Available online at www.sciencedirect.com
`
`-,,
`·:;, ScienceDirect
`
`ELSEVIER
`
`Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`ll))llJilllm'1l'lR~ llill!$lilli<CIEI
`A\N!ll)
`WNil<C.M. !Pliffl<Cm
`
`www.elsevier.com/locate/diabres
`
`The effects of the diabetes related soft tissue hand lesions
`and the reduced hand strength on functional disability
`of hand in type 2 diabetic patients
`Serpil Sava~ a,*, Banu Kale Koroglu \ Hasan Rifat Koyuncuoglu C, Ertugrul Uzar c,
`Hakan <;elik a, Numan Mehmet Tamer b
`
`a Siileyman Demirel University Medical School, Physical Medicine and Rehabilitation Department, lsparta, Turkey
`b Siileyman Demirel University Medical School, Endocrinology & Metabolism Department, lsparta, Turkey
`c Siileyman Demirel University Medical School, Neurology Department, lsparta, Turkey
`
`Received 24 May 2006; accepted 23 October 2006
`Available online 1 December 2006
`
`Abstract
`
`Objectives: The aim of the present study is to examine the effects of diabetes related soft tissue hand lesions such as Dupuytren's
`disease, trigger finger and limited joint mobility (LJM) and the reduced hand strength on the functional disability of the hand in type
`2 diabetic patients.
`Methods: Forty-four type 2 diabetic patients and 60 age and sex matched controls were included in the study. Subjects were
`examined for the presence of Dupuytren's disease, trigger finger and LJM. Grip strength was tested first with Jamar dynamometer
`followed by pinch strength measurements using by a manual pinchmeter. Electrophysiological studies were performed in both
`groups. Duruoz Hand Index (DHI) was used to assess the functional hand disability.
`Results: The mean DHI score of the diabetics was significantly higher than controls (p < 0.0001). Dupuytren's disease, trigger
`finger or LJM was not correlated with DHI in diabetic patients (p > 0.05). The grip and pinch strengths were significantly lower in
`diabetic patients than the non-diabetic controls (p < 0.05) and the grip and pinch strengths were negatively correlated with DHI in
`type 2 diabetic patients (p < 0.001).
`Conclusion: Dupuytren's disease, trigger finger and LJM did not cause to functional disability of hand but low hand strength was
`found to cause functional disability of hand in our type 2 diabetic patients.
`© 2006 Published by Elsevier Ireland Ltd.
`
`Keywords: Type 2 diabetes; Hand; Grip strength; Pinch strength; Disability
`
`1. Introduction
`
`Type 2 diabetes is a risk factor for functional
`disability particularly in older people. Multiple factors
`
`* Corresponding author at: Pasta kutusu 76, 32000 Isparta, Turkey.
`Fax: +90 246 2370240.
`E-mail address: serpilsavas@yahoo.com (S. Sava~)-
`
`have been implicated in the development of functional
`disability in type 2 diabetic patients and coronary and
`peripheral vascular disease, retinopathy, stroke, nephro(cid:173)
`pathy, neuropathy, diabetic foot problems, depression
`and cognitive impairment were demonstrated to be the
`predictors of functional disability in type 2 diabetic
`patients [ 1-11]. The incidence of type 2 diabetes and the
`life expectancy of the diabetic patient have both
`increased, resulting in the increased clinical importance
`
`0168-8227/$ - see front matter (C:) 2006 Published by Elsevier Ireland Ltd.
`doi: 10.1016/j.diabres.2006.10.020
`
`Sanofi Exhibit 2159.001
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`78
`
`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`of functional disability. Less attention is directed to
`upper extremity problems although patients with type 2
`diabetes have reported to be more disabled in self-care
`tasks and housework than non-diabetic patients [7-9].
`The effects of diabetes related soft tissue hand problems
`such as limited joint mobility, Dupuytren's disease,
`trigger finger on the functional disability of hand are
`largely unknown.
`Grip and key pinch strength was found to be lower in
`the hands of type 2 diabetics compared to the non(cid:173)
`diabetic controls [ 12-14] and the effect of the reduced
`hand strength on hand functional disability has also not
`been clearly demonstrated before.
