Accepted: 2 December 2016

DOI: 10.1111/sms.12824

REVIEW ARTICLE

Tendinopathy in diabetes mellitus patients—Epidemiology,

pathogenesis, and management

P. P. Y. Lui

Headquarter, Hospital Authority, Hong

Kong SAR, China
Chronic tendinopathy is a frequent and disabling musculo-­skeletal problem affecting
the athletic and general populations. The affected tendon is presented with local
Correspondence
­tenderness, swelling, and pain which restrict the activity of the individual. Tendon
Pauline Po Yee Lui, PhD, Headquarter,
Hospital Authority, Hong Kong SAR, degeneration reduces the mechanical strength and predisposes it to rupture. The
China. ­pathogenic mechanisms of chronic tendinopathy are not fully understood and several
Email: paulinelui00@gmail.com
major non-mutually exclusive hypotheses including activation of the hypoxia-­
apoptosis-­pro-­inflammatory cytokines cascade, neurovascular ingrowth, increased
production of neuromediators, and erroneous stem cell differentiation have been
­proposed. Many intrinsic and extrinsic risk/causative factors can predispose to the
­development of tendinopathy. Among them, diabetes mellitus is an important risk/
causative factor. This review aims to appraise the current literature on the epidemiol-
ogy and pathology of tendinopathy in diabetic patients. Systematic reviews were
done to summarize the literature on (a) the association between diabetes mellitus and
tendinopathy/tendon tears, (b) the pathological changes in tendon under diabetic or
hyperglycemic conditions, and (c) the effects of diabetes mellitus or hyperglycemia
on the outcomes of tendon healing. The potential mechanisms of diabetes mellitus in
causing and exacerbating tendinopathy with reference to the major non-mutually
exclusive hypotheses of the pathogenic mechanisms of chronic tendinopathy as
­reported in the literature are also discussed. Potential strategies for the management
of tendinopathy in diabetic patients are presented.

KEYWORDS
diabetes mellitus, epidemiology, management, pathogenesis, tendinitis, tendinopathy, tendinosis

1  |   IN TRO D U C T ION loading. In this context, metabolic factors such as diabetes

Chronic tendinopathy is a frequent, important, and disabling
musculo-­skeletal condition affecting the athletic and the gen-
eral populations. There is no effective treatment for chronic
tendinopathy at present. There are substantial individual dif-
ferences in the development and progression of the disorder.
Chronic tendinopathy can occur in individuals at relatively
high or low physical activity, suggesting that patient-­related
factors are involved. Genetics, age, trauma, mechanical im-
pingement, drugs, hormones, and blood supply can influence
the biological milieu and tendon adaption to mechanical
mellitus (DM) and obesity are frequently associated with
the development and poor prognosis of chronic tendinop-
athy. DM, as a chronic systemic disorder, is an important
risk/causative factor for the development or poor prognosis
of many chronic musculo-­skeletal disorders such as osteo-
porosis and limited joint mobility.1 Better understanding of
the relationship between DM and chronic tendinopathy, the
impact of DM on tendon structure and healing as well as
the mechanisms of DM in causing and exacerbating tendi-
nopathy will aid the development of an effective treatment
strategy.

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776     wileyonlinelibrary.com/journal/sms
© 2017 John Wiley & Sons A/S. Scand J Med Sci Sports. 2017;27:776–787.
Published by John Wiley & Sons Ltd
LUI
This review aims to summarize the epidemiological ev-
idences of the association between DM and chronic tendi-
nopathy. The pathological changes in tendon under diabetic
or hyperglycemic conditions are then reviewed. The potential
mechanisms of DM in causing and exacerbating tendinopathy
with reference to the major non-mutually exclusive hypothe-
ses of the pathogenic mechanisms of chronic tendinopathy as
reported in the literature are presented. Potential strategies
for the management of tendinopathy in diabetic patients are
finally discussed.
2  |  M ATE R IA L S A N D ME T HODS
The PubMed database was searched with the key words (“ten-
don” OR “tendinopathy”) AND (“diabetes” OR “diabetic” OR
“glucose” OR “sugar” OR “hyperglycemia” OR “insulin”) on
9 November 2015 with no restriction in language and year of
publication. Studies on the effects of lipids, adiposity, obesity,
cholesterol, triglycerides, or metabolic syndrome on tendon or
tendinopathy were excluded as they were outside the scope of
this review. Studies on plantar fascia and plantar fasciitis were
excluded due to limited space although they show many simi-
larities to tendon and tendinopathy, respectively. Only studies
on tendons for locomotion (including tail tendon of rats and
mice) were included. Studies on tendons not for locomotion
such as diaphragmatic tendon were excluded.
For understanding about the relationship between DM and
tendinopathy/tendon tears, original human studies reporting
the association between DM or hyperglycemia and tendinop-
athy, enthesopathy, or tendon tear/rupture with a possible
degenerative or overuse etiology were included. Studies on
frozen shoulder were included because frozen shoulder fre-
quently involves pathology at the rotator cuff tendons. Studies
on trigger finger, cheiroarthropathy, carpal tunnel syndrome,
Dupuytren’s disease, and limited joint mobility were outside
the scope of this review and hence were excluded.
For understanding about the effects of DM or hypergly-
cemia on the healing outcomes of tendon injury and frozen
shoulder, original clinical and preclinical studies were in-
cluded. Studies on trigger finger, cheiroarthropathy, carpal
tunnel syndrome, Dupuytren’s disease, and limited joint mo-
bility were outside the scope of this review and hence were
excluded. Studies on skin wound complications after surgery
were also excluded.
For understanding about the pathological changes in ten-
don under diabetic or hyperglycemic conditions, original
clinical and preclinical studies on otherwise asymptomatic
tendons were included. Studies that evaluate only the mo-
lecular mechanisms of collagen cross-­linking or the effects
of collagen cross-­linking using reagents that have no direct
relevance to diabetes mellitus or hyperglycemia (eg, ribose)
were excluded.
  
