Research Report

Safety of Aerobic Exercise in People

W ith Diabetic Peripheral Neuropathy:
Single-Group Clinical Trial
Patricia M. Kluding, Mamatha Pasnoor, Rupali Singh, Linda J. D'Silva, Min Yoo,
Sandra A. Billinger, Joseph W. LeMaster, Mazen M. Dimachkie, Laura ^ 5 6 1 ^
Douglas E. W right

P.M. Kluding, PT, PhD, Physical

Therapy and Rehabilitation Sci
ences, University of Kansas M ed i
cal Center, 3901 Rainbow Blvd,
Kansas City, KS 66160 (USA).
Address all correspondence to Dr
Kluding at: pkluding@ kum c.edu.
M. Pasnoor, MD, Departm ent of
Neurology, University o f Kansas
Medical Center.

Background. Exercise is recommended for people with diabetes, but little is

known about exercise in people with diabetic peripheral neuropathy (DPN).

O bjective. The primary purpose of this preliminary study was to examine adverse
events (AEs) during moderate-intensity, supervised aerobic exercise in people with
DPN. The secondary purpose was to examine changes in fatigue, aerobic fitness, and
other outcomes after intervention.
Design. This was a single-group preliminary study.
S etting. The setting was an academic medical center.
Participants. Participants were 18 people who were sedentary and had type 2
diabetes and peripheral neuropathy (mean age=58.1 years, SD= 5).
In terven tio n . The intervention was a supervised 16-week aerobic exercise pro

gram (3 times per week at 50% to >70% oxygen uptake reserve).

M easurem ents. Adverse events were categorized as related or unrelated to the

study, anticipated or unanticipated, and serious or not serious. Outcomes included

fatigue (Multidimensional Fatigue Inventory), cardiovascular fitness (peak oxygen
uptake), body composition (dual-energy x-ray absorptiometry), sleep quality, plasma
metabolic markers, and peripheral vascular function.
Results. During the study, 57 nonserious AEs occurred. Improvements were found
in general fatigue (mean change= 3.5; 95% confidence interval [95% Cl] = 1.3,
-5.3), physical fatigue (mean change=-3.1; 95% C I=-1.2, -5.0), peak oxygen
uptake (mean change=l.l ml.-kg '-min 1; 95% CI=0.2, 1.9), total body fat (mean
change = l%; 95% CI=-0.3, -1.7), fat mass (mean change=-l,780 g; 95%
Cl=~6l6.2, -2,938.7), and peripheral blood flow (mean change=2 27% 95%
CI=0.6, 4.0).
Lim itations. This was a small-scale, uncontrolled study. A future randomized
controlled trial is needed to fully assess the effects of exercise on the outcomes.
Conclusions. This study provides new support for supervised aerobic exercise in

people with DPN. However, it is important for physical therapists to carefully

prescribe initial exercise intensity and provide close monitoring and education to
address the anticipated AEs as people who are sedentary and have DPN begin an
exercise program.

R. Singh, PhD, Physical Therapy,

The Sage Colleges, Troy, New
York.
L. J. D'Silva, PT, Physical Therapy
and Rehabilitation Sciences, Uni
versity of Kansas Medical Center.
M. Yoo, MS, Physical Therapy and
Rehabilitation Sciences, University
of Kansas Medical Center.
S.A. Billinger, PT, PhD, Physical
Therapy and Rehabilitation Sci
ences, University of Kansas M edi
cal Center.
J.W. LeMaster, M D, MPH, Depart
m en t of Family M edicine, Univer
sity o f Kansas Medical Center.
M .M . Dimachkie, M D, FANA,
Departm ent of Neurology, Uni
versity of Kansas Medical Center.
L. Herbelin, BSc, PTA, Departm ent
of Neurology, University of Kansas
Medical Center.
D.E. W right, PhD, D epartm ent of
Anatom y and Cell Biology, Univer
sity of Kansas M edical Center.
[Kluding PM, Pasnoor M, Singh R,
et al. Safety of aerobic exercise in
people w ith diabetic peripheral
neuropathy: single-group clinical
trial. Phys Ther. 2015;95:223-234.]
2015 American Physical Therapy
Association
Published Ahead of Print:
October 2, 2014
Accepted: September 24, 2014
Submitted: March 11, 2014

Post a Rapid Response to

this article at:
ptjournal.apta.org
February 20 15

V o lu m e 95

N um ber 2

Physical T h e ra p y

223

Safety of Aerobic Exercise

iabetic peripheral neuropathy

(DPN) is one of the most com
mon complications of diabe
tes, with lower limb pain and sen
sory loss caused by slow peripheral
nerve degeneration. The most com
mon form of DPN is symmetrical dis
tal degeneration of peripheral nerves
combined with impaired nerve
regeneration.1*As a consequence of
DPN, people with long-standing dia
betes may have pain or significant
deficits in tactile sensitivity, vibra
tion sense, and lower-limb joint pro
prioception. These sensory deficits
may contribute to impaired balance
and gait, with increased risk of falls,
lower extremity injury, and amputa
tion.2-5 People with DPN are more
likely to be sedentary and to have
decreased daily walking distances.6

not appear to increase the risk of

foot ulcers in people with DPN.1314
The physical activity target for adults
with diabetes is a minimum of 150
minutes of moderate-intensity aero
bic activity (ie, 50%-70% of the max
imal heart rate [HR]) per week.1516
However, no studies have identified
the most appropriate rate of progres
sion to achieve this level in people
who are sedentary and have type 2
diabetes, as noted by Colberg et al.16

fall risk.20-23 No studies have exam

ined the use of aerobic exercise to
improve several other relevant out
comes in people with DPN, includ
ing fatigue, cardiovascular fitness,
sleep quality, body fat, plasma lipids,
and vascular function. Little is
known about the need for physical
therapist supervision or monitoring
during exercise interventions for
people with DPN.

Fatigue is a common symptom in

Few studies have examined whether people with diabetes, reported by
exercise provides specific benefits 24.6% of adults with type 2 diabetes
for glycemic control in people with in a recent large-scale longitudinal
DPN,1718
although
emerging survey.24 In addition to fatigue being
research has shown promising more common, people with diabetes
effects of exercise on cutaneous report higher levels of fatigue than
reinnervation and decreased neuro people without diabetes,25 and older
pathic symptoms in small, uncon adults who had diabetes and
trolled trials.1819 Several larger ran reported fatigue had lower survival
Several large-scale randomized con domized controlled trials in older rates 24 months later than people
trolled trials have established that adults with DPN have demonstrated without fatigue.24 A relationship
aerobic exercise improves physical that exercise results in increased lev between fatigue and cardiovascular
fitness, glycemic control, and insulin els of activity in the home,1417 with fitness has been found in people
sensitivity in people with diabe inconsistent results for balance and with other chronic neurologic contes.7-10 However, people with DPN
may not respond to exercise in the
same way. Neuropathic pain may
T h e B o tto m Line
interfere with a person's willingness
to participate in an exercise pro
W h a t d o w e a lr e a d y k n o w a b o u t th is to p ic ? _____________
gram, and there is evidence that neu
ropathy also may interfere with pain
Diabetes can cause damage to nerves in the legs, with resulting pain,
modulation during exercise.11 As
numbness, and difficulty walking. Exercise is essential to improve the
recently as 2008, the Standards of
health of people with diabetes, but people with diabetic nerve damage
Medical Care in Diabetes position
may have more difficulty exercising.
statement published by the Ameri
can Diabetes Association stated that
W h a t n e w in f o r m a t io n d o e s th is s tu d y o ffe r?
only non-weight-bearing activities
The study participants, all with diabetic nerve damage, were able to
should be encouraged in people
complete the exercise program without serious problems. However,
with DPN.12 Current guidelines have
several minor problems with pain or blood sugar values occurred. After
been adjusted because moderateintensity weight-bearing activities do
completing the exercise program, the participants had decreased fatigue
and other benefits.
Available With
This Article at
ptjournal.apta.org
1eFigure: S ca tte rplot o f the
C hange in General Fatigue and
th e Percentage o f Exercise
Sessions A tte n d e d