`We therefore conducted this study to determine the
`effect of diabetes related soft tissue hand complications,
`and the reduced hand strength on the functional hand
`disability in type 2 diabetic patients. We also evaluated
`the factors effecting hand strength in type 2 diabetic
`patients.
`
`2. Patients and methods
`
`Sixty consecutive type 2 diabetic patients (34 female, 26
`male) attending Suleyman Demirel University Endocrinology
`outpatient clinic and sex and age matched 60 non-diabetic
`controls (28 female, 32 male) attending to the Physical
`Medicine and Rehabilitation outpatient clinic of Suleyman
`Demirel University other than upper extremity complaints
`were included in the study. Informed consent was given to all
`subjects and the study was reviewed and approved by the local
`ethics committee.
`Criteria for the inclusion in the study were that patients had
`type 2 diabetes, have no documented history of shoulder
`adhesive capsulitis and carpal tunnel syndrome, the control
`subjects had no glucose abnormality, no documented history
`of trauma or cervical radiculopathy or hand related pain in the
`previous 12 months. Left handed subjects were not also
`included in the study.
`Patients were classified at the time of their first visit as
`having type 2 diabetes according to traditional clinical char(cid:173)
`acteristics, such as a prior history of using oral agents to
`control hyperglycemia, the presence of obesity, no history of
`ketosis, or family history of diabetes. The patients were
`performed a dilated eye examination for diabetic retinopathy
`by an ophthalmologist and a screening for microalbuminuria
`by measurement of the albumin to creatinine ratio in a random
`spot collection. Diabetic nephropathy was accepted to be
`present if urinary albumin excretion is 2:30 µg/mg creatinine.
`In all controls, blood glucose was measured. Controls with a
`blood glucose value in the diabetic range were excluded.
`Body mass index (BMI) was calculated by using the
`formula of weight (kg)/height2 (m). Smoking status and
`working status of the subjects and the patients who exercise
`regularly were noted. We classified the occupation of subjects
`
`as manual or white collar [15]. However, those classified as
`white collar on the basis of non-manual labour in the course of
`their occupation, but who practiced regular carpeting, weight
`lifting or gardening (more than 2 h, three times a week) were
`classified in the manual labour group.
`Diabetic patients were examined for the hand complications
`of diabetes by the same investigator. LJM was assessed by the
`'Prayer sign': patients were asked to bring the palmar surfaces
`of the fingers together in a praying position with the wrist
`maximally flexed. Failure of metacarpophalangeal or proximal
`interphalangeal joints to make a contact was classified as a
`positive prayer sign, which means LJM [16]. Joint mobility was
`classified according to test results as follows [ 17] ; Stage 0:
`ability to make contact at all opposing interphalangial joints in
`the prayer sign or on the imprint, Stage 1: inability to make
`contact at one interphalangial joint in the prayer sign or on the
`imprint, Stage 2: inability to make contact at two or more
`interphalangial joints in the prayer sign or on the imprint.
`The diagnosis of Dupuytren's disease was made by the
`observation of one or more of the following four features on
`examination: a palmar or digital nodule, tethering of the
`palmar or digital skin, a pretendinous band, and a digital
`flexion contracture [18].
`Trigger finger or flexor tenosynovitis was diagnosed by
`palpating a nodule or thickened flexor tendon with locking
`phenomenon during extension and flexion of any fingers [19].
`
`3. Disability assessment of the hand
`
`DHI is a self-reported questionnaire developed to
`assess hand ability in the kitchen, during dressing, while
`performing personal hygiene, office tasks, and other
`general items. DHI is derived from 18 validated
`questions to assess functional disability and handicap
`of the hand. Each answer is scored on a scale of 0 (no
`difficulty) to 5 (impossible to do) with a maximum score
`of 90. A higher score indicated worse disability or
`handicap. DHI was developed and translated into
`Turkish by Duruoz et al. and it is a reliable instrument
`for the assessment of hand functional disability in type 2
`diabetic patients [20,21].
