Annals of the Rheumatic Diseases

Diabetes-induced Osteoarthritis
From a New Paradigm to a New Phenotype
Francis Berenbaum
Disclosures
Ann Rheum Dis. 2011;70(8):1354-1356

Abstract and Introduction
Abstract
Several epidemiological and experimental data support the hypothesis that diabetes could be an
independent risk factor for osteoarthritis (OA), at least in some patients, leading to the concept of
a diabetes-induced OA phenotype. If confirmed, this new paradigm will have a dramatic impact
on prevention of OA initiation and progression.
Introduction
Osteoarthritis (OA) is the leading cause of musculoskeletal handicap in the world. Ageing and
obesity are the two main risk factors for OA. Since prevalence of these conditions are going to
exponentially expand, an epidemic of the disease in the next decade is expected, leading to a
dramatic increase in the number of total joint replacements and so entails significant costs to
society. In order to attenuate the individual and societal consequences, and because no disease-
modifying drugs have proven their efficacy yet, any preventive policies should have a dramatic
impact on the quality of life and on countries economy. A better delineation of the different risk
factors of the disease should lead to a better personalisation of the preventive messages delivered
by doctors and stakeholders. To date, the main OA phenotypes described in the literature are
ageing, post-traumatic, hormonal, genetic and metabolic OA.
[1]

Metabolic OA has been recently individualised based on recent data showing an increased
incidence of OA in patients who are overweight/obese even in non-weight bearing joints. In that
case, mechanical overload being not able to explain this increased incidence, a new paradigm
based on the role of systemic mediators called adipokines and defined as cytokines produced by
fat adipose tissue, has been proposed.
[2]
Moreover, recent epidemiological studies have
strengthened this hypothesis by showing an increased incidence of OA in patients with metabolic
syndrome (MetS). MetS, also known as syndrome X, is defined as a condition mixing several
independent risk factors for cardiovascular (CV) events, including insulin resistance (identified
by type 2 diabetes, impaired fasting glucose or impaired glucose tolerance) plus any two of the
following: hypertension, elevated plasma triglycerides, decreased high-density lipoprotein
cholesterol, obesity, proteinuria. Indeed, estimation of the prevalence of diabetes reaches over
10% of the population in industrialised countries, coexisting with obesity in specific geographic
patterns because of a convergence of prevailing social norms, community and environmental
factors, socioeconomic status and genetic risk factors among ethnically similar groups.
[3]
The
demonstration of an association between MetS and OA is challenging because obesity, a
component of the MetS, is also a strong risk factor for knee OA.
[4]
However, a large body of
evidence indicates that OA is part of a generalised metabolic disorder in which various
interrelated metabolic factors contribute to the OA process.
[5]
A recent logistic regression
analysis assessing the association between MetS and population-weighted variables in a
representative sample of the general US population showed appealing results.
[6]
Interestingly,
MetS was prevalent in 59% of the OA population and in 23% of the population without OA.
Each of the five CV risk factors that comprise MetS was more prevalent in the OA population.
This association remained strong when obesity was controlled for. It is noteworthy that in this
work, prevalence of diabetes was 30% in the OA population versus 13% in the control
population. The role of diabetes independently of obesity as a risk factor for OA remains unclear.
Epidemiological Data
The first paper describing an association between OA and diabetes was published in 1961 (Table
1).
[7]
The authors looked at the occurrence of definite radiological OA in 6 anatomical areas of
30 patients with diabetes and 30 matched controls. The correlation was statistically significant
for feet and knees. OA patterns were also studied in 809 patients with knee or hip joint
replacement due to OA according to the presence of non-insulin-dependent diabetes.
[8]
Patients
with non-insulin-dependent diabetes more frequently had bilateral OA (adjusted OR 2.2; 95% CI
0.8 to 6.4). An association with generalised OA was not seen in this study maybe due to
statistical considerations. The clinical, pathological and epidemiological relationships between
fasting plasma glucose concentrations (FPG) and the sites of lesion in OA were evaluated in
1026 patients.
[9]
The mean FPG (9922.2 mg/dl) was significantly higher in OA (p<0.01) than in
the normal controls (8819.9 mg/dl). Interestingly, erythrocyte sedimentation rate (p<0.01) and
pain at rest (p<0.02) were higher in patients with non-insulin-dependent diabetes. In all, 1003
women aged 4564 from the Chingford population study completed risk factor questionnaires for
CV events.
[10]
For knee OA in either knee, the variables significantly associated were raised
blood glucose OR 1.95 (95% CI 1.08 to 3.59) and moderately raised serum cholesterol OR 2.06
(95% CI 1.06 to 3.98). In a recent study testing the hypothesis that vascular cell adhesion
molecule 1 could be a predictor of severe knee or hip OA, the authors compared patients who did
(n=60) or who did not (n=852) undergo joint replacement surgery in 19902005 due to severe
OA.
[11]
Although not discussed in this paper, an increased prevalence of non-insulin-dependent
diabetes was seen in the group of patients who had joint replacement (18.3% vs 6.3%) but this
difference was not statistically significant (p=0.06). In contrast, one negative case-control study
found no association between an impaired oral glucose tolerance test or non-insulin-dependent
diabetes and another found a tendency but not a statistical difference.
[12 13]