224

Physical Therapy

Volume 95

If y o u 'r e a p a tie n t, w h a t m ig h t th e s e fin d in g s m e a n

f o r y o u ? ______________________________________________ _

Exercise may be helpful if you have diabetes with nerve damage in your
legs. However, it may be important to receive guidance from a physical
therapist or other health care professional when starting an exercise
program.

Number 2

February 2015

S afety o f A e ro b ic Exercise

ditions, such as stroke.26 People with

DPN may have increased fatigue
because of avoidance of physical
activity and decreased cardiovascu
lar fitness as a result of the compli
cating effects of diabetes, obesity,
lower limb pain, and sensory loss.
Because little is known about the
complications that are related to
pain, comorbidities, and diabetes
and that may occur when people
with DPN initiate an exercise pro
gram, the primary purpose of this
preliminary study was to report the
frequency, type, and severity of
adverse events (AEs) during a
moderate-intensity, 16-week super
vised aerobic exercise intervention
in people with DPN. The secondary
purpose was to examine changes in
fatigue and related outcome mea
sures
after
the
intervention.
Although this was an exploratory
study, we hypothesized that we
would find improvements in selfreported fatigue (Multidimensional
Fatigue Inventory [MFI-20]) and
increases in aerobic fitness (peak
oxygen uptake [Vo2peak] during a
graded exercise test) after the
intervention.

reported a diagnosis of type 2 diabe biopsy also was obtained for analysis
tes with symptoms of neuropathy, of intraepidermal nerve fiber density
and who were interested in the and nerve growth factors (not
study were screened by a phone reported here), additional exclusion
interview. The phone interview ary criteria included lidocaine allergy
included the Telephone Assessment and blood clotting disorder.
of Physical Activity27 to identify par
ticipants who were sedentary or After consent but before enrollment,
underactive, as determined by a a clinical examination was per
score of <5. Those who qualified formed by a neurologist (M.P.) to
provided consent by signing an insti confirm the presence of DPN on the
tutionally approved informed con basis of standard criteria28: possi
sent form and then underwent fur ble (symptoms or signs of DPN),
ther screening before enrollment to probable (symptoms and signs of
confirm the absence of the following DPN), or confirmed (abnormal
exclusionary criteria: serious cardiac nerve conduction with symptoms
pathology, unstable hypertension, or and signs of DPN). Participants also
serious musculoskeletal problems completed a graded maximal exer
that would limit the ability to exer cise test with integrated electrocar
cise; skin conditions, circulatory diography to confirm their ability to
insufficiency, or open wounds on exercise safely before enrollment
the leg; inability to ambulate inde and to provide baseline Vo2peak val
pendently; stroke or other central ues (more details about this test are
nervous system pathology; body provided in the description of car
weight of greater than 202.5 kg (450 diovascular fitness outcomes). Once
lb); inadequate cognition and com the participants were enrolled, their
munication abilities, defined as primary care physicians were noti
scores of less than 24 on the Mini- fied of their involvement in the
Mental State Examination; or preg study.
nant or planning on becoming preg
nant, confirmed with a urine Interventions
pregnancy test for women who were All participants were scheduled for
premenopausal. Because a skin 16 weeks of supervised aerobic exer-

Method
This nonrandomized, single-group
preliminary study utilized a pre
intervention-postintervention mea
surement design, with all enrolled
participants taking part in the inter
vention. The study was completed at
the University of Kansas Medical
Center,
with
data
collection
between June 2012 and July 2013.
Participants

Potential study participants were

identified either by self-referral in
response to study advertisements or
through the Frontiers Research Par
ticipation Registry program (sup
ported by a National Institutes of
Health-funded Clinical and Transla
tional Science Award). People who
were 40 to 70 years of age, who
February 2015

Table 1.
Progression o f In te n sity and T a rg e t H eart Rate (HR) D u ra tio n D u rin g A e ro b ic Exercise
In te rv e n tio n 0
D ay 1

D ay 2

T a r g e t HR

D ay 3

T a rg e t HR

T a r g e t HR

V o 2R

D u r a tio n

V o 2R

D u r a tio n

V o 2R

D u r a tio n

W eek

(% )

( m in )

(% )

(m in )

(/o )

(m in )

50

30

50

30

50

35

50

35

50

35

50

40

50

40

50

40

50

45

50

45

60

45

60

45

60

45

60

45

60

45

70

45

70

45

70

45

70

50

70

50

70

50

8 -1 6

70

50

70

50

70

50

Vo2R =oxygen uptake reserve, individ ually calculated fo r participants on the basis o f th e results of the
graded m axim al exercise test. Average heart rate ta rg e t values were 102.4 (S D = 1 1 .7 ) beats per m inu te
(b p m ) fo r 5 0 % Vo2R, 109.5 (S D = 1 3.3) b p m fo r 60% Vo2R, and 115.8 (S D = 1 4 .7 ) bp m fo r 70% V o2R.

Volume 95

Number 2

Physical Therapy

225

S afety o f A e ro b ic Exercise

cise 3 times per week (Tab. 1). The

intensity of the exercise session was
individually prescribed on the basis
of the HR response at the corre
sponding 50% to 70% of oxygen
uptake (Vo2) reserve from the
graded exercise test. The target Vo2
reserve was calculated from the test
with the following formula: [(maxi
mal Vo2 Vo2 at rest) X % intensity]
+ Vo2 at rest.29
The use of Vo2 reserve instead of
Vo2peak to calculate target intensity
does result in a higher workload than
the current guidelines of 50% to 70%
of the maximal HR.15 However, we
found that for most participants, the
HR that corresponded to 50% of
the maximal HR achieved during the
exercise test was too close to the
baseline to be an effective target dur
ing exercise. For a specific illustra
tion, we provide data here for one
participant. At rest, her HR was 64
bpm, and she achieved a maximal
HR of 160 bpm at peak effort (19.6
mL-kg~ '-min- ) during the exercise
test. A target HR of 80 bpm would
have been too close to the baseline
to be effective for exercise; her HR
was more than 80 bpm within the
first 30 seconds of the exercise test.
Therefore, we used the formula
given above to calculate Vo2 re
serve at 50% for this participant
to be: [(19.6 - 3-5 mL-kg_1,min_1)
X 0.5] + 3.5 mL-kg"1-min_1 = 11.55
mL-kg_1-min_1. The corresponding
HR for this participant at this work
load was 105 bpm, which was used
as her initial target for exercise.
Participants had access to a variety of
aerobic training equipment, includ
ing cycle ergometers, treadmills,
recumbent steppers, and elliptical
trainers. Each session began with a 5to 10-minute warm-up, ended with a
5- to 10-minute cool-down, and
included the target HR duration
noted in Table 1.