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After reviewing the titles and abstracts, the relevant studies
were selected for further assessment of eligibility. The bibli-
ographies of original and review articles were hand-­searched
for other relevant articles. The search was limited to origi-
nal articles published in peer-­reviewed journals. Single-­case
­reports, reviews, letter to editors without supporting data, and
experimental protocols were excluded. Only findings relevant
to the focus of this review were extracted and presented.
3  |   EPIDEM IOLOGY OF
TENDINOPATHY IN DIABETIC
PATIENTS
A systematic review on the association between DM and
tendinopathy/tendon tears was done by searching the origi-
nal research articles in PubMed and references of published
articles. Forty-­nine studies met the inclusion and exclusion
criteria and were included in the analysis. Appendix S1 sum-
marizes the epidemiological studies reporting the association
between DM and tendinopathy/tendon tears. There was wide
variation in the quality of the included studies such as sample
size, presence of proper internal control group, characteris-
tics of patient groups (hospital-­based, community-­based, or
working population), diagnostic criteria, and methods for the
ascertainment of diseases. Despite these differences, the ma-
jority of the previous clinical studies have generally shown
that DM was an important risk/causative factor for the de-
velopment or poor prognosis of chronic tendinopathy/tendon
tears. Besides, the presence or severity of DM was generally
reported to show worsening effects on tendinopathy/tendon
tears. For example, more severe degeneration of Achilles
tendons was observed in tendinopathic patients with DM
compared with those tendinopathic patients without DM.2
Diabetic patients with rotator cuff tears showed higher shoul-
der pain and stiffness compared with nondiabetic patients
with rotator cuff tears.3 The need for insulin treatment was
associated with higher risk of developing shoulder symptoms
persisting for more than 2 years4 and shoulder pain5 in dia-
betic patients. Shoulder periarthritis correlated significantly
with the severity of DM, as 36% of the affected patients were
insulin dependent compared with 23% of the original 800
diabetic patients.6 The percentage of patients treated with in-
sulin was higher and the duration of insulin therapy was also
longer in diabetic patients with calcific shoulder periarthritis
compared with those diabetic patients without calcific shoul-
der periarthritis.7,8 However, two studies did not find any
worsening effects of DM on tendinopathy/tendon tears.9,10
Achilles tendon and shoulder (particularly rotator cuff)
were the common sites of interest in most of the previous
studies (Appendix S1). The epidemiology of tendinopathy at
the Achilles tendons and shoulder in diabetic patients was
summarized below.
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3.1  |  Achilles tendinopathy
Asymptomatic structural abnormalities of Achilles tendon
similar to tendinopathy were observed in diabetic patients
compared with the nondiabetic controls.11–13 Disorganized
fibers and ectopic calcification of Achilles tendon were ob-
served in 89% and 24% of patients, respectively, when com-
paring 70 consecutive asymptomatic diabetic patients with 10
age-­matched nondiabetic controls by ultrasound imaging.13
Significant association between DM and symptomatic Achilles
tendinopathy was also reported.2,14,15 However, another study
has reported no significant association between Achilles en-
thesopathy and DM, although patients with symptomatic
Achilles enthesopathy showed significantly higher blood glu-
cose level compared with the asymptomatic controls.16 There
was also no significant interaction between quinolone and DM
on Achilles tendonitis and tendon rupture at any site.17
3.2  |  Shoulder tendinopathy
Rotator cuff tendinopathy is characterized by tendon pain
during shoulder movement. The reduced joint movement
because of pain can stiffen the shoulder and lead to adhe-
sive capsulitis or periarthritis (frozen shoulder). Both frozen
shoulder18–20 and rotator cuff tendinopathy7,8,21,22 are more
prevalent in diabetic patients compared with the nondiabetic
controls. Abate et al.21 have compared 48 diabetic patients
and 32 controls without symptoms of shoulder pain or dys-
function and reported significant increase in supraspinatus
and biceps tendon thickness and sonographic appearance of
supraspinatus and biceps tendon degeneration in the diabetic
group. The prevalence of supraspinatus tendon tears was also
shown to be higher in the diabetic subjects but this associa-
tion was not observed in the biceps tendon.21 In a study of
6237 adults in the population, DM was reported to be as-
sociated with unilateral shoulder joint pain in men but not in
women.22 Calcific shoulder periarthritis is common and was
reported to be three times more prevalent in type 2 diabetic
patients compared with the nondiabetic controls.7,8 Despite
the positive association reported in these studies, some stud-
ies have not found any relationship between DM and rotator
cuff tendinopathy/tears.9,23
Appendix S2 shows further analysis of the studies in-
cluded in Appendix S1. The duration of DM was reported
in 12 of 16 studies to be associated with the prevalence of
tendinopathy/tendon tears. There was inconclusive evidence
about the relationship between the degree of diabetic con-
trol and the prevalence of tendinopathy/tendon tears, with
8/12 studies reporting no association. In a large community-­
based study, there was no significant association between
short-­term glycemic exposure and incident spontaneous ten-
don rupture requiring hospitalization in diabetic patients.24
Tendinopathy/tendon tears were reported in both types 1 and
2 diabetic patients. Seven studies have compared the prev-
alence of shoulder adhesive capsulitis/shoulder tendinitis in
types 1 and 2 diabetic patients with inconsistent findings,