Based on these case-control studies, we cannot definitively conclude that
diabetes/hyperglycaemia is an independent risk factor for OA since many potential confounders
may interfere with the results, such as age, weight, level of activity etc. However, taken together,
there may be a positive signal for an independent correlation between OA and diabetes.
In Vitro Data
Chondrocytes are glycolytic cells able to sense the concentration of glucose present in the
cartilage matrix, the synovial fluid and in a less extent the subchondral bone being the sources
for glucose.
[14]
By sensing glucose, chondrocytes will then respond appropriately by adjusting
their cellular metabolism. Chondrocytes express multiple isoforms of the glucose transporter
(GLUT)/SLC2A family of glucose/polyol transporters which represent the first rate-limiting step
in glucose use.
[15]
Among them, GLUT-1 is especially important as it is regulated by anabolic
and catabolic stimuli.
[16]
However, there are very few studies assessing the role of high
extracellular glucose concentrations in articular chondrocyte functions. Hyperglycaemia
decreases dehydroascorbate transport into chondrocytes, which can compromise the synthesis of
type II collagen, and hyperglycaemia increases reactive oxygen species (ROS) production,
known to be major deleterious mediators for cartilage destruction.
[17 18]
Interestingly, although
normal chondrocytes can adjust their intracellular concentration to local glucose concentration,
OA chondrocytes exposed to high glucose are unable to down regulate GLUT-1, accumulating
more glucose and producing more ROS.
[19]

Advanced glycation end products (AGEs), the products of non-enzymatic glycation and
oxidation of proteins and lipids, accumulate in several diabetic tissues such as the vasculature
due to hyperglycaemia.
[20 21]
Similarly, AGEs accumulate in ageing and in OA cartilage leading
to matrix stiffness, becoming more sensitive to mechanical stress.
[22]
Along with their deleterious
effects on cartilage matrix, AGEs can also bind to membrane receptors called RAGE (for
'receptor for age glycation end products') present on many cell types including chondrocytes.
[20
23]
Once bound to RAGE, AGEs trigger the activation of different signalling pathways leading to
the over expression of proinflammatory and prodegradative mediators and to some alterations in
the chondrocyte differentiation phenotype.
[2426]
To the best of my knowledge, to date no
experimental studies have assessed the level of AGEs formation in diabetic cartilage compared
to normal cartilage, even in human or in animal cartilage. However, it seems realistic to consider
that an increased concentration of glucose in the diabetic cartilage matrix environment would
lead to the same deleterious result.
In Vitro Data
Chondrocytes are glycolytic cells able to sense the concentration of glucose present in the
cartilage matrix, the synovial fluid and in a less extent the subchondral bone being the sources
for glucose.
[14]
By sensing glucose, chondrocytes will then respond appropriately by adjusting
their cellular metabolism. Chondrocytes express multiple isoforms of the glucose transporter
(GLUT)/SLC2A family of glucose/polyol transporters which represent the first rate-limiting step
in glucose use.
[15]
Among them, GLUT-1 is especially important as it is regulated by anabolic
and catabolic stimuli.
[16]
However, there are very few studies assessing the role of high
extracellular glucose concentrations in articular chondrocyte functions. Hyperglycaemia
decreases dehydroascorbate transport into chondrocytes, which can compromise the synthesis of
type II collagen, and hyperglycaemia increases reactive oxygen species (ROS) production,
known to be major deleterious mediators for cartilage destruction.
[17 18]
Interestingly, although
normal chondrocytes can adjust their intracellular concentration to local glucose concentration,
OA chondrocytes exposed to high glucose are unable to down regulate GLUT-1, accumulating
more glucose and producing more ROS.
[19]