226

Physical Therapy

Volume 95

Sessions were supervised by licensed

health care professionals or health
care professional students, with no
more than 4 participants per super
visor. Blood glucose level, blood
pressure, HR, and rate of perceived
exertion (RPE) were monitored dur
ing each session. A visual foot exam
ination was performed once each
week to ensure the absence of devel
oping foot ulcers, and participants
were encouraged to inspect their
feet on a daily basis. If individual par
ticipants had difficulty achieving the
target HR during the session, a mod
erate RPE level (11-13 on the
17-point scale)30 was used to indi
cate a comparable work level.31
Participants were not permitted to
exercise if resting blood pressure
was greater than 200 mm Hg (sys
tolic) or greater than 110 mm Hg
(diastolic). Responses to blood glu
cose levels followed recommended
guidelines15:
If hypoglycemic (<100 mg/dL),
carbohydrate snacks were pro
vided, and glucose testing was
repeated.
If hyperglycemic (>300 mg/dL)
and the participant was not taking
insulin, exercise was permitted
with close monitoring of blood glu
cose every 10 to 15 minutes to
ensure that the blood glucose level
did not increase with activity.
If hyperglycemic (>300 mg/dL)
and the participant was taking insu
lin, urine was checked for ketosis.
If the ketone test result was posi
tive, then exercise was postponed.
If the ketone test result was nega
tive, then exercise was permitted
with close monitoring of blood glu
cose every 10 to 15 minutes.
D o c u m e n ta tio n o f AEs

During each study visit, participants

were asked about AEs, including
falls, changes in medical status, or
problems that occurred during study
participation. These events were
classified as either related or unre

Number 2

lated to study procedures; antici

pated (included in consent form) or
unanticipated (not included in con
sent form); and serious (grade 4 of
Common Terminology Criteria for
Adverse Events [CTCAE v3.0])32 or
not serious (grade 1, 2, or 3 of
CTCAE v3.0). A neurologist (M.M.D.)
without financial interest in this proj
ect served as the independent data
and safety monitor for this study.
The number of participants screened
or enrolled, the number of dropouts,
and the number, frequency, and
response to AEs were reviewed by
the data and safety monitor quarterly
during the project.
O u tc o m e s

Assessments were completed at

baseline and after the 16-week
intervention.
F atig u e. The
Multidimensional
Fatigue Inventory is a questionnaire
consisting of 20 statements scored in
5 subscales: general fatigue, physical
fatigue, mental fatigue, reduced
motivation, and reduced activity.33
Reliability and validity were estab
lished in people with cancer and
chronic fatigue syndrome,33-34 and
this instrument was used in previous
studies of fatigue in people with dia
betes.3536 Each item is scored from 1
to 5 (from agreement with the
accompanying statement [yes, that
is true] to disagreement [no, that is
not true]). Total scores can range
from the minimum of 4 to the max
imum of 20, and a higher score indi
cates more fatigue.
C a rd io vascu la r fitness. Peak oxy
gen uptake during the graded exer
cise test was assessed with a meta
bolic cart (TrueOne 2400, Parvo
Medics, Sandy, Utah) and integrated
electrocardiography. A standardized
exercise test protocol with a total
body recumbent stepper (TBRS-XT)
(T5xr, NuStep, Ann Arbor, Michi
gan)37 was administered by an exer
cise physiologist with a medical

February 2015

S afety o f A e ro b ic Exercise

monitor present to monitor the test.

Compared with a standard treadmill
protocol, the TBRS-XT was validated
and found to be reliable in adults
who were healthy.37 The TBRS-XT
consists of 2-minute stages, with
gradually increasing workloads dur
ing the stages (eg, 50 W during stage
1, 75 W during stage 2, and 100 W
during stage 3). Cadence was main
tained at 115 steps per minute
throughout the test.

sure sleep quality with a series of

questions to arrive at a score ranging
from 0 (very good) to 3 (very bad).38
This index was found to be a re
liable and valid measure of sleep
disturbances in a wide range of
people.38-42
Body
c o m p o s itio n . Participants
were scanned with dual-energy x-ray
absorptiometry (Lunar iDXA, GE
Healthcare, a subsidiary of General
Electric, Little Chalfont, Bucking
hamshire, United Kingdom). Out
come measures included total body
fat (percentage), fat mass (grams),
lean mass (grants), visceral fat vol
ume (cubic centimeters), visceral fat
mass (grams), and bone mineral den
sity (g/cm2).

In addition to continuous monitoring

of HR and rhythm during the test,
blood pressure and RPE were mea
sured at the end of each stage (ie,
2-minute intervals) until maximal
effort was achieved. Criteria for a
maximal exercise test included
reaching a plateau in Vo2 with
increased workload, a respiratory P la s m a in s u lin , g lu c o s e , a n d lip id
exchange ratio of greater than or le v e ls . Glycated hemoglobin Ajc
equal to 1.15, a peak HR within 85% (HbAlc) was measured with a dispos
of the age-predicted maximal HR, able fingerstick blood testing kit
and an RPE of greater than or equal (AICNow, Bayer, Whippany, New
to 18.29 The test was stopped before Jersey). After an overnight fast,
maximal effort was achieved if any of blood was drawn for analysis of
the following occurred: angina, dys plasma insulin levels (mU/L), plasma
pnea, fatigue (voluntary exhaustion glucose levels (mrnol/L), and a stan
or inability to maintain a stepping dard lipid profile: total cholesterol,
cadence of >110 steps per minute), high-density lipoprotein, low-density
hypertension (>250 mm Hg systolic lipoprotein, and triglycerides. The
or > 115 mm Hg diastolic), hypoten homeostasis model assessmentsion, or ischemic electrocardiogra insulin resistance index was calcu
phy abnormalities.
lated from values for fasting plasma
insulin (rnU/L) and fasting plasma
The same exercise physiologist glucose (mmol/L) with the following
administered tests both before and equation: [fasting plasma insulin
after the intervention and used stan (mU/L) X fasting plasma glucose
dardized procedures to minimize (mmol/L)]/22.5. Compared with the
bias (timed encouragement scripts, gold standardthe hyperinsulinemicno review of preintervention test euglycemic clamp methodthe
results
before
postintervention homeostasis model assessment for
tests). The Vo2peak (mL-kg-1- insulin resistance was found to be a
min ') obtained from these tests well-validated index of insulin
was used as an outcome measure resistance.43
and to calculate a moderate intensity
(50%-70% of Vo2 reserve) for the aer P e r ip h e r a l
v a s c u la r
fu n c tio n .
obic training program as described Flow-mediated dilation (FMD) in the
previously.
brachial artery was assessed after an
overnight fast with previously
S le e p
q u a lity . The
Pittsburgh described methods.44 Participants
Sleep Quality Index was used to mea were asked to refrain from food or
February 20 15

caffeine for 12 hours and vigorous

activity for 24 hours before the FMD
procedure. Participants rested in the
supine position for 20 minutes
before the FMD procedure at a con
trolled temperature (22C-24C). An
automated cuff with a rapid inflation
system (DE Hokanson, Bellevue,
Washington) was placed just distal to
the olecranon process.4546 Once a
satisfactory image of the brachial
artery was obtained, the transducer
was stabilized with a customdesigned holder. Because we per
formed repeated scans, the location
of the transducer was marked, and
measurements from the olecranon
process (reference point) were
recorded to ensure identical loca
tion. Baseline diameter and blood
flow velocity^ were recorded contin
uously for 60 seconds. Then, the
automated cuff was inflated to 220
mm Hg, and the inflation was main
tained for 5 minutes. Twenty sec
onds before cuff deflation, record
ings of diameter and blood flow
velocity were resumed. At 5 min
utes, the cuff was deflated, and ultra
sound images continued to be
recorded for another 3 minutes. All
images were stored on a computer
and analyzed offline with specialized
software (Brachial Analyzer, Medical
Imaging Applications, Coralville,
Iowa) and an automated mathemati
cal algorithm to determine the peak
FMD.
D a ta M a n a g e m e n t

