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`Journal of Diabetes Science and Technology
`Volume 5, Issue 1, January 2011
`© Diabetes Technology Society
`
`ORIGINAL ARTICLES
`
`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and
`Type 2 Diabetes Mellitus
`
`Julia Pfiitzner, MD.,1 Juliane Hellhammer, M.Sc.,2 Petra Musholt, MD.,1 Anke H. Pfiitzner, PhD.,1
`Jan Bohnke, M.Sc,2 Torsten Hero, M.Sc.,2 Ildiko Amann-Zalan, MD., Ph.D.,3 Manfred Ganz, MD.,3
`Thomas Forst, M.D.,1 and Andreas Pfiitzner, MD., Ph.D.1
`
`Abstract
`
`Background:
`Daily routine for insulin-treated patients with diabetes mellitus requires correct performance of self-monitoring
`of blood glucose and insulin injections several times a day. Dexterity skills may play an important role in
`the performance efficacy of these procedures.
`
`Methods:
`We collected data of insulin-treated (>10 years) patients with different age ranges [healthy controls,
`14 female/11 male, age (mean ± standard deviation) 55 ± 7 years; type 1 diabetes mellitus (TlDM) patients,
`12/13, 45 ± 9 years, disease duration 23.9 ± 6.5 years; T2DM patients, 8/17, 64 ± 6 years, 16.2 ± 6.9 years;
`T2DM patients (>70 years of age), 9/16, 75 ± 4 years, 19.7 ± 7.0 years]. After assessment of neuropathy
`(temperature, pain, and vibration perception), the patients participated in two dexterity test batteries [Jebsen-Taylor
`hand-function test (JHFT) and motoric performance series (MPS)].
`
`Results:
`Patients with type 2 diabetes showed disturbed vibration perception as compared to the other groups.
`The dexterity results were influenced by age to a large extent. Older T2DM patients performed worst in the
`majority of the subtests (e.g., JHFT, writing nondominant hand: control, 40.8 ± 11.7 s; TlDM, 46.3 ± 50.9 s,
`not significant versus control; old T2DM, 68.1 ± 29.5 s, p < .05; young T2DM, 52.5 ± 26.2 s, p < .05). Patients with
`type 1 diabetes showed similar JHFT and MPS results than the 10-year-older control subjects and performed
`outside of the age-dependent normal reference range.
`
`Conclusions:
`Manual skills and dexterity differed between the groups, and age-corrected reduced skills were common
`in both TlDM and T2DM patients in this study. Our findings underline the importance of considering dexterity
`and manual skills when designing medical devices for patients with diabetes mellitus.
`
`J Diabetes Sci Technol 2011;5(1):158-165
`
`Author Affiliations: 1IKFE, Institute for Clinical Research and Development, Mainz, Germany; 2DaaCro, Diagnostic Assessment and Clinical
`Research Organization, Trier, Germany; and 3Roche Diagnostics GmbH, Mannheim, Germany
`
`test, (MPS) motoric performance series, (SMBG) self-monitoring of blood glucose,
`Abbreviations: (JHFT) Jebsen-Taylor hand-function
`(TlDM) type 1 diabetes mellitus, (T2DM) type 2 diabetes mellitus
`
`Keywords: dexterity, hand function test, motor function, neuropathy
`
`Corresponding Author: Andreas Pfotzner, M.D., Ph.D., IKFE, Institute for Clinical Research and Development, Parcusstr. 8, D-55116 Mainz,
`Germany; email address andreasp@ikfe.de
`
`158
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
`Introduction
`
`I nsulin-treated patients with type 1 and type 2 diabetes
`mellitus (TlDM and T2DM), are asked to measure their
`blood glucose several times a day for therapeutic purposes
`(e.g., in the morning, prior to each major meal, and at
`bedtime, to be able to correctly calculate the required
`insulin doses in case of multiple injection therapy).1
`
`Adherence to this requirement is important for achieving
`the therapeutic targets but is influenced by multiple
`factors, including, but not limited to, patient education,
`type of therapy, type and practicability of the used
`blood glucose meter, age, physical and mental capacity,
`dexterity, and prevalence of secondary complications.2,3
`
`Psychomotor function is an important domain of mental
`function that has not been systematically studied with
`respect to an association with diabetes. Psychomotor
`performance encompasses motoric strength, hand-eye
`coordination, balance, dexterity, tracking, and other skills.