with four studies reporting no significant differences,10,20,25,26
two studies reporting significantly higher prevalence in type
2 diabetic patients,18,27 and one study reporting that both
chronic rotator cuff tendinitis and shoulder joint pain were
significantly associated with type 1 but not type 2 DM.22
Diabetic patients undergo surgery more frequently for
sport medicine-­related conditions including tendinopathy and
experience inferior surgical outcomes compared with nondia-
betic patients.28 A systematic review was done to understand
the effects of DM or hyperglycemia on the outcomes of tendon
repair. Nine original human and seven animal studies were in-
cluded. A summary of the findings is shown in Appendix S3.
Five human studies showed poor surgical outcomes of rotator
cuff tears or frozen shoulder after surgery with higher retear
rate, pain, and deficit in range of motion. However, the other
four human studies reported no significant differences in these
aspects. The follow-­up time of those studies reporting poor
outcomes in diabetic patients was generally shorter than those
studies reporting no differences (Appendix S3). In a system-
atic review of prognostic factors associated with successful
recovery after arthroscopic rotator cuff repair, the absence
of DM and obesity was associated with better recovery.29
Further well-­controlled clinical studies with longer follow-­up
time and larger sample size are needed to better understand
the effects of DM on the healing outcomes after injury. All
the animal studies reported inferior tendon or tendon to bone
(TBJ) healing after injuries (Appendix S3). The biomechan-
ical properties of injured tendons were lower in the diabetic
compared with the nondiabetic animals (Appendix S3).
4  |   PATHOLOGICAL CHANGES I N
TENDON IN DIABETIC PATIENTS
A systematic review was done on the pathological changes
in tendon under diabetic or hyperglycemic conditions, and a
summary was shown in Appendix S4. Diabetic tendon was
characterized by the loss of normal glistering white appear-
ance and swelling. Clinical studies have shown that there
was an increase in tendon structural abnormalities,30 thick-
ness,31,32 volume,33 and stiffness.34 Electron microscopic
investigation showed that the collagen fibrils of Achilles
tendons of patients with long-­term DM were smaller.35 They
were twisted, curved, and otherwise disorganized.35 Focal
collagen degeneration without inflammatory cell infiltration
was observed in tendons harvested from diabetic patients.36
The number of elastin fibers was reduced. Signs of microrup-
tures were observed in ultrasound imaging.21 X-­ray diffrac-
tion analysis showed that DM altered the lateral packing of
collagen molecules and the axial structure of human extensor
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tendons, and the changes were different from aging tendons.37
The alterations in collagen structure affected the mechanical
function of tendons. For the Achilles tendons in diabetic pa-
tients, the increase in tendon stiffness might alter foot me-
chanics and increase the risk of developing foot ulcers.34,38
Calcification was more commonly observed in tendons of
diabetic patients as shown by US imaging,13 consistent with
the higher prevalence of calcific shoulder periarthritis in type
2 diabetic patients compared with the nondiabetic controls.7,8
Diabetes mellitus also induced significant tissue, cel-
lular, and molecular changes in injured tendons in human
(Appendix S1). Ultrasound imaging showed that the preva-
lence and degree of neovascularization were lower in asymp-
tomatic tendinopathic patients presented with DM compared
with those tendinopathic patients without DM in one study12
but no difference in asymptomatic11 and symptomatic2 ten-
dinopathic patients with and without DM in other studies.
The level of pro-­inflammatory cytokine IL-­1β was higher in
the subacromial fluid of diabetic compared with nondiabetic
patients with rotator cuff tears.3
Animal studies have allowed more detailed characteriza-
tion of the effects of DM or hyperglycemia on tendons without
(Appendix S4) and with (Appendix S3) injury at the tissue,
cellular, and molecular levels. Consistent with the findings in
human studies, DM was reported to alter tendon mechanical
properties and dynamic response to load in various animal
models of DM.39–41 There have been few preclinical studies
investigating the histological, cellular, and molecular other
than the biomechanical aspects of diabetic tendons. The col-
lagen content changed in tendons of diabetic rats with some
studies reporting higher level,42,43 while another study report-
ing lower level.40 The ultrastructure of collagen fibrils was
altered in tendons of diabetic rats and was characterized by
smaller fibril diameter,44 higher cross-­linking,45,46 larger fibril
spacing,44,47 disorganization,44 and degeneration,39,44,48 but
there was no difference in D-­band periodicity.47,49,50 Collagen
fiber microtears were observed in tendons of diabetic mice.44
Connizzo et al. has reported similar glycosaminoglycan con-
tent in tendons of diabetic and nondiabetic mice.40 However,
another study has shown that hyperglycemia reduced the pro-
teoglycan levels of porcine tendon ex vivo.51 Ahmed et al.52
have reported similar immunohistochemical expression of
matrix metalloproteinase-­3 (MMP-­3), MMP-­13, and extra-
cellular matrix components (collagen type I, collagen type II,
biglycan, versican) in the intact Achilles tendons of transgenic
diabetic rats and control rats. However, tendon cells isolated
from rat Achilles tendons showed increased mRNA expres-
sion of MMP-­9 and MMP-­13 as well as increased MMP-­9
activity upon glucose stimulation.53
The cell density increased in tendons of diabetic rats,42,43,45
similar to tendinopathy.54 The patellar tendons of diabetic
rats demonstrated less and unorganized fibrocartilage at the
tibial tubercle enthesis compared with the healthy rats.55
  