Advanced glycation end products (AGEs), the products of non-enzymatic glycation and
oxidation of proteins and lipids, accumulate in several diabetic tissues such as the vasculature
due to hyperglycaemia.
[20 21]
Similarly, AGEs accumulate in ageing and in OA cartilage leading
to matrix stiffness, becoming more sensitive to mechanical stress.
[22]
Along with their deleterious
effects on cartilage matrix, AGEs can also bind to membrane receptors called RAGE (for
'receptor for age glycation end products') present on many cell types including chondrocytes.
[20
23]
Once bound to RAGE, AGEs trigger the activation of different signalling pathways leading to
the over expression of proinflammatory and prodegradative mediators and to some alterations in
the chondrocyte differentiation phenotype.
[2426]
To the best of my knowledge, to date no
experimental studies have assessed the level of AGEs formation in diabetic cartilage compared
to normal cartilage, even in human or in animal cartilage. However, it seems realistic to consider
that an increased concentration of glucose in the diabetic cartilage matrix environment would
lead to the same deleterious result.
In Vivo Data
In the well known streptozotocin-induced diabetes rat model which mimics type I diabetes,
cartilage becomes resistant to the anabolic action of insulin-like growth factor 1 (IGF-1), a
condition that is correctable by hypophysectomy, suggesting a metabolic impairment at the tissue
level.
[27]
In this model, it is noteworthy that after 70 days, there are intense remodelling and
collagen deposition in the synovium.
[28]

Human Experimental Data
Motor and sensory dysfunction of muscle may be important factors in the pathogenesis of
articular damage.
[29]
It is well accepted that patients with OA have muscle weaknesses and a
vibratory sense loss in the regional OA joint.
[30]
Interestingly, this neurological dysfunction is
present locally and throughout the body, at least in patients with hip OA, suggesting a
generalised alteration of the peripheral nervous system.
[31]
Two main neurological syndromes
have been described in diabetes. The first is the Charcot neuroarthropathy, a rare but devastating
complication leading to joint deformity and eventually amputation or secondary OA. The second
is a symmetric, mainly sensory polyneuropathy often accompanied by autonomic neuropathy.
[32]