`During episodes of
`iatrogenic hypoglycemia, people
`with insulin-treated diabetes have frequently been reported
`to suffer from a deterioration of fine motor skills.4,5
`
`Manual dexterity may have an enormous impact on
`occupational performance as well as on activities of daily
`living, such as frequent daily measurements of blood
`glucose. This situation has not been thoroughly explored
`in any larger clinical investigation, and very limited
`information can be obtained from the current literature.
`
`Using validated clinical tests and standardized controls,
`Casanova and colleagues6 measured hand function in
`subjects with diabetes. Fifteen diabetes patients with
`a median age of 48 years, all having used insulin for
`a minimum of 5 years, were randomly selected from
`inpatient and outpatient services. Testing was done on
`an outpatient basis. The three hand function tests used
`were the Purdue pegboard, O'Connor tweezer dexterity,
`and Smith hand-function
`test. Hand function was
`significantly decreased in the group with diabetes, and
`the decrease was out of proportion to patients' own
`subjective pretest assessments.
`
`with a battery of clinical and laboratory tests, including
`hand assessment, and a questionnaire. As expected,
`hemoglobin Ale was highest in the diabetes patients.
`A limited joint mobility (e.g., prayer sign and Dupuytren's
`contracture) was most common in individuals with
`diabetes, followed by individuals with impaired glucose
`tolerance. Vibrotactile sense was impaired symmetrically
`in the index and little fingers in diabetes patients.
`The authors, however, found no differences for sensibility,
`dexterity, grip strength, and cold intolerance between
`the study cohorts when applying their methods of
`investigation. In an earlier investigation, the same group
`described increased vibration thresholds in the fingertips
`in subjects with T2DM, which may lead to decreased
`dexterity.8
`
`A general evaluation of these few study reports on dexterity
`in diabetes is basically impossible, as no standardized
`methods of dexterity assessment have been applied in the
`different investigations. A systematic exploratory approach
`requires, therefore, a cross-sectional pilot examination to
`assess the prevalence of potential dexterity impairment
`by means of scalable and reproducible methods.
`
`One standardized way to assess hand function is the
`modified Jebsen test of hand function, which has been
`validated in patients with stroke, multiple sclerosis,
`and other head injury and which has been suggested
`as a measure for gross functional dexterity.9,10 Another
`standardized and scalable method is the Schoppe test,
`which has been predominately reported to be used with
`patients suffering from Parkinson's disease.11,12
`
`The goal of this pilot investigation was to assess the
`prevalence of potential dexterity problems in different
`patient populations
`(25
`healthy
`control
`subjects
`40-70 years of age, 25 TlDM patients <60 years of age,
`25 T2DM patients 40-70 years of age, and 24 T2DM
`patients >70 years of age) in the context of potential
`confounding prevalence of neuropathy.
`
`Patients and Methods
`
`Cederlund and associates7 examined hand disorders,
`symptoms, overall hand function, activities of daily
`living, and life satisfaction in elderly men with T2DM,
`with impaired glucose tolerance, and with normal glucose
`tolerance. The subjects were interviewed and evaluated
`
`This cross-sectional single-center study was approved
`by an institutional review board and was performed in
`compliance with the Declaration of Helsinki and local
`legal and ethical regulations. Type 1 and type 2 diabetes
`patients were selected based on the following inclusion
`
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`
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
`criteria: insulin treatment > 10 years, experience with
`self-monitoring of blood glucose (SMBG), and specific
`age ranges (25 TlDM <60 years of age, 25 T2DM at
`40-70 years, and 24 T2DM >70 years). In addition,
`25 nondiabetic healthy control subjects were enrolled
`(40-70 years). Exclusion criteria were disease duration
`<10 years, any neurological disorder known to impair
`dexterity (e.g., Parkinson's disease), known neuropathy
`of other origin than diabetes, arthritis/ arthrosis, other
`impairments of manual dexterity (e.g., accident or handicap),
`central neurologic disorders (e.g., Alzheimer's disease,
`dementia, stroke, chronic dihydration syndrome), any
`neurodegenerative or musculodegenerative disease
`resulting in impairment of manual dexterity, cancer,
`or any other life-threatening condition. Patients with
`visual impairment (visus <0.5) were excluded from study
`participation. After signing written informed consent,
`the patients participated in a series of neuropathy
`assessment and dexterity tests during a single visit.