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Chondrocyte-­like cells were observed in the Achilles tendons
of leptin-­deficient type 2 diabetic mice.44
There was an increased expression of IL-­1β in the supra-
spinatus tendons of diabetic rats.45 While no infiltration of in-
flammatory cells was observed in the diabetic human Achilles
tendons,36 infiltration of neutrophil39 and mast cells42 were
observed in the Achilles tendons of diabetic animal models,
consistent with the increased numbers of mast cells in patients
with symptomatic chronic patellar tendinopathy.56 While
Ahmed et al.52 reported no major difference in histology in
the intact tendons between the transgenic diabetic rats and
control rats, vascularity and/or VEGF expression increased
in tendons of diabetic animal models compared with intact
tendons in healthy animals in other studies.42,44 The controls
in these animal studies were healthy animals which may ac-
count for the apparent discrepant outcomes on vascularity
compared with the clinical studies which the comparisons
were made with tendinopathic patients without DM.2,11,12
Also, the animals in these included studies did not have nat-
urally occurring diabetes. As reported in the next paragraph
and Appendix S3, the animal data on DM followed by tendon
injury appeared to show better consistency with the clinical
data on tendinopathy regarding vascularization. This is in
line with the hypothesis that delayed healing and accumula-
tion of micro-­injuries in DM patients may predispose them to
the development and poor prognosis of tendinopathy.
As mentioned, DM was reported to impair both TBJ and
tendon repair after injury (Appendix S3). The number of in-
flammatory cells, blood vessels, and proliferating cells were
lower; the deposition and structural organization of collagen
fibers and proteoglycans were impaired and the expression
of MMPs was dysregulated in diabetic animals compared
with the nondiabetic animals after tendon injury (Appendix
S3). Osteochondroid metaplasia was noticed in the diabetic
group but not in the nondiabetic group as early as day 1557
and week 658 after Achilles tendon transection and repair in
rat models. The delayed healing responses have implications
on the early and more frequent development of tendinopathy
after microtrauma and the poor prognosis of tendinopathy in
diabetic patients.
In summary, DM induces notable structural, inflamma-
tory, and vascular changes in tendons, which may predispose
diabetic patients to a greater risk of chronic tendinopathy
and/or traumatic rupture.
5  |   POTENTIAL PATHOGENIC
M ECHANISM S
5.1  |  Non-mutually exclusive pathogenic
mechanisms of chronic tendinopathy
There are several major non-mutually exclusive hypotheses of
pathogenic mechanisms of chronic tendinopathy as reported
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780       LUI
in the literature. The activation of hypoxia59-­apoptosis60-­pro-­
inflammatory cytokines61 cascade is suggested as an impor-
tant pathogenic mechanism for tendon pain and degeneration
in chronic tendinopathy. Neurovascular ingrowth is also sug-
gested as the cause of tendon pain in chronic tendinopathy.62
Other investigators proposed that the excessive production of
neuromediators including substance P, neuropeptide Y, gluta-
mate, and acetylcholine were causative factors for proliferative,
nociceptive, and degenerative responses in tendinopathy.63
The erroneous differentiation of tendon-­ derived stem cells
(TDSCs) to nontenocytes and hence the reduced number of
TDSCs available for tendon repair after tendon injury was also
suggested to contribute to tissue metaplasia and failed healing,
respectively, in chronic tendinopathy.64,65 How these major
non-mutually exclusive hypothesized pathogenic mechanisms
of chronic tendinopathy can be applied to explain the more
frequent, early onset, and poor outcomes of tendinopathies in
diabetic patients have not been explored until recently.
5.2  |  Potential key pathological players
Although the precise mechanisms of DM in causing and exac-
erbating tendinopathy remain unclear, the systematic effects
related to insulin deficiency/resistance and high glucose levels
in DM are likely to be causally involved. The excessive pro-
duction of advanced glycation end products (AGEs) may also
play a significant role in the pathogenesis of tendinopathy in
DM. AGEs are proteins or lipids that become nonenzymati-
cally glycated and oxidized after exposure to sugars. Proteins
are usually glycated through their lysine resides.66,67 The
side chains of arginine, histidine, tryptophan, and cysteine
residues are other glycation sites. In human, histones, colla-
gen, human serum albumin, IgG, IgA, IgM, and hemoglobin
are rich in lysine and are examples of glycated proteins. In
addition to the formation of AGEs on proteins, AGEs can
also form on lipids such as high-­density lipoprotein (HDL)
F I G U R E   1   Schematic diagram summarizing the potential mechanisms of diabetics in causing and exacerbating tendinopathy with reference