This latter diabetic neuropathy could be one of the suggested alteration of the peripheral nervous
system seen in patients with OA leading to muscle weaknesses and joint laxity. I speculate that
such peripheral nerve impairment induced by diabetes could be an added risk factor for OA in
patients with diabetes.
Diabetes was first considered as a non-inflammatory disease. However, we now know that
hyperglycaemia can trigger a low-grade systemic inflammation which would explain the
increased risk of CV events seen in patients with diabetes.
[3336]
Low-grade systemic
inflammation is associated with cartilage loss.
[37]
Although MetS is a well known association
with mild systemic inflammation, I propose that an independent hyperglycaemia-induced
systemic inflammation may also have an impact on the progression of OA.
Based on these strong signals for a correlation between diabetes and OA (see figure 1), it is time
to encourage the scientific community to perform prospective studies devoted to confirm or
invalidate this hypothesis. In vitro and in vivo experimental studies should now be designed in
order to have a better understanding of the mechanisms underlying the potential interactions
between both diseases. These clinical and experimental studies would also help to decipher the
respective roles of type 1 and type 2 diabetes in this suspicion of increased risk for OA. Finally, a
better knowledge of the specificities of a diabetes-induced OA phenotype compared to the others
should lead to a personalised approach of preventive and curative treatments for OA.
Figure 1.
A general paradigm for a diabetes-induced OA phenotype. Hypothesis: hyperglycaemia is the
main trigger of joint degradation in OA. Local increased concentration of glucose alters the
cartilage matrix by increasing the formation of AGEs that can, in turn, activate chondrocytes and
synoviocytes to produce prodegradative and proinflammatory mediators and modify the quality
of the subchondral bone. Alterations in the function of the glucose transporters at the surface of
chondrocytes participate in the perpetuation of the deleterious process. Moreover,
hyperglycaemia induces a low-grade systemic inflammation state that aggravates the OA
process. Finally, the neurotoxicity of hyperglycaemia leads to a neuromuscular deficiency, which
will also worsen OA by destabilising the joint. AGEs, advanced glycation end products; OA,
osteoarthritis.
Research Agenda
What is the prevalence of OA in patients with non-insulin-dependent and insulin-
dependent diabetes?
Is insulin a potential protector against cartilage degradation?
What are the characteristics of a diabetes-induced OA phenotype?
Are antidiabetic drugs active for counteracting the OA process? (Such as peroxisome
proliferator-activated receptor agonists, etc.)
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Diabetes diinduksi Osteoarthritis
Dari Paradigma Baru ke Fenotip Baru
Francis Berenbaum
Pengungkapan
Ann Rheum Dis. 2011; 70 (8) :1354-1356

Abstrak dan Pendahuluan
Abstrak
Beberapa data epidemiologi dan eksperimental mendukung hipotesis bahwa diabetes bisa menjadi
faktor risiko independen untuk osteoarthritis (OA), setidaknya pada beberapa pasien, yang mengarah ke
konsep diabetes yang disebabkan OA fenotipe. Jika dikonfirmasi, paradigma baru ini akan memiliki
dampak yang dramatis pada pencegahan OA inisiasi dan progresi.