`
`Jebsen-Taylor Hand-Function Test
`The Jebsen-Taylor hand-function test (JHFT) is a widely
`used assessment of common everyday motor skills.13
`It has a good validity and reliability, and normative
`data are available for different ages and both genders.14
`The test consists of seven subtests: writing a sentence,
`turning over cards, picking up small objects and
`placing them in a can, picking up small objects with a
`teaspoon and placing them in a can (simulated feeding),
`stacking checkers, moving large light cans, and moving
`heavy cans. Patients were instructed to perform the
`tasks as rapidly and accurately as possible according to
`standardized instructions.13 Subtest JHFT times were
`recorded with a stopwatch for analysis.
`
`Motoric Performance Series (Motorischer
`Leistungstest)
`The motoric performance series (MPS) is a comprehensive
`fine motor abilities test battery. The battery measures
`fine motor abilities through static and dynamic tasks for
`finger, hand, and arm movement and is applicable from
`7 years onward. It has been developed by Schoppe11
`based on Fleishman's factor-analytic examinations of fine
`motor abilities.15 The MPS is administered via a work
`panel with boreholes, grooves, and contact surfaces and
`consists of four subtests (steadiness, line tracing, aiming,
`and
`tapping) for each hand. Results are expressed
`as
`speed or accuracy measurements. After
`short
`introduction to the work panel, patients had to perform
`one sequence (left and right hand) within 10 minutes.
`
`Neuropathy Assessment
`Temperature, pain, and vibration perception thresholds
`were assessed by means of the Medoc TSA 2001 device
`(Medoc Advanced Medical Systems, Eilat,
`Israel).
`For thermal testing, a thermode (30 x 30 mm) was secured
`at the tested side (right-hand palmar thenar) with an
`elastic band. To avoid tactile or pressure stimulation,
`the probe was kept in contact with the skin for the entire
`duration of the test. Cold and warm detection thresholds
`were measured first. Then thermal pain thresholds
`(hot and cold) were determined. The mean threshold
`temperature from five consecutive trials per site and test
`was calculated. To detect the vibration threshold, the
`middle fingertip was placed on the simulating probe with
`a diameter of 1.00 cm. The vibratory stimulus was
`delivered at 100 Hz, and the method of limits was used
`for analysis. The machine delivered the stimulus with
`increasing intensity in the steps of 0.3 µm. The participant
`was instructed to click the mouse as soon as she/he
`perceived the vibration. The test was repeated five times.
`The mean vibration detection threshold was computed
`from the five consecutive experiments.
`
`Statistical Methods
`All statistical analyses were performed with SPSS
`(Version
`15.0). Hypotheses were
`tested with
`a
`significance level of a = 0.05. Adjustment of the a-level
`for multiple comparisons was done according to the
`Sidak procedure.16
`
`Continuous data were analyzed using analysis of variance
`procedures with experimental group as a fixed factor.
`Possible interfering variables were controlled as covariate
`using analysis of covariance procedures. In case of
`violations of the assumption of normal distributed test
`scores (testing for kurtosis and skewness), Kruskal-Wallis
`tests were performed for these variables. Relations between
`variables were analyzed by means of correlation techniques
`(Pearson, Spearman). A p value < .05 was considered
`to be statistically significant.
`
`Results
`
`A total of 100 patients were initially enrolled into the
`study. One patient (T2DM, >70 years) did not participate
`in all of the applied tests. The demographic characteristics
`of the patients are provided in Table 1.
`
`As shown in Figure 1, the results of the JHFT were
`consistent if the test was performed with the dominant
`
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
`Table 1.