Case report forms for this project

were developed on the basis of gen
eral common data element forms
developed for neuromuscular dis
ease by the National Institutes of
Health.47 Data from these forms
were entered into a spreadsheet
(Microsoft Excel 2010, Microsoft
Corp, Redmond, Washington). A
100% quality audit was performed by
the study team after the completion
of data collection to ensure the accu
racy of data entry.

V o lu m e 95

Num ber 2

Physical T h era py

227

S a fety o f A e ro b ic Exercise
D a ta Analysis

F igure 1.
Consolidated Standards of Reporting Trials (CONSORT) diagram.

T a b le 2.
Participant Characteristics (N = 18)
C h a r a c t e r is t ic

V a lu e

A g e , y, X (S D )

58.1 (5 )

Sex ( w o m e n /m e n )

1 3 /5

Race o r e th n ic ity
N o n -H is p a n ic w h ite

N o n -H is p a n ic b la c k

H isp a n ic

D u ra tio n o f d ia b e te s , y , X (S D )

15.1 (6 .5 )

D u ra tio n o f n e u ro p a th y , y, X (SD )

6 .5 (4 )

R esting h e a rt ra te , b p m , X (SD )

74 (9 .2 )

R esting sys to lic b lo o d pressure, m m H g , X (SD )

R esting d ia s to lic b lo o d pressure, m m H g , X (S D )

1 2 7 .5 (1 3 .7 )
74 (9 .3 )

S m oke r
Yes

No

16

The frequency of AEs was deter

mined for each participant and for all
participants for each week of the
intervention. No power analysis was
completed for this study because it
was an exploratory preliminary
study. Data from the spreadsheet
were imported into statistics soft
ware (IBM SPSS v20, IBM Corp,
Armonk, New York) for analysis, and
the alpha level was set at .05 for all
statistical analyses. For each of the
outcome measures, descriptive sta
tistics (mean and standard deviation)
were calculated, with identification
of outliers. Normal distribution was
confirmed through the KolmogorovSmirnov z statistic. Outcome mea
sures obtained before the interven
tion were compared with those
obtained after the intervention by
use of a 2-tailed paired t test. For
significant findings, the 95% confi
dence interval of the difference was
also calculated. Additional analyses
included comparison of participants
who completed greater than 80% of
the exercise sessions with those who
completed less than 80% of the exer
cise sessions by use of an indepen
dent t test and determination of
associations between exercise atten
dance and changes in outcomes by
use of the Pearson (r) correlation
coefficient.

T a k in g d a ily in s u lin

Role o f th e F u n d in g Source
Yes

11

No

T a k in g b e ta -b lo c k e r
Yes

No

12

A u to n o m ic s y m p to m s 6
Yes

No

15

T o ta l n e u ro p a th y score, X (SD )

1 1 .4 (5 .9 )

S ural n e rve response

Yes

No

Values are re p o rte d as n u m b e rs o f p a rtic ip a n ts , unless o th e rw is e in d ic a te d . b p m = b e a ts p e r m in u te .

6 For a u to n o m ic s y m p to m s , "y e s " w as re c o rd e d if th e p a rtic ip a n t re p o rte d th e p re sence o f an
a u to n o m ic s y m p to m (e g , fa in tin g , im p o te n c e , c o n s tip a tio n , o r loss o f b la d d e r o r b o w e l c o n tro l).

228

Physical Therapy

Volume 95

Number 2

This work was supported by Clinical

and Translational Science Award
(CTSA) program grants from the
National Center for Advancing Trans
lational Sciences (NCATS), awarded
to the University of Kansas Medical
Center for Frontiers: The Heart
land Institute for Clinical and Trans
lational Research UL1TR000001 and
TL1TR000120 (for M.Y.). Support
also was provided by grants
T32HD057850 (for L.J.D.) and
K01HD067318 (for S.A.B.) from the
Eunice Kennedy Shriver National
Institute of Child Health and Human
Development. The content is solely
February 2015

S afety o f A e ro b ic Exercise

the responsibility of the authors and

does not necessarily represent the
official views of the Eunice Kennedy
Shriver National Institute of Child
Health and Human Development,
NCATS, or the National Institutes of
Health.
Results
The numbers of participants who
consented, enrolled, and completed
the study are shown in the Consoli
dated Standards of Reporting Trials
(CONSORT) diagram (Fig. 1). Screen
failures after consent were second
ary to exclusion criteria (n=3),
uncontrolled hyperglycemia (n = l;
referred to a physician for follow
up), or difficulty with the exercise
test (n=3; 2 participants had angina
and ST segment depression during
the cool-down phase of the exercise
test, and all 3 participants were
referred to a physician for follow-up
and were not enrolled in the study).
After enrollment, 2 participants
withdrew1 before starting the
intervention secondary to a new
open wound that required hospital
ization and 1 voluntary withdrawal
after starting the intervention
because of knee pain.
Participant demographics and medi
cal information are shown in Table 2.
Although dose and type of medica
tion may have changed during the
study, only one participant reported
stopping or starting a medication
from using insulin at the beginning
of the study to not using insulin at
the end of the study. On the basis of
standard criteria,28 DPN was identi
fied as confirmed in the majority of
participants (n=12; 66.7%), proba
ble in 4 participants (22%), and pos
sible in 2 participants (11%).
Attendance at the 48 scheduled exer
cise sessions was 67.8% (SD=19.9%,
range=33-3%-93.8%). On several
occasions, participants missed the
scheduled supervised sessions and
reported exercising at home instead.
February 20 15

1
11

__________________

1
1 T
T
i t IJ I t t
.

_______________________________

Till
1

10

11

12

13

14

15

16

W eek o f Exercise

Figure 2.
Frequency h isto g ra m o f exercise-related adverse events th a t req u ire d in te rv e n tio n
d u rin g each w eek o f th e 16 -w eek exercise p ro g ra m .

Inclusion of the home exercise ses

sions increased the mean exercise
adherence to 76.6% (SD=l6.5%,
range=33.3%-95.8%).
Summary of AEs

No serious AEs occurred in enrolled

participants as a result of the study
procedures, and no unanticipated
AEs occurred as a result of the study
procedures. A total of 57 grade 2 AEs
(clinical symptoms that required
minimal, noninvasive intervention)
occurred in the 18 participants dur

ing the 16-week study intervention.