`
`4. Electrodiagnostic studies
`
`All studies were performed with the patient supine, at a
`room temperature of 25 °C, using a Nihon Kohden(cid:173)
`Neuropack MEB 5504K (Tokyo, Japan). Motor nerve
`conduction velocity (MNCV) and amplitude of the
`compound muscle action potential (CMAP) were
`measured in the dominant median nerve and the non(cid:173)
`dominant peroneal nerve. Sensory nerve conduction
`velocity (SNCV) and amplitude of the sensory nerve
`action potential (SNAP) were measured in the non(cid:173)
`dominant sural nerve and the dominant median nerve. The
`
`Sanofi Exhibit 2159.002
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`79
`
`normal limits routinely used in our laboratory were as
`follows: sural nerve SNCV 2': 40 mis, sural nerve
`SNAP 2': 8 µ V, median nerve MNCV 2': 50 mis, median
`nerve CMAP 2': 4 m V, peroneal nerve MNCV > 43 mis
`and peroneal nerve CMAP 2': 2 m V Case reports were
`searched for other explanations of polyneuropathy and all
`patients were examined by a trained neurologist including
`sensory, motor and reflex examinations, who decided
`whether the findings were typical of diabetic neuropathy.
`The diagnosis of diabetic polyneuropathy was based on
`both clinical and electrophysiological studies.
`Sixteen patients with type 2 diabetes who had carpal
`tunnel syndrome in ENMG were excluded in order to
`eliminate the effect of CTS on hand strength.
`
`5. Handgrip and pinch strength measurements
`
`Grip strength was tested first with a single calibrated
`Jamar dynamometer (Sammons Preston, Inc., Bolling(cid:173)
`brook, IL) followed by lateral, palmar and tip pinch
`measurements by using a manual pinchmeter (Sammons
`Preston, Inc., Bollingbrook, IL). For each tests of hand
`strength, the standard test position approved by the
`American Society of Hand Therapists was used [22] . This
`testing position is described as sitting in a straight-backed
`chair with feet flat on the floor, the shoulder adducted and
`neutrally rotated, elbow flexed at 90°, forearm in a neutral
`position, and the wrist between 0° and 30° extension and
`between 0° and 15° ulnar deviation. In all cases the arm
`should not be supported by the examiner or by an armrest.
`For grip strength measurement, the dynamometer is
`presented vertically and in line with the forearm to
`maintain the standard forearm and wrist positions. For
`standardization, the handle of Jamar dynomometer is set
`at the second handle position (3.8 cm) for all subjects. For
`pinch strength the pinch gauge was positioned between
`the pad of the thumb and the radial side of the middle
`phalanx of the index finger. For tip strength the pinch
`gauge was positioned between the tip of the thumb and
`the tip of the index finger. For palmar strength the pinch
`gauge was positioned between the pad of the thumb and
`the pad of the index and middle fingers. For each strength
`test the scores of three successive trials were recorded and
`the mean of three trials was used. Both the dynamometer
`and pinch gauge were reset to zero prior to each reading
`and were read to the nearest increment of the two scale
`divisions.
`
`6. Statistics
`
`Results were given as mean ± standard deviation
`(S.D.) and range. The difference between groups was
`
`evaluated with a two-tailed Student's t-test in para(cid:173)
`metric variables and Mann-Whitney U test in non(cid:173)
`parametric variables. Pearson's correlation analysis in
`parametric variables and Spearman correlation analysis
`in non-parametric variables was used to express the
`strength of the association between two variables. The
`significance level was set at p < 0.05 for all tests.
`Analyses were performed using the software program
`SPSS Statistics 11.0 (SPSS International BV, Chicago,
`IL, USA).
`
`7. Results
`
`Forty-four type 2 diabetic patients (18 female, 26
`male) with a mean age of 60.22 ± 8.88 years (46-75)
`and 60 controls (28 female and 32 male) with a mean
`age of58.98 ± 9.07 years (45-75) took part in the study.
`There was no difference for the mean age (p = 0.48) and
`sex (p = 0.56) between the groups. The mean BMI did
`not differ between the groups (28.05 ± 3.76 versus
`28.31 ± 4.41, p = 0.76). Eight (18.2%) patients with
`diabetes and 8 (13.3%) controls were regular smokers
`(p = 0.71). None of the patients and the subjects was
`exercising regularly. Clinical characteristics of the
`diabetic patients are shown in Table 1.
`In the diabetic group, 22 patients were house-wives,
`14 patients were retired, 5 patients were officials, 3
`patients were tradesmen. In the control group, 30
`subjects were house-wives, 19 subjects were retired, 4
`subjects were officials, 6 subjects were tradesmen, 1
`subject was a manager. Self-reported working status of
`all subjects was classified as all white collar workers.