`Demographic Characteristics of the Study
`Participants
`
`Characteristics
`
`N
`
`Gender
`female
`male
`
`age (years)
`
`Body mass
`index (kg/m 2)
`
`Diabetes
`duration (years)
`
`Hemoglobin
`A1c (%)
`
`Neuropathy
`
`Retinopathy
`
`Nephropathy
`
`Group A
`
`Group B
`
`Group C
`
`Group D
`
`Healthy
`control
`(40-70
`years)
`
`25
`
`14
`11
`
`T1DM
`(<60 years)
`
`T2DM
`(40-70
`years)
`
`T2DM
`(>70 years)
`
`25
`
`12
`13
`
`25
`
`8
`17
`
`25
`
`9
`16
`
`55 ± ?8
`
`45 ± 9 8
`
`64 + 68
`
`75 + 48
`
`300 ± 5.1
`
`27.0 ± 4.1b 34.5 ± 6.~ 31.4 ± 4.7
`
`-
`
`-
`
`0%
`
`0%
`
`0%
`
`23.9 ± 6.5
`
`16.2 ± 6.9
`
`19.7 ± 7.0
`
`7.5 ± 1.2
`
`6.4 ± 0.5
`
`7.4 ± 1.3
`
`28%
`
`36%
`
`12%
`
`44%
`
`16%
`
`8%
`
`52%
`
`12%
`
`8%
`
`8 p < .05 versus all other groups.
`b p < .05 versus control.
`
`the nondominant hand. For both hands,
`hand or
`T2DM patients older than 70 years show consistently
`worse results and needed more time for the subtests
`as compared to the healthy controls. Post hoc group
`comparisons revealed significant differences for several
`of the individual subtests, e.g., for the nondominant
`hand, simulated page turning, healthy controls < T2DM
`(old); lifting large, light objects, healthy controls = TlDM
`< T2DM (young) = T2DM (old); and lifting large, heavy
`objects, healthy controls < T2DM (young and old); TlDM
`< T2DM (old). As shown in Figure 2, all three groups
`with diabetes showed impaired results when compared
`to the age-correlated normal reference values.14
`
`For the analysis of the MPS dexterity test, single subtests
`were summarized to four factors of fine motor abilities
`(hand flurry/tremor, precision of arm-hand movements,
`arm-hand speed, and wrist-finger speed). The scores
`(means ± standard deviation)
`for
`the
`individual
`subtests are provided in Figure 3. Group differences
`on the MPS factors
`tremor and wrist-finger speed
`reached significance with T2DM (old) patients showing
`significantly lower values than TlDM patients (p <
`.001). For wrist-finger speed, T2DM patients older than
`70 years additionally show higher values than healthy
`controls (p < .001).
`
`To check whether both JHFT and MPS are measuring
`related constructs, bivariate correlations were computed
`as well as a principal component analysis for all MPS
`and JHFT measures. There were mixed results with
`the whole range from low to medium-high correlations
`present. However, these results have to be seen as
`preliminary and can be interpreted only with caution
`for this analysis since the number of patients was rather
`small.
`
`In order to investigate a potential effect of neuropathy on
`the obtained results, sensory perception thresholds were
`determined by means of the MEDOC TSA 2001 device.
`The results of these tests are summarized in Table 2.
`Since assumption of normality seemed to be violated in
`some groups, for consistency of results Kruskal-Wallis
`tests were performed for all five variables. In five related
`tests, the hypothesis was tested that groups do not differ
`in neuropathy. According to Holland and DiPonzio
`Copenhaver,16 the a level was corrected to 0.0102. With
`this approach, highly significant differences (p < .001)
`between the healthy controls and the T2DM patients
`were identified for both sensitivity tests and the vibration
`perception test.
`
`Discussion
`
`In our cross-sectional study with different groups of
`diabetes patients, we investigated motoric skills that
`may have an influence on the performance of complex
`routine diagnostic and
`therapeutic procedures, such
`as blood glucose measurements or insulin injections.