A frequency distribution of these
events is shown in Figure 2. Slightly
more than half of the events (56%)
occurred in the first 8 weeks of the
16-week exercise program.
The following anticipated AEs
occurred and were attributed to
study participation (percentages of
participants are shown in Fig. 3):
Joint or muscle pain that affected
exercise duration or attendance

80
70

Joint/Muscle Pain Hypoglycemia

Hyperglycemia

Angina

Cold/Flu

Figure 3.
Frequency h isto g ra m o f th e percentages o f p a rticip a n ts re p o rtin g various types o f
adverse events.

V o lu m e 95

Num ber 2

Physical T h e ra p y

229

Safety of Aerobic Exercise

Table 3.
Outcome Measures Before and After the Exercise Intervention 0
X (S D )
O u tc o m e
P rim a ry

M e a s u re

1 6 .2 (3 .6 )

1 7 .3 (4 .0 )

.0 1 7 b

1 5 .7 ( 2 .3 )

1 2 .2 (4 .2 )

,0 0 4 b

Physical fa tig u e , M F I-2 0

1 5 .5 (2 .4 )

1 2 .4 (3 .7 )

,0 0 3 b

M e n ta l fa tig u e , M F I-2 0

1 0 .6 5 (3 .6 )

9 .5 9 (3 .7 )

.2 2 9

11 (3 .7 )

1 0 .4 (3 .2 )

.5 6 4

H b A lc , %
In s u lin , m t l/ L
G luco se, m m o l/L

1 4 (3 .2 )

1 1 .8 (4 .6 )

.0 7 8

7 .6 5 (1 .9 2 )

7 .7 6 (1 .7 4 )

.5 4 5

4 2 .7 7 (5 7 .2 )

4 3 .7 6 (6 7 .5 )

.8 4 9

1 7 6 .8 (9 0 )

1 6 5 .4 ( 7 0 .6 )

.6 1 8

In s u lin resistance, H O M A -IR

2 .4 4 (4 .2 5 )

1 .5 3 (1 .6 5 )

.2 6 3

T o ta l c h o le s te ro l

1 7 3 .4 (4 3 .2 )

1 8 3 .7 6 (5 0 .5 )

.1 0 9

H D L c h o le s te ro l

4 1 .6 5 (1 1 .8 )

4 4 (1 5 )

.0 7 8

LD L c h o le s te ro l

1 0 2 .8 8 (2 8 .2 2 )

1 0 8 .0 6 (3 0 .5 3 )

.3 0 6

1 7 1 .7 6 (1 2 3 )

1 8 8 .5 9 (1 9 0 .7 9 )

.4 2 2

T rig ly c e rid e s

O th e r

G e n era l fa tig u e , M F I-2 0

R educed a c tiv ity , M F I-2 0

B o d y c o m p o s itio n

A f t e r In t e r v e n t i o n

V o 2peak, m L - k g ^ '- m in - '

R educed m o tiv a tio n , M F I-2 0

Plasma

B e fo r e In t e r v e n t i o n

B M I, k g / m 2

3 5 .8 4 (5 .2 1 )

3 5 .1 9 (5 .3 8 )

.0 4 7 '

T o ta l b o d y fa t, %

4 4 .7 9 (6 .6 2 )

4 3 .7 9 (6 .6 4 )

.0 0 8 '

Fat mass, g

4 3 ,1 4 2 (1 3 ,2 3 6 .1 )

4 1 ,3 6 2 .6 ( 1 2 ,4 8 5 .5 )

.0 0 5 '

Lean mass, g

5 1 ,8 2 9 .7 (9 ,7 2 3 )

5 1 ,8 7 9 .5 ( 1 0 ,1 1 7 .4 )

.8 9 0

V isceral fa t v o lu m e , c m 3

2 ,6 9 0 .6 ( 1 ,5 3 7 .2 )

2 ,5 5 7 .6 (1 ,4 8 2 .9 )

.0 5 3

V isceral fa t mass, g

2 ,5 3 8 .2 (1 ,4 5 0 .2 )

2 ,4 1 5 .7 ( 1 ,3 9 7 .7 )

.061

B one d e n s ity , g / c m 2

1 .2 3 (0 .1 8 )

1 .2 3 ( 0 .1 8 )

.5 2 4

F lo w -m e d ia te d d ila tio n , %

4 .9 2 (3 .7 )

7 .1 9 (4 .3 9 )

.0 1 2 b

Sleep q u a lity , PSQI

9 .9 4 (4 .3 )

9 .0 6 (4 .5 )

.2 9 5

V o 2p e a k = p e a k o x y g e n u p ta k e d u r in g a g ra d e d exe rcise te s t, M F I-2 0 = M u ltid im e n s io n a l F a tig u e In v e n to ry , H b A ,c= g ly c a te d h e m o g lo b in A 1c, H O M A IR = h o m e o sta sis m o d e l a s s e s s m e n t-in s u lin resistance in d e x , H D L = h ig h -d e n s ity lip o p ro te in , L D L = lo w - d e n s ity lip o p ro te in , B M I = b o d y mass in d e x ,
PSQI = P itts b u rg h Sleep Q u a lity In d e x .
b P s . 0 5 , as d e te rm in e d w it h a 2 -ta ile d p a ire d t test.

Significant hypoglycemia (blood

glucose level of <70 mg/dL)
Chest pain and shortness of breath
(occurred in one participant during
peak effort in the final graded exer
cise test of the postintervention
testing session; no electrocardiog
raphy changes were noted; the par
ticipant was referred to a cardiolo
gist, but no cardiac diagnosis was
identified)

Other AEs that were not related to

the study procedures but that did
affect participation in exercise
occurred. For example, significant
hyperglycemia (blood glucose level
of >300 mg/dL) was not caused by

230

P h y s ic a l T h e r a p y

V o lu m e 9 5

exercise but resulted in close moni

toring during exercise for safety, and
cold or flu symptoms occasionally
caused cancellation of exercise ses
sions. One participant developed a
foot ulcer after wearing new shoes in
the community (not during study
exercise), and a wound care special
ist approved continued, non-weightbearing exercise in a recumbent
stepper with an offloading boot. Sev
eral other issues were noted by the
study team and resulted in a physi
cian referral; these included signifi
cant foot swelling (n = l), hypergly
cemia with a positive urine ketone

Num ber 2

test result (n = l), and significant

hypertension at rest (n= 1).
Changes in Outcomes

A comparison of means before and

after the intervention is shown in
Table 3- Missing data occurred for a
variety of reasons:
General fatigue (n=17): 1 missing
data point because of an incom
plete form
Vo,peak (n= l6): 2 missing data
points because final tests were not
completed due to illness
Sleep quality (n= l6): 2 missing
data points because of incomplete
forms

F e b ru a ry 2 0 1 5

S afety o f A e ro b ic Exercise

Bone density (n=17): 1 missing

data point because of report error
Plasma analysis (n= 16): 2 missing
insulin results and 1 missing all
plasma results because of labora
tory errors
FMD (n=17): 1 missing data point
because the test was not completed