to the major non-mutually exclusive hypotheses of the pathogenic mechanisms of chronic tendinopathy as reported in the literature. AGEs,
advanced glycation end products; ROS, reactive oxygen species; TIMP, tissue inhibitor of metalloproteinase; MMP, matrix metalloproteinase.
and low-­density lipoprotein (LDL). The formation of AGEs
results in the denaturation and cross-­linking of the targeted
proteins, and the AGEs are nearly irreversible once formed.
AGEs can also downregulate VEGF expression, induce cell
cycle arrest and pro-­inflammatory changes, enhance oxida-
tive stress, block nitric oxide (NO) activity, activate NFkB,
bind inflammatory cells and endothelial cells to induce
­secretion of cytokines in cells via engaging receptor for AGE
(RAGE), leading to increase in apoptosis, tissue stiffness, in-
flammation, calcification, microvascular and macrovascular
complications.67 In diabetic patients, the formation of AGEs
is accelerated because of the increased availability of glucose.
The amount of AGEs in tendon was reported to increase with
the duration of DM and reduce with the control of glycemic
status in rats.46 The presence and accumulation of AGEs can
impair the extracellular and intracellular structures and hence
functions of the affected tendon.68 The metabolic risk factors
for DM may also contribute to the pathogenesis of tendinopa-
thy in diabetic patients. DM is associated with being over-
weight, visceral adiposity, and other metabolic disorders. In
this regard, dyslipidemia was associated with Achilles ten-
dinopathy.69 Systematic reviews have shown that adiposity
was associated with tendon injury70 and obesity was a risk
factor for tendinopathy.71 Both tendon mechanical overload
and systematic dysregulation of metabolic factors as a result
of adiposity may contribute to the pathogenesis of chronic
tendinopathy in diabetic patients. The mechanisms of these
potential pathological factors in triggering and worsening
tendinopathy in diabetic patients with reference to the major
non-mutually exclusive hypothesized pathogenic mecha-
nisms are discussed below and summarized in Figure 1.
5.3  |  Collagen cross-­linking
AGEs were reported to modify collagens in tendon which
led to an increase in collagen cross-­
links. The collagen
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cross-­links reduced fiber sliding and viscoelasticity of ten-
don and hence increased its stiffness and brittleness.72 While
cross-­linked fibers of tendon were more resistant to colla-
genase digestion when unloaded, the fibers became suscep-
tible to collagenase digestion upon mechanical loading.73
This was due to the local microunfolding of the triple helix
of the glycated collagen during tensile load transmission,
which increased its susceptibility to proteolytic cleavage.
The presence of DM therefore could weaken the structure
and biomechanical properties of tendon,55 making it more
susceptible to traumatic injury and the development of tendi-
nopathy upon mechanical loading. The ability of the affected
tendon to undergo matrix remodeling is also reduced.
5.4  |  Persistent low-­grade chronic
inflammation
Diabetic patients have consistently higher serum levels
of pro-­ inflammatory cytokines such as prostaglandin E2
(PGE2),74 TNF-­α,75 IL-­6,76 and leukotriene B4.77 This is in
agreement with the postulated roles of PGE2,78 TNF-­α,79
­IL-­6,80 and leukotriene B478 as pro-­inflammatory cytokines
in the pathogenesis of chronic tendinopathy.
AGEs can modify the action of hormones, cytokines, and
reactive oxygen species (ROS) via the engagement of cell
surface receptors (ie, AGE-­R1, AGE-­R2, AGE-­R3, receptor
for AGE (RAGE)) and impact the functions of intracellular
proteins. The binding of AGEs to RAGE triggers pro-­oxidant
and pro-­inflammatory events via NFkB signaling. A previ-
ous study has shown that AGEs induced NFkB activation,
cell cycle arrest, pro-­inflammatory cytokines release (IL-­6
and TNF-­α) and also reduced the viability of human os-
teoarthritic fibroblast-­like synovial cells.81 AGEs were also
shown to inhibit nitric oxide synthase (NOS) activity and
quench released NO which is a potent vasodilator and anti-­
inflammatory and pro-­angiogenic agent.82
As discussed, DM is associated with adiposity. Adipocytes
secrete adipokines, such as leptin, resistin, and adiponectin,
which regulate metabolism and inflammation in various cell
types. Dysregulation of adipokines and production of pro-­
inflammatory cytokines as a result of obesity contribute to
inflammation and insulin resistance and hence the develop-
ment of DM.83 Previous studies have shown that adipokines
modulated cytokines (IL-­6) and production of MMPs (MMP-­
3, MMP-­9) in chondrocytes.75 Hyperglycemia also has direct
effects on tendons and was reported to regulate MMP expres-
sion and activity of rat tendon cells.53
The low-­grade, subclinical, but persistent inflammation in
DM may lead to tendon pain and swelling as seen in tend-
inopathy. It may also enhance the imbalance of MMP and
TIMP production that cause matrix destruction, amplify the
deleterious effect of change in tendon loading, and predis-
pose to tendon rupture.
  