`In any case, the results of this pilot investigation need
`to be
`interpreted with caution. Mean age differed
`significantly in the four study groups. In this respect,
`an interesting result of this study is that TlDM patients
`and nondiabetic controls performed similar
`in
`the
`dexterity tests, although the TlDM cohort was about
`10 years younger. In turn, psychomotor function seems
`to be less affected by hypoglycemia in patients with
`TlDM as compared to healthy subjects. 5
`
`that patients with
`It has been shown previously
`neuropathy
`and visual
`impairment have
`tactual
`deficits.17 Highly significant differences in neuropathy
`were identified for both sensitivity tests and for the
`vibration perception
`test versus controls. Sensitivity
`measures show similar results for healthy subjects and
`TlDM patients group, with mean diabetes duration
`of 23 years. Interestingly, heat applied to the right
`hand showed opposite results than cold applied to the
`left hand. Patients with type 2 diabetes-especially
`
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
`the older population-had a higher prevalence of
`neuropathy. The differences were most pronounced for
`vibration perception at the finger ball. Cederlund and
`associates7 have investigated hand disorders, symptoms,
`overall hand function, activities of daily living, and
`life satisfaction in elderly men with T2DM, impaired
`glucose tolerance, and normal glucose tolerance. They
`showed that hand disorders and impaired vibrotactile
`sense in fingertips occurred in patients with diabetes but
`not in those with impaired glucose tolerance, although
`limited joint mobility was observed in both groups. A
`longer duration of diabetes was associated with more
`severe neuropathy. Life satisfaction was high, and hand
`disorders did not have a significant impact on activities
`of daily living.
`
`Our dexterity tests showed consistent results (some
`reaching significance) for the JHFT; the dominant hand
`assessment shows that patients with T2DM older than
`
`Table 2.
`Summary of the Neuropathy Test Scores for All
`Four Study Groups
`
`Group A
`
`Group B
`
`Group C
`
`Group D
`
`Variable
`
`Healthy
`control
`(40-70
`years)
`
`T1DM
`(<60
`years)
`
`T2DM
`(40-70
`years)
`
`T2DM
`(>70 years)
`
`Sensitivity heat
`right hand
`
`Sensitivity cold
`left hand
`
`Pain heat
`right hand
`
`Pain cold
`left hand
`
`Vibration right
`finger ball
`
`34.2 ± 1.1
`
`34.1 ± 2.1
`
`35.1 ± 1.6
`
`36.2 ± 3.2
`
`30.5 ± 0.8 29.9 ± 3.6
`
`30.0 ± 1.0 29.2 ± 1.58
`
`46.1 ± 3.8 45.4 ± 4.5 47.5 ± 2.5 8
`
`45.5 ± 4.3
`
`11.6 ± 8.2
`
`11.7 ± 9.2
`
`9.2 ± 8.7
`
`12.3 ± 9.3
`
`1.6 ± 1.3
`
`2.1 ± 3.9
`
`3.8 ± 3.4a
`
`3.1 ± 1.78
`
`a p < .05 versus healthy control.
`
`*
`
`Nondominant hand
`
`*
`
`*
`
`*
`
`*
`
`*
`I * r 7
`*
`
`Writing
`(value - 30)
`
`Simulated
`page turning
`
`Lifting
`small objects
`
`Simulated
`feeding
`
`Stacking
`checkers
`
`Lifting large
`light objects
`
`Lifting large
`heavy objects
`
`*
`
`Dominant hand
`
`□ Healthy subjects
`■ Type 1
`r.li'l Type 2 young
`tXi Type 2 old
`
`*
`
`* *
`
`I
`
`A
`
`~
`a>
`E
`i=
`
`B
`
`40
`
`30
`
`20
`
`10
`
`0
`
`25
`
`20
`
`~ 15
`Q)
`E 10
`i=
`
`5
`
`0
`
`Writing
`(value - 10)
`
`Simulated
`page turning
`
`Lifting
`small objects
`
`Simulated
`feeding
`
`Stacking
`checkers
`
`Lifting large
`light objects
`
`Lifting large
`heavy objects
`
`Figure 1. Results of the individual JHFT items. Values are given as mean values ± standard deviation. The asterisk represents p < .01.
`
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
`70 years of age perform worse in most subtests than
`nondiabetic controls. Emphasizing very
`fine motor
`skills, the MPS seems to add a different piece of
`information: it was observed that, in two out of four
`subscales ("tremor" and "wrist-finger speed"), again
`the T2DM patients older than 70 years of age performed
`worse than controls. It is to be expected that the higher
`prevalence of neuropathy is interfering with these results.
`Studies with nondiabetic patients with hereditary
`motoric and sensoric neuropathy also applying the JHFT
`have shown major limitations in activities related to
`upper extremity function in 25% of this population.18,19
`
`This was a pilot study with a limited number of patients,
`and the study was conducted to collect first data on
`
`dexterity and confounding variables in patients with
`insulin-treated diabetes mellitus. Levels of significance
`should not be overestimated and significant results could
`not be expected.