Pengantar
Osteoarthritis (OA) merupakan penyebab utama cacat muskuloskeletal di dunia. Penuaan dan obesitas
merupakan dua faktor risiko utama untuk OA. Karena prevalensi kondisi ini akan memperluas secara
eksponensial, wabah penyakit dalam dekade berikutnya diperkirakan, yang mengarah ke peningkatan
dramatis dalam jumlah penggantian total sendi dan sebagainya memerlukan biaya yang signifikan bagi
masyarakat. Dalam rangka untuk melemahkan konsekuensi individu dan masyarakat, dan karena tidak
ada penyakit-memodifikasi obat telah membuktikan keberhasilan mereka belum, setiap kebijakan
preventif harus memiliki dampak yang dramatis pada kualitas hidup dan perekonomian negara. Sebuah
penggambaran yang lebih baik dari faktor-faktor risiko penyakit yang berbeda harus mengarah pada
personalisasi yang lebih baik dari pesan-pesan pencegahan disampaikan oleh dokter dan para pemangku
kepentingan. Sampai saat ini, fenotip OA utama dijelaskan dalam literatur penuaan, pasca-trauma,
hormonal, genetik dan OA metabolik. [1]
Metabolik OA telah baru-baru individual berdasarkan data terbaru menunjukkan peningkatan insiden
OA pada pasien yang kelebihan berat badan / obesitas bahkan di non-berat bantalan sendi. Dalam hal
ini, overload mekanis yang tidak mampu menjelaskan peningkatan kejadian ini, paradigma baru yang
didasarkan pada peran mediator sistemik disebut adipokines dan didefinisikan sebagai sitokin yang
dihasilkan oleh jaringan adiposa lemak, telah diusulkan. [2] Selain itu, studi epidemiologi baru-baru ini
memiliki memperkuat hipotesis ini dengan menunjukkan peningkatan insiden OA pada pasien dengan
sindrom metabolik (Mets). Mets, juga dikenal sebagai sindrom X, didefinisikan sebagai suatu kondisi
pencampuran beberapa faktor risiko independen untuk kardiovaskular (CV) peristiwa, termasuk
resistensi insulin (diidentifikasi dengan diabetes tipe 2, glukosa puasa terganggu atau toleransi glukosa
terganggu) ditambah dua dari berikut: hipertensi, trigliserida plasma meningkat, penurunan high density
lipoprotein kolesterol, obesitas, proteinuria. Memang, estimasi prevalensi diabetes mencapai lebih dari
10% penduduk di negara-negara industri, hidup berdampingan dengan obesitas pada pola geografis
tertentu karena konvergensi norma-norma sosial yang berlaku, masyarakat dan faktor lingkungan,
status sosial ekonomi dan faktor risiko genetik antara kelompok-kelompok etnis mirip [3]. Demonstrasi
hubungan antara Mets dan OA menantang karena obesitas, komponen dari Mets, juga merupakan
faktor risiko yang kuat untuk OA lutut. [4] Namun, tubuh besar bukti menunjukkan bahwa OA
merupakan bagian dari gangguan metabolisme umum di mana berbagai faktor metabolik saling
berkontribusi pada proses OA. [5] Sebuah analisis regresi logistik baru-baru ini menilai hubungan antara
Mets dan variabel populasi berbobot dalam sampel yang representatif dari populasi umum di AS
menunjukkan hasil yang menarik. [6] Menariknya, Mets merata di 59% dari populasi OA dan di 23% dari
populasi tanpa OA. Masing-masing dari lima faktor risiko CV yang terdiri dari Mets adalah lebih umum
pada populasi OA. Asosiasi ini tetap kuat saat obesitas dikontrol untuk. Perlu dicatat bahwa dalam
pekerjaan ini, prevalensi diabetes adalah 30% pada populasi OA dibandingkan 13% pada populasi
kontrol. Peran diabetes independen dari obesitas sebagai faktor risiko OA masih belum jelas.

Epidemiologis data
Makalah pertama menggambarkan hubungan antara OA dan diabetes diterbitkan pada tahun 1961
(Tabel 1). [7] Para penulis melihat terjadinya pasti OA radiologi di 6 bidang anatomi dari 30 pasien
dengan diabetes dan 30 kontrol cocok. Korelasi secara statistik signifikan untuk kaki dan lutut. Pola OA
juga dipelajari dalam 809 pasien dengan lutut atau penggantian sendi panggul akibat OA sesuai dengan
kehadiran diabetes non-insulin-dependent [8] Pasien dengan diabetes non-insulin-dependent lebih
sering memiliki OA bilateral (disesuaikan OR 2.2.; 95% CI 0,8-6,4). Sebuah asosiasi dengan umum OA
tidak terlihat dalam penelitian ini mungkin karena pertimbangan statistik. Hubungan klinis, patologis dan
epidemiologi antara konsentrasi glukosa plasma puasa (FPG) dan situs lesi di OA dievaluasi dalam 1.026
pasien. [9] Mean FPG (99 22,2 mg / dl) secara signifikan lebih tinggi di OA (p < 0,01) dibandingkan
dengan kontrol normal (88 19,9 mg / dl). Menariknya, laju endap darah (p <0,01) dan nyeri saat
istirahat (p <0,02) lebih tinggi pada pasien dengan diabetes non-insulin-dependent. Secara keseluruhan,
1.003 perempuan berusia 45-64 dari studi populasi Chingford menyelesaikan kuesioner faktor risiko
untuk acara CV. [10] Untuk OA lutut di kedua lutut, variabel signifikan terkait dibesarkan glukosa darah
OR 1,95 (95% CI 1,08-3,59) dan cukup mengangkat kolesterol serum OR 2,06 (95% CI 1,06-3,98). Dalam
sebuah studi baru-baru ini menguji hipotesis bahwa molekul adhesi sel vaskuler 1 bisa menjadi prediktor
lutut parah atau OA panggul, penulis membandingkan pasien yang melakukan (n = 60) atau yang tidak (n
= 852) menjalani operasi penggantian sendi pada tahun 1990 -2005 karena OA parah. [11] Meskipun
tidak dibahas dalam makalah ini, peningkatan prevalensi diabetes non-insulin-dependent terlihat pada
kelompok pasien yang mengalami penggantian sendi (18,3% vs 6,3%), tetapi perbedaan ini tidak
signifikan secara statistik (p = 0,06). Sebaliknya, satu studi kasus-kontrol negatif tidak menemukan
hubungan antara gangguan tes toleransi glukosa oral atau diabetes non-insulin-dependent dan lain
menemukan kecenderungan tetapi tidak perbedaan statistik. [12 13]
Berdasarkan studi kasus-kontrol ini, kita tidak bisa sepenuhnya menyimpulkan bahwa diabetes /
hiperglikemia merupakan faktor risiko independen untuk OA karena banyak potensi pembaur dapat
mengganggu hasil, seperti usia, berat badan, tingkat aktivitas dll Namun, diambil bersama-sama, ada
mungkin menjadi sinyal positif bagi korelasi independen antara OA dan diabetes.