`The mean DHI score was 4.75 ± 8.99 (0-40) in
`0.06 ± 0.31
`diabetics
`and
`(0-2) m
`controls
`(p < 0.0001).
`Twenty ( 45 .5 % ) diabetic patients had LJM consist(cid:173)
`ing of 18 (40.9%) stage 1 and 2 (4.5%) stage 2 LJM.
`Thirteen (29.5%) diabetic patients had Dupuytren's
`disease and 4 (9 .1 % ) patients had trigger finger. None of
`the patients with Dupuytren's disease had digital flexion
`contracture. None of the controls had LJM, Dupuytren's
`disease or trigger finger. LJM, Dupuytren's disease or
`
`Table 1
`Characteristics of the type 2 diabetic patients
`
`Diabetes duration (years)
`HbAlc (%)(mean± S.D.)
`Retinopathy (n, % )
`Nephropathy (n, %)
`Polyneuropathy (n, % )
`
`Diabetic patients ( n = 44)
`
`12.15 ± 5.28 (5-28)
`9.37 ± 1.60 (5.20-12.90)
`24 (54.5)
`28 (63.6)
`29 (65.9)
`
`Sanofi Exhibit 2159.003
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`80
`
`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`Table 2
`Comparison of the hand strength measurements of the diabetic patients and controls (mean± S.D.)
`
`Measurement
`
`Grip (kg)
`Pinch lateral (kg)
`Pinch tip (kg)
`Pinch palmar (kg)
`
`All diabetic subjects (n = 44)
`
`Control subjects (n = 60)
`
`27.48 ± 9.26
`7.50 ± 2.17
`4.00 ± 1.56
`6.01 ± 1.79
`
`31.72 ± 9.86
`8.65 ± 2.43
`4.90 ± 1.23
`7.20 ± 1.71
`
`p
`
`0.02
`0.01
`0.001
`0.001
`
`Table 3
`Comparison of electrophysiological parameters (mean± S.D.)
`
`Type 2 diabetes
`(n = 44)
`
`Controls
`(n = 60)
`
`31.50 ± 19.86
`9.63 ± 8.40
`48.66 ± 4.45
`12.60 ± 3.36
`41.11 ± 8.63
`3.02 ± 2.50
`
`47.59 ± 4.62a
`19.87 ± 9.24a
`55.94 ± 4.08a
`15.35 ± 4.70a
`49.99 ± 4.31 a
`6.88 ± 4_35a
`
`L sural nerve SNCV
`L sural nerve SNAP
`R median nerve MNCV
`R median nerve CMAP
`L peroneal nerve MNCV
`L peroneal nerve CMAP
`
`a p < 0.05.
`
`trigger finger was not correlated with DHI score in
`diabetic patients (p > 0.05).
`The grip and pinch strengths were significantly lower
`in diabetic patients than the non-diabetic controls in
`both hands (p < 0.05) (Table 2). The mean grip and
`pinch strengths was significantly correlated between the
`right and left hands in both groups (p < 0.0001) so, the
`right hands were taken into consideration for the
`statistical analyses. The mean grip strength, palmar
`pinch strength, and key pinch strength was negatively
`correlated with the mean DHI in type 2 diabetic
`patients (r = -0.47, p = 0.002; r = -0.44, p = 0.004
`and r = 0.54, p = 0.0001, respectively). The mean tip
`pinch strength was not correlated with the mean DHI
`score (r = -0.26, p = 0.12). The grip and pinch strength
`measurements were not correlated with the duration of
`diabetes, HbAlc levels and presence of retinopathy or
`nephropathy (p > 0.05).
`Twenty-nine (65.9%) diabetic patients had symetric
`distal sensorymotor polyneuropathy. None of the
`controls had polyneuropathy or carpal tunnel syndrome.
`Electrophysiological measurements are summarized in
`
`Table 3. Polyneuropathy was not correlated with the
`mean DHI score (p > 0.05) and with the grip and pinch
`measurements (p > 0.05). The grip and the pinch
`strength values were not different between the diabetic
`patients with or without polyneuropathy (p > 0.05)
`(Table 4).