Significant improvements were

found in the following outcomes
(with 95% confidence intervals
for changes): general fatigue (95%
CI= 1.3,
-5.3),
physical fa
tigue (95% CI= 1.2, -5.0), Vo2
peak (95% 0 = 0 .2 , 1.9), total body
fat (95% C I= 0.3, -1.7), fat mass
(95% 0 = - 6 1 6 .2 , -2,938.7), and
peripheral blood flow (95% 0 = 0 .6 ,
4.0). No significant changes were
noted in the other outcome
measures.
A comparison of changes in primary
outcomes between participants who
completed less than 80% of the exer
cise sessions (n=10) and those who
completed greater than 80% of the
exercise sessions (n=8) revealed a
significant difference between the
groups for both Vo2peak and general
fatigue. A significant correlation was
noted between a change in general
fatigue and percentage of exercise
sessions attended (r= .72, P=.01),
as shown in the eFigure (available at
ptjournal.apta.org), but not between
a change in Vo2peak and percentage
of exercise sessions attended (r=. 3,
P=.253).
D is c u s s io n

The present study demonstrated that

a moderate-intensity, 16-week super
vised aerobic exercise intervention
was feasible in people with DPN, in
the sense that 18 of 20 enrolled par
ticipants (90%) completed the study
and no serious AEs occurred as a
result of the study. Our findings are
consistent with those of a systematic
review of 47 randomized controlled
trials of exercise in people with dia
betes: dropout rates of less than 20%

February 2015

and adherence rates of greater than

75%.48 However, a surprising num
ber of minor AEs that required inter
vention from our physical therapist
team occurred throughout the
16-week intervention in the present
study.

The results of the present study sup

ported our hypotheses that aerobic
exercise would improve selfreported fatigue and increase
Vo2peak in people with DPN. These
findings add to a body of emerging
research that has shown promising
effects of exercise on various out
It is possible that the use of the Vo2 comes in people with DPN.18' 22
reserve formula to calculate target However, this exploratory prelimi
HR may have led to an intensity of nary study had significant limita
aerobic exercise that was too high tions, especially the small sample
and that contributed to the high fre size, lack of a control or comparison
quency of AEs. However, the target group, and multiple dependent vari
HR was used as a goal to work ables, which may increase the type I
toward rather than a minimum error rate. Although there was a
threshold for effort, and a moderate potential for bias with regard to the
RPE level was used to supplement hypothesized changes because of a
the target HR. As AEs were highest lack of masking and participant
upon initiation of the exercise pro expectations for change, several of
gram and during progression from the outcome measures (eg, Vo2peak,
50% to 70% of Vo2 reserve, it is pos body composition, and plasma mea
sible that increases in session inten sures) were obtained by people who
sity and duration may have been too were not part of the study team, and
fast. Although the progression of standardized procedures were used
exercise was consistent with pub for all tests to minimize bias.
lished recommendations for people
with diabetes,31 a slower progres Despite these limitations, to our
sion may have been more tolerable knowledge the present study is the
for the participants, who were sed first to report the effects of exercise
entary and had low aerobic fitness. on fatigue outcomes in people with
Only a small number of previous DPN. Improvements in self-reported
studies on exercise in people with fatigue were found for the general
diabetes reported nonserious AEs, and physical fatigue subscales but
but those that were reported most not for the measures of mental
commonly included hypoglycemia, fatigue, motivation, or activity. At
cardiovascular events, and musculo baseline, the values for general and
skeletal injuries.48-49
physical fatigue in our participants
(15.7 and 15.5, respectively) were
The data raise a concern for people higher than those previously
who may be exercising at home reported (12-12.7) in people with
without supervision and may not diabetes,36-51 perhaps reflecting the
consistently check their blood glu influence of neuropathy in our par
cose or blood pressure. Complaints ticipants. The changes in these out
of joint or muscle pain were also comes in our participants after exer
common barriers to exercise adher cise ( 3-5 and 3-1, respectively)
ence and were not necessarily neu not only were statistically significant
ropathic in origin. Delayed-onset but also were above the minimal
muscle soreness is common after the clinically important differences
initiation of a new exercise regi (2.0-2.1) established for these mea
men,50 but the complaints occurred sures in people with cancer-related
throughout the 16-week interven fatigue.34
tion in the present study.

Volume 95

Num ber 2

Physical Therapy

231

S afety o f A e ro b ic Exercise

At baseline, the participants in the

present study had Vo2peak values
well below the very poor thresh
old of 19-3 mL,kg~1-min_1, indicat
ing that they were less fit than the
lowest 1% of people who were 50 to
59 years old.29 Maximum Vo2 levels
below the 20th percentile are asso
ciated with an increased risk of death
from all causes, indicating that our
participants were at high risk if they
did not improve their fitness.29
These extremely low values may
reflect the difference between
Vo2peak in the present study and the
comparison maximum Vo2. All of
our participants achieved a respira
tory exchange ratio of greater than
1.0 and an RPE of greater than or
equal to 17 of 20 (indicating very
hard effort) during each exercise
test. However, 15 of the 18 partici
pants (83-3%) did not achieve 85% of
the age-predicted maximal HR dur
ing the baseline and follow-up tests.
Diabetes is known to blunt the HR
response during exercise,29 and the
use of beta-blockers in 6 participants
(33-3%) likely contributed to this
finding, along with fatigue and mus
cle endurance.
Although no other studies have
reported changes in Vo2peak after
exercise specifically in people with
DPN, the effects of exercise in peo
ple with type 2 diabetes have been
extensively studied. A large-scale ran
domized controlled trial in people
with type 2 diabetes showed a
mean increase in Vo2peak of 1.73
nil.-kg '-min 1after 6 months of aer
obic training.8 This change was
greater than that in the present
study, possibly reflecting the longer
duration of the intervention. In other
studies, submaximal tests were used
to estimate aerobic fitness,14'4952
making a comparison of values
difficult.
It was interesting that a significant
relationship was found between a
change in general fatigue and exer
232

Physical Therapy

Volum e 95

cise attendance but not between a

change in aerobic fitness and exer
cise attendance, as would be
expected. Fatigue is a complex con
struct with multiple potential con
tributing factors, including sleep
quality, pain, obesity, and depres
sion.26-53 The increased response of
fatigue to the dose of exercise may
have been due to the cumulative
effects of exercise on these factors
and may reflect motivational influ
ences as well.
We did note significant decreases in
body fat and increases in peripheral
vascular blood flow after the exer
cise intervention. Other studies have
identified peripheral vascular dys
function as an important contributor
to decreased exercise capacity in
people with type 2 diabetes54 55 and
have reported that aerobic exercise
can improve FMD,56-57 but these
parameters were not previously stud
ied or reported specifically in people
with DPN.
The baseline HbAlc values in our par
ticipants indicated that many would
not be considered to have wellcontrolled diabetes, as the average
HbAlc value was above the recom
mended goal of 7%.15 People with
HbAlc values of greater than 7% have
been found to have higher levels of
oxidative stress and inflammatory
markers than people who have dia
betes and HbAlc values of less than
7%.58 The lack of change in FIbAlc in
our participants after exercise was
surprising and inconsistent with a
large body of research on the change
in HbAlc with exercise in people
with diabetes.59 However, this
parameter has not been extensively
studied in people with DPN.
In conclusion, the present study pro
vides new support for improvements
in fatigue, fitness, and several poten
tial contributing factors after a super
vised exercise intervention in people
with DPN. However, a future large-