In Vitro data
Kondrosit adalah sel glikolitik dapat merasakan konsentrasi glukosa hadir dalam matriks tulang rawan,
cairan sinovial dan dalam batas kurang tulang subchondral menjadi sumber glukosa. [14] Dengan
penginderaan glukosa, kondrosit kemudian akan merespons dengan tepat dengan menyesuaikan selular
mereka metabolisme. Kondrosit mengungkapkan beberapa isoform dari transporter glukosa (GLUT) /
SLC2A keluarga transporter glukosa / poliol yang merupakan langkah pertama tingkat-pembatas dalam
penggunaan glukosa. [15] Di antara mereka, GLUT-1 sangat penting seperti yang diatur oleh anabolik
dan rangsangan katabolik. [16] Namun, ada sedikit studi menilai peran konsentrasi glukosa ekstraseluler
yang tinggi dalam fungsi kondrosit artikular. Hiperglikemia menurun transportasi dehydroascorbate ke
kondrosit, yang dapat membahayakan sintesis kolagen tipe II, dan hiperglikemia meningkatkan spesies
oksigen reaktif (ROS) produksi, dikenal sebagai mediator merugikan besar bagi kerusakan tulang rawan.
[17 18] Menariknya, meskipun kondrosit normal dapat menyesuaikan mereka konsentrasi intraseluler
dengan konsentrasi glukosa lokal, OA kondrosit terkena glukosa tinggi tidak dapat turun mengatur-GLUT
1, mengumpulkan lebih banyak glukosa dan memproduksi lebih ROS. [19]
Produk lanjutan akhir glikasi (AGEs), produk glikasi non-enzimatik dan oksidasi protein dan lipid,
menumpuk di beberapa jaringan diabetes seperti pembuluh darah akibat hiperglikemia. [20 21]
Demikian pula, AGEs terakumulasi dalam penuaan dan OA tulang rawan terkemuka untuk matriks
kekakuan, menjadi lebih sensitif terhadap stres mekanik. [22] Seiring dengan efek merusak mereka pada
matriks tulang rawan, AGEs juga dapat mengikat reseptor membran yang disebut RAGE (untuk 'reseptor
untuk produk akhir glikasi usia') hadir pada banyak jenis sel termasuk kondrosit [20 23] Setelah terikat
Rage, AGEs memicu aktivasi jalur sinyal yang berbeda yang mengarah ke atas ekspresi proinflamasi dan
mediator prodegradative dan beberapa perubahan di fenotip diferensiasi kondrosit.. [24-26] Untuk yang
terbaik dari pengetahuan saya, sampai saat ini belum ada penelitian eksperimental telah menilai tingkat
pembentukan AGEs dalam tulang rawan diabetes dibandingkan dengan tulang rawan normal, bahkan
pada manusia atau tulang rawan hewan. Namun, tampaknya realistis untuk menganggap bahwa
peningkatan konsentrasi glukosa dalam diabetes tulang rawan lingkungan matriks akan mengarah pada
hasil yang merusak yang sama.

