test. Analysis was performed using the Statistical Package for the Social Sciences version 11.0.1 (SPSS Inc., Chicago, IL), and significance was set at P < 0.05.

RESULTS

Patients and controls were well matched for age, height, weight, and BMI (Table 1). Achilles tendinopathy subjects showed evidence of underlying dyslipidemia (Table 2). They had higher triglyceride (TG) levels (P = 0.039), lower %HDL-C (P = 0.016), and higher TG/HDL-C ratio (P = 0.036) in comparison to the matched control group. Furthermore, Achilles tendinopathy subjects had elevated apolipoprotein B concentration (P = 0.017) in comparison to control subjects (Table 3). There were no differences in lipid profile between the Australian and the Swedish control subjects (data not shown).

T1-5
TABLE 1:
Demographic data for subjects with chronic painful midportion Achilles tendinopathy and matched controls.
T2-5
TABLE 2:
Serum lipid profile for subjects with chronic painful midportion Achilles tendinopathy and matched controls.
T3-5
TABLE 3:
Lipoprotein and apolipoprotein profile for subjects with chronic painful midportion Achilles tendinopathy and matched controls.

DISCUSSION

Serum lipid profile appears to be related to Achilles tendinopathy. In comparison to the gender-, age-, and BMI-matched control group, the subjects with chronic painful midportion Achilles tendinopathy were dyslipidemic. They had significant elevations in TG, TG/HDL-C ratio, and apolipoprotein B along with significant reductions in %HDL-C. This combination of abnormalities affecting the lipid profile has striking similarity to the lipid profile described in relation to insulin resistance (20,25,28). Possible metabolic involvement in midportion Achilles tendinopathy is likely as often it affects middle-aged, nonactive, and overweight individuals (6,7,10,26).

Insulin resistance describes a condition where an elevated insulin concentration fails to stimulate increased glucose uptake into muscle. Insulin resistance is extremely common in the community at large, including otherwise healthy individuals. It presents as a spectrum from hyperinsulinemia to fasting hyperglycemia, impaired glucose tolerance, and eventually type II diabetes mellitus (24).

It has been long recognized that subjects who display even mild insulin resistance have an associated dyslipidemic profile (16,20,24,28). These characteristics include an elevation in fasting plasma TG along with reduced HDL-C but normal LDL-C. Recently, the TG/HDL-C ratio has been proposed as a simple, sensitive, and specific marker of insulin resistance (20). This ratio also correlates strongly with LDL particle diameter (r = −0.77, P < 0.0001) (20).

The development of dyslipidemia in the presence of insulin resistance is driven by differences in insulin sensitivity between different organs and tissues. In spite of muscle and adipose tissue insulin resistance, the liver remains insulin sensitive, and elevated insulin levels signal the liver to increase very low density lipoprotein-triglyceride (VLDL-TG) synthesis and secretion. Later these particles interact with HDL-C, exchanging TG for cholesterol. The sum result is an elevation in TG with an associated fall in HDL-C, with LDL-C remaining relatively unchanged (21,24).

Dyslipidemia, which is characteristic of insulin resistance, among subjects with Achilles tendinopathy has not previously been reported. Several research articles suggest that serum lipids may be involved in Achilles tendinopathy; lipid accumulation has been shown in biopsies from tendinopathy subjects (11,29), and the lipid content of tendon increases and the esterified fraction of cholesterol doubles with increasing age (4). Interestingly, elevations in intramyocellular fat are correlated with insulin resistance (13,14), and the previously mentioned findings regarding intratendinous lipid and cholesterol (4,11,29) may have a similar underlying mechanism.

Clinically based tools are used to diagnose metabolic syndrome (cf. insulin resistance syndrome), and an elevated waist circumference or an elevated waist to hip ratio is one criteria in the metabolic syndrome (5,21,25,28). A connection between insulin resistance syndrome and tendinopathy is supported by previous research, which shows links between either waist to hip ratio (9,27) or waist circumference (18,27) and tendinopathy. Thus, perhaps we should view tendinopathy as a comorbid condition of cardiovascular disease (CVD) similar to recent suggestions for low back pain (12,17). It is possible that other features of insulin resistance may be associated with the pathophysiology of tendinopathy, including altered angiogenesis, impaired healing, and increased systemic inflammation that are all associated with this syndrome (28,30).

This research is limited by the absence of quantitative assessment of insulin resistance and fat partitioning. As such, although the dyslipidemia is characteristic of the insulin resistance syndrome, it is not possible to confirm this hypothesis with the current data. Also, because the data are cross-sectional, the question of cause and effect remains open. We plan to address these issues in future studies in which we will assess insulin resistance, fat partitioning, intramyocellular fat, and intratendinous fat in addition to lipid profile.

In conclusion, subjects with chronic painful midportion Achilles tendinopathy have a lipid profile characteristic of a dyslipidemia that is most commonly seen alongside the insulin resistance syndrome. This is the first time that systemic metabolic variables have been shown to differ between subjects with tendinopathy and well-matched controls. If we can draw upon the substantial body of knowledge regarding the insulin resistance syndrome and also research into improving outcomes for patients with CVD through risk factor reductions, perhaps we can make inroads into understanding the mechanisms underlying tendinopathy.

The authors thank Miss Fellon Robson-Long for assisting in the collection of blood samples.

This study was supported by a seeding grant from The Centre for Physical Activity and Nutrition Sciences (C-PAN) at Deakin University.

Financial assistance was received from the Swedish Research Council for Sports.

All authors declare that they have no conflict of interest.

A Felice Rosemary-Lloyd scholarship was awarded to J. E. Gaida to enable him to travel to Sweden and conduct this research. He is also a recipient of the Australian Postgraduate Award (APA) scholarship.

This work was presented at the Sports Medicine Australia Conference in October 2008.

The results of the present study do not constitute endorsement by ACSM.

Disclosure of funding: No funding was obtained from the NIH, the Wellcome Trust, and the HHMI.

Role of the funding source: Funding support was obtained from the organizations listed below. These sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

The Felice Rosemary-Lloyd Travel Scholarship (JEG), the Centre for Physical Activity and Nutrition Research (C-PAN) seeding grant, the Swedish Research Council for Sports, and the Australian Government-Australian Postgraduate Award (JEG).

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Keywords:

ACHILLES TENDON; MIDPORTION; SERUM; LIPID

©2009The American College of Sports Medicine