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5.5  |  Impairment of angiogenesis and
tenocyte proliferation/differentiation
Vascularization was impaired in tendinopathic tendons of
diabetic patients.12 This may promote tissue hypoxia and
generation of ROS and hence failed tendon healing after in-
jury. The RAGE and NF-­kB signaling pathway was involved
in the impairment of angiogenesis in DM.84 The mRNA and
protein expression of VEGF and Tβ-­4 were significantly
downregulated in injured tendons of diabetic compared with
the injured tendons in the nondiabetic rats,85 suggesting that
tendon repair is impaired and this may contribute to failed
healing in tendinopathy in diabetic patients. Hyperglycemia
alters the response of tenocytes to oxidative stress from ana-
bolic to pathogenic. While H2O2 promoted collagen synthesis
in primary human tenocytes in the presence of low glucose
in vitro, it induced cell apoptosis at high glucose concentra-
tion.86 Carboxylmethyl lysine-­collagen (CML collagen), an
AGE, but not unmodified collagen, induced apoptosis of
­fibroblasts.87 AGEs were also reported to modify and reduce
the activity of mitogenic proteins such as bFGFs,88 which are
important growth factors for tendon repair. PGE2 inhibited
the proliferation and collagen synthesis of human patellar
tendon fibroblasts.89 Insulin is an established mitogen90 and
is also a potent regulator of vascular functions.91 A recent
study has shown that a subpopulation of insulin-­producing
tendon cells were stem/progenitor cells and insulin might
guide tenogenic differentiation stem/progenitor cells or
maintain differentiated state of mature tenocytes. Consistent
to this speculation, it has been shown that insulin induced dif-
ferentiation of bone marrow-­derived stem cells (BMSCs) to-
ward a tendon cell-­like phenotype.92 Insulin was also shown
to protect pancreatic beta cells from apoptosis via Pdx1 at
physiological concentrations93 and human tendon cells from
dexamethasone-­induced damage in vitro.94 The inhibition of
angiogenesis, cell proliferation, and tenogenic differentiation
as well as the enhancement of apoptosis in diabetic patients
may impair tendon repair after injury and predispose to failed
healing in tendinopathy.
5.6  |  Erroneous stem cell differentiation
Advanced glycation end products likely also play roles in
the mechanisms of ectopic calcification and failed healing
in tendinopathy in diabetic patients. The colony size and
number of BMSCs isolated from the diabetic rat model
were reduced, and the changes were likely mediated by
AGE-­induced apoptosis and senescence.95 The effects of
AGEs on TDSCs have not been examined. A recent study
has shown that AGEs increased BMP-­2 expression and ac-
celerated progression of artherosclerotic calcification in dia-
betes.96,97 AGEs were also reported to increase the mRNA
expression of BMP2, BMP4, and osteogenic markers of
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782       LUI
human yellow ligament cells isolated from the cervical
spine.98 Besides its pro-­inflammatory functions, PGE2 was
reported to induce nontenogenic differentiation of TDSCs
via BMP-­2 expression. These findings were consistent with
the recent reports by our group and others that erroneous
differentiation of TDSCs to the chondrocyte and osteoblast
lineages was mediated by the chondro-­osteogenic BMPs
and WNT-­β-­catenin signaling pathways and contributed to
the mechanisms of ectopic chondro-­ossification in chronic
tendinopathy.64,65
Matrix stiffness is known to regulate the differentiation
of mesenchymal stem cells (MSCs).99 AGEs were reported
to increase transglutaminase activity in tenocytes in vitro.100
Transglutaminase 2 is a cross-­linking enzyme of ECM pro-
teins and it also facilitates cell-­ECM interaction through in-
tegrins. The increase in matrix stiffness as a result of AGE
formation and transglutaminase 2 activation may modify the
niche and hence promote nontenocyte differentiation of stem
cells in tendons.64,65 In this regard, transglutaminase 2 was
reported to regulate osteoblast differentiation in vitro101 and
to mediate the activation of the β-­catenin signaling pathway
which is central in vascular calcification.102
Proteoglycans are key regulators of tendon function and
are responsible for cell migration, differentiation, collagen
fibril assembly, and fiber sliding. Dysregulation of proteo-
glycans is associated with altered tendon structures.103 The
patellar tendons were thinner, more translucent and cellular;
showed disorganized collagen fibers with large gaps between
fibers and calcification as early as 6 days after birth in a fibro-
modulin and biglycan double knockout mouse model.103 The
proteoglycan levels in tendon and the proteoglycan produc-
tion by tenocytes were shown to be significantly reduced in
high-­glucose media in an AGE-­independent manner.51 Other
studies reported that AGEs induced degradation of proteo-
glycans in cartilage explants104 and inhibited the production
of proteoglycans in intervertebral disk cells.105 Increase in
proteoglycan deposition, particularly the oversulfated form,
is commonly observed in tendinopathic tendons. The differ-
ence in proteoglycan expression in the presence of glucose
or AGE compared with tendinopathic tendons in patients
might be due to the use of explant culture or cell culture
models in these previous studies which might not be able to
mimic the complicated environment in vivo.51,104,105 Two of
the references cited were actually data on cartilage explants
and nucleus pulposus cells which might exhibit differences
compared with tenocytes or tendon stem cells.104,105 There
has been no clinical study about the proteoglycan content
in tendons of diabetic patients. However, one animal study
has reported similar glycosaminoglycan content in tendons