In Vitro data
Kondrosit adalah sel glikolitik dapat merasakan konsentrasi glukosa hadir dalam matriks tulang rawan,
cairan sinovial dan dalam batas kurang tulang subchondral menjadi sumber glukosa. [14] Dengan
penginderaan glukosa, kondrosit kemudian akan merespons dengan tepat dengan menyesuaikan selular
mereka metabolisme. Kondrosit mengungkapkan beberapa isoform dari transporter glukosa (GLUT) /
SLC2A keluarga transporter glukosa / poliol yang merupakan langkah pertama tingkat-pembatas dalam
penggunaan glukosa. [15] Di antara mereka, GLUT-1 sangat penting seperti yang diatur oleh anabolik
dan rangsangan katabolik. [16] Namun, ada sedikit studi menilai peran konsentrasi glukosa ekstraseluler
yang tinggi dalam fungsi kondrosit artikular. Hiperglikemia menurun transportasi dehydroascorbate ke
kondrosit, yang dapat membahayakan sintesis kolagen tipe II, dan hiperglikemia meningkatkan spesies
oksigen reaktif (ROS) produksi, dikenal sebagai mediator merugikan besar bagi kerusakan tulang rawan.
[17 18] Menariknya, meskipun kondrosit normal dapat menyesuaikan mereka konsentrasi intraseluler
dengan konsentrasi glukosa lokal, OA kondrosit terkena glukosa tinggi tidak dapat turun mengatur-GLUT
1, mengumpulkan lebih banyak glukosa dan memproduksi lebih ROS. [19]
Produk lanjutan akhir glikasi (AGEs), produk glikasi non-enzimatik dan oksidasi protein dan lipid,
menumpuk di beberapa jaringan diabetes seperti pembuluh darah akibat hiperglikemia. [20 21]
Demikian pula, AGEs terakumulasi dalam penuaan dan OA tulang rawan terkemuka untuk matriks
kekakuan, menjadi lebih sensitif terhadap stres mekanik. [22] Seiring dengan efek merusak mereka pada
matriks tulang rawan, AGEs juga dapat mengikat reseptor membran yang disebut RAGE (untuk 'reseptor
untuk produk akhir glikasi usia') hadir pada banyak jenis sel termasuk kondrosit [20 23] Setelah terikat
Rage, AGEs memicu aktivasi jalur sinyal yang berbeda yang mengarah ke atas ekspresi proinflamasi dan
mediator prodegradative dan beberapa perubahan di fenotip diferensiasi kondrosit.. [24-26] Untuk yang
terbaik dari pengetahuan saya, sampai saat ini belum ada penelitian eksperimental telah menilai tingkat
pembentukan AGEs dalam tulang rawan diabetes dibandingkan dengan tulang rawan normal, bahkan
pada manusia atau tulang rawan hewan. Namun, tampaknya realistis untuk menganggap bahwa
peningkatan konsentrasi glukosa dalam diabetes tulang rawan lingkungan matriks akan mengarah pada
hasil yang merusak yang sama.

In Vivo data
Dalam diabetes tikus model terkenal streptozotocin diinduksi yang meniru tipe I diabetes, tulang rawan
menjadi resisten terhadap aksi anabolik insulin-like growth factor 1 (IGF-1), suatu kondisi yang diperbaiki
dengan hipofisektomi, menunjukkan gangguan metabolik di tingkat jaringan. [27] Dalam model ini, perlu
dicatat bahwa setelah 70 hari, ada renovasi intens dan deposisi kolagen pada sinovium. [28]