`The presence of Dupuytren's disease, trigger finger
`and LJM was not correlated with the grip and pinch
`strength measurements in type 2 diabetic patients
`(p > 0.05).
`
`8. Discussion
`
`Hand is an important target for diabetic musculos(cid:173)
`keletal complications in type 2 diabetes. The upper
`extremity complications, known as
`'diabetic hand',
`include not only more specific diabetic-related condi(cid:173)
`tions such as LJM, but conditions related to the non(cid:173)
`diabetic hand, such as trigger finger, Dupuytren's
`disease and CTS [23,24]. Whether diabetic hand
`complications effect hand functional disability, defined
`as difficulty in performing activities of daily living, in
`type 2 diabetes has not been investigated before.
`LJM is a common manifestation of type 2 diabetes
`which results in painless, non-inflammatory limitation
`of the hand, feet and larger joints [25] . It is thought to be
`a manifestation of the diffuse collagen abnormalities
`found in diabetic patients [26]. LJM is not usually
`disabling enough to make a patient seek treatment [27] .
`In line with this data, LJM did not cause functional hand
`disability in our diabetic patients.
`Trigger finger is reported to be a common cause of
`pain and disability in the hand [28]. However in our study
`trigger finger did not cause any functional hand disability
`
`Table 4
`Comparison of the hand strength measurements of the diabetic patients with and without polyneuropathy (mean ± S.D.)
`
`Measurement
`
`Diabetics with polyneuropathy (n = 29)
`
`Diabetics without polyneuropathy (n = 15)
`
`Grip (kg)
`Pinch lateral (kg)
`Pinch tip (kg)
`Pinch palmar (kg)
`
`26.26 ± 9.22
`7.52 ± 2.09
`3.75 ± 1.55
`5.95 ± 1.80
`
`29.84 ± 9.20
`7.47 ± 2.40
`4.49 ± 1.50
`6.13 ± 1.81
`
`p
`
`0.23
`0.94
`0.13
`0.75
`
`Sanofi Exhibit 2159.004
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`81
`
`compared to controls. Since we had only four patients
`with trigger finger, studying with a larger group of
`patients with trigger finger may give more precise results.
`Dupuytren's disease did not cause to hand disability
`in our diabetic patients. The reason for this result may
`be that the disease form was mild since none of our
`diabetic patients had contracture of the fingers. It is
`known that Dupuytren's disease is milder in diabetic
`patients than the normal population, it rarely causes to
`severe contracture of the fingers and it has a benign
`prognosis in those patients [29] . Our result supports this
`data.
`Our patients with type 2 diabetes had low grip and
`pinch strength values than the non-diabetic controls and
`the reduced hand strength caused to hand functional
`disability. There are few studies in the literature
`assessing the hand strength in type 2 diabetic patients.
`Sayer et al. [12] assessed 1391 men and women with
`type 2 diabetes aged between 60 and 70 years and they
`reported that known diabetes status was associated with
`significantly lower grip strength, particularly in men.
`Ozdirenc; et al. [13] compared the hand grip strength in
`30 type 2 diabetic patients with non-diabetic controls
`and found that the handgrip strength is impaired in
`diabetic patients. Herriott et al [30] used I -RM values
`for type 2 diabetic subjects and did not found a
`difference from controls however the number of the
`patients was only nine and the test they used was not
`sensitive. Hand disability was not assessed in these
`three studies although hand grip strength is known to be
`an independent factor of ADL disability among older
`adults [31]. The only study assessing the effect of the
`reduced hand strength on the daily life was <;etinus
`et al.'s study [14]. In that study, they found low hand
`grip strength and pinch power in 76 type 2 diabetic
`patients compared to 4 7 non-diabetic controls and
`implications on life and activities, as a consequence of
`the patients' lower hand grip and pinch strength values,
`were investigated by asking the patient if their hand
`power and the daily activities was affected. 34.9% of
`their patients stated that decreased hand strength
`affected their daily activities but the methodology used
`in that study was rather subjective. In the present study,
`we demonstrated hand functional disability in type 2
`diabetics due to the reduced hand strength with a more
`objective method.