of diabetic and nondiabetic mice.40 There was also lower
protein expression of biglycan in tendons of diabetic rats
compared with that in the wild-­type animals at week 2 after
injury.52 Further study is needed to confirm the changes in
proteoglycans in tendons of diabetic patients and animals
with and without tendinopathy.
The dysregulation of adipokines may also contribute to
tissue metaplasia in tendinopathy in DM. Chondrocyte-­like
phenotypes, together with degeneration of tenocytes, vas-
cular proliferation, and ruptures at the TBJ, were observed
in the Achilles tendon of leptin-­deficient mice.44 However,
another study has reported that leptin expression was associ-
ated with ectopic ossification in healing tenotomized Achilles
tendon in rats.106 The interaction of an injury with leptin level
in the later study might contribute the different observation.
5.7  |  Dysregulated neuropeptide signaling
The peripheral nervous system plays an important role in ten-
don homoeostasis and repair as well as in tendinopathy. In ad-
dition to the classical afferent functions (ie, mechanoception,
nociception, and vasomotor modulation), it also regulates
many efferent functions including cell proliferation, expres-
sion of cytokines and growth factors, inflammation, immune
responses, and hormone release.63 Damage to the peripheral
nervous system (polyneuropathy) is common in diabetic pa-
tients.107 Pain perception is reduced in diabetic patients107 and
hence the patients may overuse their tendons as a result of lack
of warning signals, predisposing to the development of tendi-
nopathy. Altered expression of neuropeptides was reported in
diabetic patients. Some studies reported increased circulating
levels of neuromediators including substance P, neuropeptide
Y, and calcitonin gene-­related peptide (CGRP) in diabetic pa-
tients compared with the nondiabetic controls.108,109 However,
another study reported significantly lower serum levels of
substance P and CGRP in diabetic patients compared with the
control group.96,97 The decrease in sensory neuropeptide re-
lease such as substance P, somatostatin, and CGRP was also
observed in diabetic animal model.110 On the contrary, an ab-
errant increase in sprouting sensory nerves and increased ex-
pression of substance P were observed in clinical samples111
and in a collagenase-­induced tendon injury rat model112 of
tendinopathy. The dysregulation of neuropeptide signaling in
diabetic patients can negatively affect tendon homoeostasis,
resulting in chronic pain and failed tendon healing.
6  |   M ANAGEM ENT OF
TENDINOPATHY IN DIABETIC
PATIENTS
Although there are clinical trials on the treatment of tendi-
nopathy, studies specifically addressing diabetic patients are
limited. The strict control of DM may help, and the contem-
porary treatment methods of the pathological tendon with
some precautions are strategies for the management of tendi-
nopathy in diabetic patients.
LUI
6.1  |  Control of diabetes mellitus
The strict control of DM to slow down the progression of
asymptomatic and symptomatic tendinopathy as well as to
enhance its recovery is suggested. An appropriate control of
glucose level and a diet rich in antioxidant agents are recom-
mended for diabetic patients. Aerobic physical training can
improve the diabetic situation by increasing the uptake of
peripheral glucose and glycogen metabolism. Also, stretch-
ing and strengthening exercises can prevent and reduce tissue
stiffness. In this regard, moderate-­intensity aerobic training
has been reported to restore normal mechanical properties of
tendons in diabetic animals.41 Counseling to avoid certain ac-
tivities such as aggressive and prolonged exercises that place
diabetic patients at substantial risk of tendon injury is needed.
The administration of insulin was reported to reduce the ac-
cumulation of AGEs,46 to prevent the changes in mechanical
properties in diabetic tendons113 and also to restore normal
inflammatory response, neovascularization, and cell prolifer-
ation during repair in a collagenase-­induced Achilles tendon
injury rat model.114 Adiposity is amenable to change through
diet and exercise. However, caution is necessary during ex-
ercising because the tendons may have subclinical damage
when overload and easily reach the symptomatic threshold.
Strategies that regulate adipokines may be promising for the
management of DM. In this regard, adiponectin was reported
to promote proliferation and tendon-­related marker expres-
sion in human diabetic-­ridden TDSCs,115 indicating that it
may be useful for the treatment of tendinopathy in diabetic
patients.116 Several drugs, which can interfere with AGE
formation (eg, pyridoxamine, glucosamine, rutin, and its
derivatives) and removal (AGE-­breaker compounds such as
N-­phenacylthiazolium bromide (PTB), soluble RAGE iso-
forms) are under study. In experimental animal models, these
drugs are effective in reducing diabetic complications due to
AGE formation.117
6.2  |  Treatment of tendinopathic tendons
Stretching and strengthening exercises have been shown
to improve the short-­term clinical outcomes of tendinopa-
thy, but the effect is not lasting.118 However, there has been
no reported negative effects of the rehabilitation protocols
and hence supports their use as the first-­line option for the
treatment of tendinopathy. The use of injectable substances
such as platelet-­rich plasma, autologous blood, polidocanol,
aprotinin, corticosteroids, and nonsteroid anti-­inflammatory
drugs (NSAID) in and around tendons is popular, but there
is minimal clinical evidence supporting their use.119 A sys-
temic review has shown that while corticosteroid injection
reduced the pain of tendinopathy in the short term, the ef-
fect was reversed at the intermediate-­long term.119 A meta-­
analysis of controlled studies has shown that platelet-­rich
  