N um ber 2

scale randomized controlled trial is

needed to fully assess the effects of
exercise on these outcomes. Physi
cal therapists can play an important
role in the prescription of exercise
intensity on the basis of the initial
level of aerobic fitness and may need
to provide close monitoring and edu
cation to address the anticipated AEs
related to glycemic control and mus
culoskeletal pain as people who are
sedentary and have DPN begin an
exercise program.
Dr Kluding, Dr Singh, Ms D'Silva, M r Yoo, Dr
Dimachkie, and Dr W rig h t provided concept/idea/research design. Dr Kluding, M r
Yoo, Dr Billinger, Dr LeMaster, Dr Dim ach
kie, Ms Herbelin, and Dr W rig h t provided
w ritin g . Dr Kluding, Dr Pasnoor, Dr Singh,
Ms D'Silva, M r Yoo, and Dr Billinger pro
vided data collection. Dr Kluding, Ms
D'Silva, M r Yoo, Dr Billinger, Dr LeMaster, Dr
Dimachkie, and Dr W rig h t provided data
analysis. Dr Kluding, Ms D'Silva, M r Yoo, and
Dr W rig h t provided project m anagem ent. Dr
Kluding provided fun d procurem ent, partic
ipants, and institutional liaisons. Dr Kluding,
Dr Billinger, Ms Herbelin, and Dr W rig h t pro
vided facilities/equipm ent. M r Yoo provided
adm inistrative support. Dr Pasnoor, Dr
Singh, Ms D'Silva, Dr Billinger, Dr LeMaster,
Dr Dimachkie, and Dr W rig h t provided con
sultation (including review of the m anuscript
before submission). The authors acknow l
edge the essential contributions of Bill Hen
dry, CES, and the medical m onitors and
nursing staff at the Clinical and Translational
Science U nit fo r exercise testing; |ason-Flor
Sisante fo r vascular scans; Christian Pearson
fo r nerve testing; and Katherine M artin, Gurpreet Singh, Ali Bani-Ahmed, Chelsea Kufahl,
Kayla Lingenfelter, and Sara Nelson for
supervising the exercise sessions and assist
ing w ith data entry and data managem ent.
Institutional review board approval fo r the
project was received from the Human Sub
jects Com m ittee at the University of Kansas
Medical Center.
The prim ary findings were presented as a
poster presentation at the American Diabe
tes Association's 74 Scientific Sessions; June
13-17 , 2014; San Francisco, California. Pre
lim inary results of this project also were pre
sented at the 2014 Com bined Sections
M eeting of the American Physical Therapy
Association; February 4 - 6 , 2014; Las Vegas,
Nevada.

February 2015

S afety o f A e ro b ic Exercise
This w o rk was supported by Clinical and
Translational Science Award (CTSA) pro
gram grants from the National Center for
Advancing Translational Sciences (NCATS),
awarded to the University of Kansas Medical
Center fo r Frontiers: The Heartland Institute
fo r Clinical and Translational Research
UL1TR000001
and
TL1TR000120
(for
M.Y.). Support also was provided by
grants T32H D057850 (for L.J.D.) and
KOI H D 067318 (for S.A.B.) from the Eunice
Kennedy Shriver National Institute o f Child
Health and Human Developm ent. The con
te n t is solely the responsibility of the authors
and does n o t necessarily represent the o ffi
cial views of the Eunice Kennedy Shriver
National Institute o f Child Health and
Human Developm ent, NCATS, or the
National Institutes of Health.
ClinicalTrials.gov
NC T01764373.

trial

registration:

DOI: 10 .2 5 2 2 /p tj.2 0 1 40108

R eferences
1 Pasnoor M, Dimachkie M, Kluding P,
Barohn RJ. Diabetic neuropathy, part 1:
overview and symmetric phenotypes.
Neurol Clin. 2013;31:425-445.
2 Richardson JK. Factors associated with
falls in older patients with diffuse polyneu
ropathy./A m Geriatr Soc. 2002;50:17671773.
3 Thurman D, Stevens J, Rao J. Practice
parameter: assessing patients in a neurol
ogy practice for risk of falls (an evidencebased review). Neurology. 2008:70:473479.
4 Mueller MJ, Minor SD, Sahrmann SA, et al.
Differences in the gait characteristics of
patients with diabetes and peripheral neu
ropathy compared with age-matched con
trols. Phys Ther. 1994;74:299-308.
5 Simoneau GG, Ulbrecht JS, Derr JA, et al.
Postural instability in patients with dia
betic sensory neuropathy. Diabetes Care.
1994;17:1411-1421.
6 van Sloten TT, Savelberg HH, DuimelPeeters IG, et al. Peripheral neuropathy,
decreased muscle strength and obesity are
strongly associated with walking in per
sons with type 2 diabetes without mani
fest mobility limitations. Diabetes Res Clin
Pract. 2011;91:32-39.
7 Boule NG, Haddad E, Kenny GP, et al.
Effect of exercise on glycemic control and
body mass in type 2 diabetes mellitus: a
meta-analysis of controlled clinical trials.
JAMA. 2001;286:1218-1227.

10 Davidson LE, Hudson R, Kilpatrick K, et al.

Effects of exercise modality on insulin
resistance and functional limitation in
older adults: a randomized controlled trial.
Arch Intern Med. 2009;169:122-131.
11 Knauf MT, Koltyn KF. Exercise-induced
modulation of pain in adults with and
without painful diabetic neuropathy. J
Pain. 2014;15:656-663.
12 American Diabetes Association. Standards
of medical care in diabetes2008. Diabe
tes Care. 2008;31(suppl 1):S12-S54.
13 American Diabetes Association. Standards
of medical care in diabetes2010. Diabe
tes Care. 2010;33(suppl l):S ll-S 6 l.
14 LeMaster JW, Mueller MJ, Reiber GE, et al.
Effect of weight-bearing activity on foot
ulcer incidence in people with diabetic
peripheral neuropathy: Feet First random
ized controlled trial. Phys Ther. 2008:88:
1385-1398.
15 American Diabetes Association. Standards
of medical care in diabetes2014. Diabe
tes Care. 20l4;37(suppl 1):S14-S80.
16 Colberg SR, Sigal RJ, Fernhall B, et al. Exer
cise and type 2 diabetes: the American
College of Sports Medicine and the Amer
ican Diabetes Association joint position
statement. Diabetes Care. 2010;33:147167.
17 Mueller MJ, Tuttle LJ, LeMaster JW, et al.
Weight-bearing versus nonweight-bearing
exercise for persons with diabetes and
peripheral neuropathy: a randomized con
trolled trial. Arch Phys Med Rehabtt. 2013;
94:829-838.
18 Kluding P, Pasnoor M, Singh R, et al. The
effect of exercise on neuropathic symp
toms, nerve function, and cutaneous
innervation in people with diabetic
peripheral neuropathy. J Diabetes Com
plications. 2012;26:424-42919 Smith AG, Russell JW, Feldman EL, et al.
Lifestyle intervention for pre-diabetic neu
ropathy. Diabetes Care. 2006;29:12941299.
20 Song C, Petrofsky J, Lee S, et al. Effects of
an exercise program on balance and trunk
proprioception in older adults with dia
betic neuropathies. Diabetes Technol
Ther. 2011; 13:803-811.
21 Richardson JK, Sandman D, Vela
focused exercise regimen improves
cal measures of balance in patients
peripheral neuropathy. Arch Phys
Rehabil. 2001;82:205-209.