`The reason for the low hand strength in patients with
`type 2 diabetes was explained by the severity of
`neuropathy in Cetinus' study [14] although they did not
`analyze diabetic neuropathy in their study. Diabetic
`polyneuropathy usually presents with sensory distur(cid:173)
`bances. Later on, motor disturbances can occur in more
`
`severe cases, leading to distal weakness and atrophy of
`the muscles of the muscles of the lower leg and foot
`[32]. It is well known that impaired muscle strength at
`the ankle and knee in type 2 diabetic patients is related
`to the presence and the severity of peripheral motor
`neuropathy which causes axonal loss and muscle
`atrophy and the weakness is progressive [32,33]. In
`the present study, we could not find a relationship
`between the presence of diabetic distal symmetric
`polyneuropathy and hand strength values. Somewhat
`although not reaching statistical significance, lower grip
`and pinch tip strength was detected in the neuropathic
`patients as compared with the non-neuropathic patients.
`The low statistical power may be due to the exclusion of
`16 patients with carpal tunnel syndrome. With our
`result, we may also assume that motor neuropathy in our
`patients was not severe enough to cause hand muscle
`weakness.
`that stiffness of the
`stressed
`[34]
`Lundbaek
`subcutaneous tissue in the hand of diabetic patients
`might have an
`influence on
`the hand strength
`measurements. In the present study the presence of
`LJM was not correlated with
`the hand strength
`measurements however the lack of a negative correla(cid:173)
`tion may be due to the presence of mild form of LJM in
`our diabetic patients.
`Although we did not analyzed, reduced physical
`fitness may be responsible for the reduced hand muscle
`strength in our diabetic patients by causing reduced
`general muscle strength. Physical functional capacity is
`found to be lower in type 2 diabetic patients than in age(cid:173)
`matched control subjects [13,35]. Ozdirenc; et al. [13]
`found that low functional capacity caused to decreased
`muscle strength of lower extremities and they con(cid:173)
`cluded that physical fitness evaluation should be taken
`into consideration when exercise programs as designed
`for type 2 diabetic patients. Sayer et al. [12] found a
`graded association between the weaker grip strength
`and impaired physical capacity
`in
`their diabetic
`patients.
`It was previously reported that, hyperglycemia can
`effect contractile function and force generation in
`animal models [36]. Sayer et al. [12] demonstrated an
`association between the increased glucose levels and
`weaker hand strength in type 2 diabetic patients but they
`conclude that low levels of physical activity could
`explain the relationship between the increased glucose
`level and reduced grip strength. After adjustment for
`level of physical activity they concluded that the
`observed association may be causal [12]. Andersen
`et al. [33] also found no correlation between the blood
`glucose, HbAlc and the reduced strength at the knee
`
`Sanofi Exhibit 2159.005
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`82
`
`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`and ankle in patients with type 2 diabetes. In the present
`study, we could not find a relationship between the
`HbAlc levels and the hand strength values and our
`results are in line with the results of the previous studies.
`In conclusion, we detected functional hand disability
`due to the reduced hand strength in our patients with
`type 2 diabetes. Functional disability of the hand may be
`important especially for the diabetic patients who make
`self-monitoring of blood glucose or daily insulin
`injections. Further studies are needed in order to clarify
`the causes of the reduced hand strength in type 2
`diabetic patients.
`
`References
`
`[ 11 D.G. Bruce, W.A. Davis, T.M. Davis, Longitudinal predictors of
`reduced mobility and physical disability in patients with type 2
`diabetes: the Fremantle Diabetes Study, Diab. Care 28 (10)
`(2005) 2441-2447.
`[21 E.W. Gregg, G.L.A. Beckles, D.E. Williamson, S.G. Leveille,
`J.A. Langlois, M.M. Engelgau, et al., Diabetes and physical
`disability among older U.S. adults, Diab. Care 23 (9) (2000)
`1272-1277.
`[31 S. Maggi, M. Noale, C. Gallina, C. Marzari, D. Bianchi, F.
`Limongi, et al., Physical disability among older Italians with
`diabetes: the ILSA study, Diabetologia 47 (2004) 1957-1962.
`[41 T.E. Seeman, P.A. Charpentier, L.F. Berkman, M.E. Tinetti, J.M.
`Guralnik, M. Albert, et al., Predicting changes in physical
`performance in a high functioning elderly cohort: MacArthur
`studies of successful aging, J. Gerontol. 49 (1994) 97-108.