|
   783
plasma ameliorated pain in the intermediate-­long term com-
pared with the control interventions.120 However, the sample
size was small.120 Other modalities such as low-­level laser
therapy, therapeutic ultrasound, extracorporeal shockwave,
and topical glycerin trinitrate have also been tested for the
management of chronic tendinopathy, but the evidences
about their effectiveness are inconclusive.118 If the conserv-
ative treatment fails, surgery is performed aiming to excise
the fibrotic adhesions and areas of failed healing, to disrupt
the abnormal neo-­innervation and to stimulate the remain-
ing viable cells to initiate healing. However, the repaired
tendon did not regain its original structure and biomechani-
cal properties after surgery. Cell therapy has been tested for
the treatment of tendinopathy, but the current evidence is
insufficient to make a conclusion about its safety and effec-
tiveness.121 Patients with DM are a treatment challenge of
tendinopathy because of the increased risks of side effects
of steroid injection and surgery, such as transient elevation
of blood glucose level after steroid injection122 and delayed
healing (Appendix S3). Corticosteroids might additionally
impair wound and tendon healing123 and therefore injections
should be avoided immediately before surgery for diabetic
patients.
7  |  CONCLUSION
Despite variation in study quality, current epidemiological
evidence generally suggests that DM is an important risk/
causative factor for early onset, progress, and poor treatment
prognosis of chronic tendinopathy. Tendon abnormalities are
common in diabetic patients. DM induces notable structural,
inflammatory, and vascular changes in tendons, which may
predispose diabetic patients to a greater risk of chronic ten-
dinopathy and/or traumatic rupture. The potential roles of
insulin deficiency/insensitivity, AGEs, hyperglycemia, and
adiposity in the development of tendinopathy in diabetic pa-
tients were put in the context of the four major non-mutually
exclusive hypothesized pathogenic mechanisms of tendinop-
athy (ie, inflammation, neurovascular ingrowth, erroneous
stem cell differentiation, neuropeptide signaling dysfunc-
tion). The strict control of DM may help and the contempo-
rary treatment methods of the pathological tendon with some
precautions are options for the management of tendinopathy
in diabetic patients.
8  |  PERSPECTIVES
The quality of the previous studies examining the association
of DM and tendinopathy varied. Large-­scale well-­controlled
case-­control and cohort studies are needed to obtain an ac-
curate estimation of the prevalence/incidence and risk of
 |
784       LUI
tendinopathy in diabetic patients. Both preclinical and clini-
cal studies are needed to clarify the potential roles of hyper-
glycemia, AGE, insulin deficiency/resistance, and adipokine
dysregulation mediated by adiposity in the pathogenesis of
tendinopathy in DM, particularly their relationships with the
major hypothesized pathogenic mechanisms of chronic ten-
dinopathy. Both preclinical and clinical studies are needed
to address the usefulness of contemporary conservative and
surgical approaches for the management of tendinopathy
­specifically in diabetic patients.
POTENTIAL CONFLICT OF INTEREST
I declare that I do not have any conflict of interest.
STATEMENT OF HUMAN AND ANIMAL
RIGHTS
This article does not contain any studies with human or ani-
mal subjects performed by any of the authors.
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How to cite this article: Lui PPY. Tendinopathy in
diabetes mellitus patients—Epidemiology, pathogenesis,
and management. Scand J Med Sci Sports. 2017;27:
776–787. https://doi.org/10.1111/sms.12824