Human data Eksperimental
Motor dan disfungsi sensorik otot dapat menjadi faktor penting dalam patogenesis kerusakan artikular.
[29] Hal ini diterima dengan baik bahwa pasien dengan OA memiliki kelemahan otot dan hilangnya rasa
getaran dalam OA sendi regional. [30] Menariknya, disfungsi neurologis ini hadir secara lokal dan
seluruh tubuh, setidaknya pada pasien dengan OA panggul, menunjukkan perubahan umum dari sistem
saraf perifer. [31] Dua sindrom neurologis utama telah dijelaskan dalam diabetes. Yang pertama adalah
neuroarthropathy Charcot, komplikasi yang jarang namun menghancurkan menyebabkan deformitas
sendi dan akhirnya amputasi atau OA sekunder. Yang kedua adalah simetris, polineuropati sensorik
terutama sering disertai dengan neuropati otonom. [32] neuropati diabetes yang terakhir ini bisa
menjadi salah satu perubahan yang disarankan dari sistem saraf perifer terlihat pada pasien dengan OA
menyebabkan kelemahan otot dan kelemahan sendi. Saya berspekulasi bahwa seperti saraf perifer
gangguan yang disebabkan oleh diabetes bisa menjadi faktor risiko tambahan untuk OA pada pasien
dengan diabetes.
Diabetes pertama kali dianggap sebagai penyakit non-inflamasi. Namun, kami sekarang tahu
hiperglikemia yang dapat memicu peradangan sistemik ringan yang akan menjelaskan peningkatan risiko
kejadian CV terlihat pada pasien dengan diabetes. [33-36] inflamasi sistemik Low-grade dikaitkan
dengan kehilangan tulang rawan. [37] Meskipun Mets adalah asosiasi terkenal dengan peradangan
sistemik ringan, saya mengusulkan bahwa peradangan sistemik hiperglikemia yang diinduksi independen
juga dapat berdampak pada perkembangan OA.
Berdasarkan sinyal-sinyal yang kuat untuk hubungan antara diabetes dan OA (lihat gambar 1), sekarang
saatnya untuk mendorong komunitas ilmiah untuk melakukan studi prospektif yang ditujukan untuk
mengkonfirmasi atau membatalkan hipotesis ini. In vitro dan in vivo studi eksperimental sekarang harus
dirancang agar memiliki pemahaman yang lebih baik tentang mekanisme yang mendasari potensi
interaksi antara kedua penyakit. Studi-studi klinis dan eksperimental juga akan membantu untuk
menguraikan peran masing-masing tipe 1 dan diabetes tipe 2 dalam kecurigaan ini peningkatan risiko
untuk OA. Akhirnya, pengetahuan yang lebih baik tentang kekhususan dari diabetes yang disebabkan OA
fenotipe dibandingkan dengan yang lain harus mengarah pada pendekatan personal perawatan
preventif dan kuratif untuk OA.

Gambar 1.
Sebuah paradigma umum untuk diabetes diinduksi OA fenotipe. Hipotesis: hiperglikemia adalah pemicu
utama degradasi bersama di OA. Peningkatan konsentrasi lokal glukosa mengubah matriks tulang rawan
dengan meningkatkan pembentukan AGEs yang dapat, pada gilirannya, mengaktifkan kondrosit dan
synoviocytes untuk menghasilkan mediator prodegradative dan proinflamasi dan memodifikasi kualitas
tulang subchondral. Perubahan dalam fungsi transporter glukosa pada permukaan kondrosit
berpartisipasi dalam kelangsungan proses merugikan. Selain itu, hiperglikemia menginduksi tingkat
rendah sistemik peradangan negara yang memperburuk proses OA. Akhirnya, neurotoksisitas
hiperglikemia menyebabkan kekurangan neuromuskuler, yang juga akan memperburuk OA dengan
mendestabilisasi sendi. AGEs, produk akhir glikasi maju; OA, osteoarthritis.

Agenda Penelitian
Berapa prevalensi OA pada pasien dengan diabetes non-insulin-dependent dan dependent insulin-?
Apakah insulin pelindung potensial terhadap degradasi tulang rawan?
Apakah karakteristik dari diabetes yang disebabkan OA fenotipe?
Apakah obat antidiabetes aktif untuk menangkal proses OA? (Seperti Peroksisom proliferator-
diaktifkan reseptor agonis , dll)