`[51 E.W. Gregg, C.M. Mangione, J.A. Cauley, T.J. Thompson, A.V.
`Schwartz, K.E. Ensrud, et al., Diabetes and incidence of func(cid:173)
`tional disability in older women, Diab. Care 25 (2002) 61-67.
`[61 L.A. Wray, M.B. Ofstedal, K.M. Langa, C.S. Blaum, The effect
`of diabetes on disability in middle-aged and older adults, J.
`Gerontol. A: Biol. Sci. Med. Sci. 60 (9) (2005) 1206-1211.
`[71 S.C. Mathy, L.P. Freid, S. Volpato, J. Williamson, F.L. Brancati,
`C.S. Blaum, Patterns of disability related to diabetes mellitus in
`older women, J. Geontol. A: Biol. Sci. Med. Sci. 59 (2) (2004)
`148-153.
`[81 K.L. Chou, I. Chi, Functional disability related to diabetes
`mellitus in older Hong Kong Chinese adults, Gerontology 51
`(5) (2005) 334-339.
`[91 W.J.C. Grauw, van de Lisdonk Eloy, RR.A. Behr, W.H.E.M. van
`Gerwen, H.J.M. Van den Hoogen, C. van Wee!, The impact of
`type 2 diabetes mellitus on daily functioning, Fam. Pract. 16
`(1999) 133-139.
`[ 101 S. Volpato, L. Ferrucci, C. Blaum, G. Ostir, A. Cappola, L.P.
`Fried, et al., Progression of lower-extremity disability in older
`women with diabetes: the Women's Health and Aging Study,
`Diab. Care 26 (2003) 70-75.
`[ 11 l S. Volpato, C. Blaum, H. Resnick, L. Ferrucci, L.P. Fried, J.M.
`Guralnik, Comorbidities and impairments explaining the asso(cid:173)
`ciation between diabetes and lower extremity disability, Diab.
`Care 25 (4) (2002) 678-683.
`[ 121 A.A. Sayer, E.M. Dennison, H.E. Syddall, H.J. Gilbody, D.I.W.
`Phillips, C. Cooper, Type 2 diabetes, muscle strength, and
`impaired physical function. The tip of the iceberg? Diab. Care
`28 (2005) 2541-2542.
`
`[ 131 M. Ozdirenc;:, S. Biberoglu, A. Ozvan, Evaluation of physical
`fitness in patients with type 2 diabetes mellitus, Diab. Res. Clin.
`Pract. 60 (2003) 171-176.
`[ 141 E. <;:etinus, M.A. Biiyiikbe~e, M. Uzel, H. Ekerbic;:er, A. Kar(cid:173)
`aoguz, Hand grip strength in patients with type 2 diabetes
`mellitus, Diab. Res. Clin. Pract. 70 (3) (2005) 278-286.
`[ 151 D.J.S. Fernando, J. Vernidharan, Limited joint mobility in Sri
`Lankan patients with non-insulin-dependent diabetes, Br. J.
`Rheum. 36 (1997) 374-376.
`[ 161 W.L. Sibbitt, R.P. Eaton, Corticosteroid responsive tenosynovitis
`is a common pathway for limited joint mobility in the diabetic
`hand, J. Rheumatol. 24 (1997) 931-936.
`[171 Y.C. Lu, P.W. Wang, R.T. Liu, S.C. Tung, W.Y. Chien, S.L.
`Hung, et al., Limited joint mobility of the hand: prevalence and
`relation to chronic complications in non-insulin-dependent dia(cid:173)
`betes mellitus patients, J. Formos. Med. Assoc. 92 (2) (1993)
`139-143.
`[ 181 J. Noble, J.G. Heatcote, H. Cohen, Diabetes mellitus in the
`aetiology of Dupuytren's disease, J. Bone Joint Surg. (Br.) 66
`(1984) 322-325.
`[191 E. Cagliero, W. Apruzze, G.S. Perlmutter, D.M. Nathan, Mus(cid:173)
`culoskeletal disorders of the hand and shoulder in patients with
`diabetes mellitus, Am. J. Med. 112 (2002) 487-490.
`[201 M.T. Duruiiz, S. Poiraudeau, J. Fermanian, C.S. Menkes, B.