`
`However, we believe that the following conclusions can
`be drawn from our results:
`
`1. The JHFT and the MPS are simple, established
`methods and may be
`suitable
`for dexterity
`assessment
`in patients with diabetes mellitus.
`It has to be investigated in future studies whether
`it is possible to generate a link between these
`performance measures and safety or performance
`constraints for diabetes patients. Also, patients with
`
`A
`Dominant hand
`12 - - - - - - - - - - - -
`
`B
`18
`
`Nondominant hand
`
`10 + - - - - - - - - - ------..- - - -
`
`■
`
`0
`
`8 -.!!?..
`
`Q)
`E
`:,::::;
`C: 6
`C\'I
`Q)
`E
`I-
`LL
`J: ..,
`
`4
`
`2 -
`
`0 - -~ - -~ -~ - -~ -
`40
`70
`50
`60
`80
`Mean age (years)
`
`16
`
`14
`
`12
`
`-.!!?..
`
`Q)
`E
`:,::::; 10
`C:
`C\'I
`Q)
`E
`LL 8
`I-
`J: ..,
`
`6
`
`4
`
`2
`
`0
`40
`
`■
`
`0
`
`Control subjects 0
`■
`Type 1
`I:::,.
`
`Type 2 younger
`
`Type 2 old
`
`..
`
`50
`
`70
`60
`Mean age (years)
`
`80
`
`Figure 2. Mean JHFr times for the dominant and nondominant hand for all four groups in relation to their age. The gray shadowed areas present
`the normal references.14
`
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`
`Pfutzner
`
`50
`
`40
`
`30
`
`20
`
`10 -ti) -Cl)
`
`0
`E
`t= 40
`
`30
`
`20
`
`10
`
`0
`
`□ Healthy subjects
`• Type 1
`IZl Type 2 young
`CSl Type 2 old
`
`Right hand
`
`Left hand
`
`..,
`
`.,,
`...
`Steadiness
`
`...
`Line tracing
`
`'v"
`Aiming
`
`T
`I
`Tapping
`
`Figure 3. Results of the individual items of the MPS. Values are given as mean values ± standard deviation. The asterisk represents p < .001.
`
`visual impairment should be included in these
`evaluations because of the major impact of this
`condition on dexterity skills. 20
`
`2. This pilot data set provides first results on dexterity
`measures for
`insulin-treated TlDM and T2DM
`patients compared to nondiabetic controls. The
`results show that reduced dexterity skills were
`common in TlDM and in both groups of T2DM
`patients. In further studies, these results should be
`confirmed and study protocols should be adapted
`in line with results of this pilot study.
`
`investigation should be more intensively investigated
`in future clinical trials, because impaired dexterity and
`sensory nerve function may be more prevalent, even in
`younger patients with TlDM. It may be worthwhile to
`take this into consideration when new devices are being
`developed for blood glucose measurement and insulin
`delivery.
`
`Funding:
`
`This study was funded by Roche Diagnostics.
`
`Disclosures:
`
`In conclusion, insulin-treated TlDM and T2DM patients
`showed different degrees of impaired results regarding
`dexterity and nerve function as compared to a healthy
`control group. These factors may influence the outcome
`of
`complex diagnostic and
`treatment procedures
`routinely performed by these patients in daily life, such
`as SMBG and insulin injections. The tests used in this
`
`Andreas Pfutzner, Anke Pfutzner, and Thomas Forst have received
`research grants from Roche Diagnostics. Ildiko Amann-Zalan and
`Manfred Ganz were employees of Roche Diagnostics.
`
`Acknowledgment:
`
`The authors thank all participating patients, physicians, and study
`nurses from IKFE clinic and research laboratory who participated in
`the study.
`
`J Diabetes Sci Technol Vol 5, Issue 1, January 2011
`
`164
`
`www. iournalofdst. orq
`
`Sanofi Exhibit 2125.007
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`Evaluation of Dexterity in Insulin-Treated Patients with Type 1 and Type 2 Diabetes Mellitus
`
`Pfutzner
`
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`Sanofi Exhibit 2125.008
`Mylan v. Sanofi
`IPR2018-01676
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