`Amor, M. Dougados, et al., Development and validation of a
`rheumatoid hand functional disability scale that assesses func(cid:173)
`tional handicap, J. Rheumatol. 23 (1996) 1167-1172.
`[21 l Y. Turan, T. Duruiiz, E. Akku~, A. Gfugan, Diabetes mellituslu
`hastalarda el fonksiyonlarinin degerlendirilmesi, in: Proceedings
`of the Second National Rheumatic Diseases Congress, Antalya,
`Turkey, April 26-30, 2006.
`[221 V. Mathiowetz, K. Weber, G. Volland, N. Kashman, Reliability
`and validity of grip and pinch strength evaluations, J. Hand Surg.
`9A (1984) 222-226.
`[23] F. Ard1c;:, F. Soyupek, Y. Kahraman, R. Yorganc10glu, The
`musculoskeletal complications seen in type II diabetics: pre(cid:173)
`dominance of hand involvement, Clin. Rheumatol. 22 (2003)
`229-233.
`[241 J.C. Crispin, J. Alcocer-Varela, Rheumatologic manifestations of
`diabetes mellitus, Am. J. Med. 114 (2003) 753-757.
`[251 A.L. Rosenbloom, J.H. Silverstein, D.C. Lezotte, K. Richardson,
`M. McCallum, Limited joint mobility in childhood diabetes
`indicates increased risk for microvascular disease, N. Engl. J.
`Med. 305 (1981) 191-194.
`[261 J.R. Seibold, J. Uitto, B.B. Dorwart, D.J. Prockop, Collagen
`synthesis and collagenase activity in dermal fibroblasts from
`patients with diabetes and digital sclerosis, J. Lab. Clin. Med.
`105 (1985) 664-667.
`[271 P.E. Arkkila, J. Gautier, Musculoskeletal disorders in diabetes
`mellitus: an update, Best Pract. Res. Clin. Rheumatol. 17 (6)
`(2003) 945-970.
`[281 S. Akhtar, M.J. Bradley, D.N. Quinton, F.D. Burke, Management
`and referral for trigger finger/thumb, BMJ 331 (2005) 30-
`33.
`[291 K.G. Gudmundsson, R. Arngrimsson, N. Sigfusson, A. Bjorns(cid:173)
`son, T. Johns son, Epidemiology of Dupuytren's disease: clinical,
`serological, and social assessment. The Reykjavik Study, J. Clin.
`Epidemiol. 53 (2000) 291-296.
`[301 M.T. Herriott, S.R. Colberg, H.K. Parson, T. Nunnold, A. Vinik,
`Effects of 8 weeks of flexibility and resistance training in older
`adults with type 2 diabetes, Diab. Care 27 (12) (2004) 2988-
`2989.
`
`Sanofi Exhibit 2159.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`S. SavaI et al. I Diabetes Research and Clinical Practice 77 (2007) 77-83
`
`83
`
`[311 S. Al Snih, K.S. Markides, K.J. Ottenbacher, M.A. Raji, Hand
`grip strength and incident ADL disability in elderly Mexican
`Americans over a seven-year period, Aging Clin. Exp. Res. 16
`(6) (2004) 481-486.
`[321 C.S. Andreassen, J. Jakobsen, H. Andersen, Muscle weakness. A
`progressive late complication in diabetic distal symmetric poly(cid:173)
`neuropathy, Diabetes 55 (2006) 806-812.
`[331 H. Andersen, A. Nielsen, C.E. Mogensen, J. Jakobsen, Muscle
`strength in type 2 diabetes, Diabetes 53 (2004) 1543-1548.
`
`[341 K. Lundbaek, Stiff hands in long-term diabetes, Acta Med.
`Scand. 158 (1957) 447-451.
`[35] A. Cimbiz, 0. Cakir, Evaluation of balance and physical fitness
`in diabetic neuropathic patients, J. Diab. Complications 19
`(2005) 160-164.
`[361 I. Helander, H. Westerblad, A. Katz, Effects of glucose on
`contractile function, [Ca2+li, and glycogen in isolated mouse
`skeletal muscle, Am. J. Physiol. Cell Physiol. 282 (2002) 1306-
`1312.
`
`Sanofi Exhibit 2159.007
`Mylan v. Sanofi
`IPR2018-01675
`
`