S. A
clini
with
Med

22 Allet L, Arrnand S, De Bie R, et al. The gait

and balance of patients with diabetes can
be improved: a randomised controlled tri
al. Diabetologia. 2010:53:458-466.

8 LaroseJ, Sigal RJ, Boule NG, et al. Effect of

exercise training on physical fitness in
type II diabetes mellitus. Med Sci Sports
Exerc. 2010;42:1439-1447.

23 Kruse RL, LeMaster JW, Madsen RW. Fall

and balance outcomes after an interven
tion to promote leg strength, balance, and
walking in people with diabetic peripheral
neuropathy: Feet First" randomized con
trolled trial. Phys Ther. 2010;90:15681579.

9 Sigal RJ, Kenny GP, Boule NG, et al. Effects

of aerobic training, resistance training, or
both on glycemic control in type 2 diabe
tes: a randomized trial. A nn Intern Med.
2007;147:357-369.

24 Sudore RL, Karter AJ, Huang ES, et al.

Symptom burden of adults with type 2
diabetes across the disease course: Diabe
tes & Aging Study. J Gen Intern Med.
2012;27:1674-1681.

February 2015

25 Singh R, Kluding P. Fatigue and related

factors in people with type 2 diabetes.
Diabetes Educ. 2013;39:320-326.
26 Tseng BY, Billinger SA, Gajewski BJ, Klud
ing PM. Exertion fatigue and chronic
fatigue are two distinct constructs in peo
ple post-stroke. Stroke. 2010:41:29082912.
27 Mayer CJ, Steinman L, Williams B, et al.
Developing a Telephone Assessment of
Physical Activity (TAPA) questionnaire for
older adults. Prev Chronic Dis. 2008;5:
A24.
28 Dyck PJ, Albers JW, Andersen H, et al. Dia
betic polyneuropathies: update on
research definition, diagnostic criteria and
estimation of severity. Diabetes Metab Res
Ret. 2011;27:620-628.
29 American College of Sports Medicine.
ACSMs Guidelines fo r Exercise Testing
and Prescription. 8th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2010.
30 Chen MJ, Fan X, Moe ST. Criterion-related
validity of the Borg ratings of perceived
exertion scale in healthy individuals: a
meta-analysis. J Sports Sci. 2002;20:873899.
31 Colberg SR, Sigal RJ. Prescribing exercise
for individuals with type 2 diabetes: rec
ommendations and precautions. Phys
Sportsmed. 2011;39:13-26.
32 Common Terminology Criteria for
Adverse Events v3.0 (CTCAE). Published
August 9, 2006. Available at: h ttp ://
ctep.cancer.gov/protocolD evelopm ent/
electronic_applications/docs/ctcaev3.pdf.
Accessed October 10, 2014.
33 Smets EM, Garssen B, Bonke B, De Haes
JC. The Multidimensional Fatigue Inven
tory (MFI) psychometric qualities of an
instrument to assess fatigue. J Psychosom
Res. 1995;39:315-325.
34 Purcell A, Fleming J, Bennett S, et al.
Determining the minimal clinically impor
tant difference criteria for the Multidimen
sional Fatigue Inventory in a radiotherapy
population. Support Care Cancer. 2010;
18:307-315.
35 Lasselin J, Laye S, BarreauJB, et al. Fatigue
and cognitive symptoms in patients with
diabetes: relationship with disease pheno
type and insulin treatment. Psychoneu
roendocrinology. 2012;37:1468-1478.
36 Lasselin J. Laye S, Dexpert S, et al. Fatigue
symptoms relate to systemic inflammation
in patients with type 2 diabetes. Brain
Behav Im m un. 2012;26:1211 -1219.
37 Billinger SA, Loudon JK, Gajewski BJ.
Validity of a total body recumbent stepper
exercise test to assess cardiorespiratory fit
n ess./ Strength Cond Res. 2008;22:15561562.
38 Buysse DJ, Reynolds CF III, Monk TH, et al.
The Pittsburgh Sleep Quality Index: a new
instrument for psychiatric practice and
research. Psychiatr Res. 1989;28:193-213.
39 Buysse DJ, Yu L, Moul DE, et al. Develop
ment and validation of patient-reported
outcome measures for sleep disturbance
and sleep-related impairments. Sleep.
2010;33:781-792.

Volum e 95

Num ber 2

Physical Therapy

233

S afety o f A e ro b ic Exercise
40 Cole JC, Motivala SJ, Buysse DJ, et al. Val
idation of a 3-factor scoring model for the
Pittsburgh Sleep Quality Index in older
adults. Sleep. 2006;29:112-116.
41 Nishiyama T, Mizuno T, Kojirna M, et al.
Criterion validity of the Pittsburgh Sleep
Quality Index and Epworth Sleepiness
Scale for the diagnosis of sleep disorders.
Sleep Med. 2014;15:422-429.
42 Spira AP, Beaudreau SA, Stone KL, et al.
Reliability and validity' of the Pittsburgh
Sleep Quality Index and the Epworth
Sleepiness Scale in older men. J Gerontol
A Biol Sci Med Sci. 2012;67:433-439.
43 Sarafidis PA, Lasaridis AN, Nilsson PM,
et al. Validity and reproducibility of
HOMA-IR, 1/HOMA-IR, QUICKI and McAuleys indices in patients with hypertension
and type II diabetes. J H um Hypertens.
2007;21:709-716.
44 Billinger SA, Mattlage AE, Ashenden AL,
et al. Aerobic exercise in subacute stroke
improves cardiovascular health and phys
ical performance. J Neurol Phys Ther.
2012;36:159-165.
45 Corretti MC, Anderson TJ, Benjamin EJ,
et al. Guidelines for the ultrasound assess
ment of endothelial-dependent flowmediated vasodilation of the brachial
artery: a report of the International Bra
chial Artery Reactivity Task Force. J Am
Coll Cardiol. 2002;39:257-265.
46 Thijssen DH, Black M, Pyke KE, et al.
Assessment of flow-mediated dilation in
humans: a methodological and physiolog
ical guideline. Am J Physiol Heart Circ
Physiol. 2011;300:H2-H12.

234

Physical T h e ra p y

V o lu m e 95

47 National Institutes of Health. Neuromuscu

lar diseases. NINDS Common Data Ele
ments Web site. 2014. Available at: http://
w w w .com m ondataelem ents.ninds.nih.
gov/N M D .aspx#tab = D ata_Standards.
Accessed October 10, 2014.
48 Umpierre D, Ribeiro PA, Kramer CK, et al.
Physical activity advice only or structured
exercise training and association with
HbAlc levels in type 2 diabetes: a system
atic review and meta-analysis./W A 2011;
305:1790-1799.
49 Herbert RD, de Noronha M, Kamper SJ.
Stretching to prevent or reduce muscle
soreness after exercise. Cochrane Data
base Syst Rev. 2011;7:CD004577.
50 Balducci S, Zanuso S, Cardelli P, et al.
Effect of high- versus low-intensity super
vised aerobic and resistance training on
modifiable cardiovascular risk factors in
type 2 diabetes: the Italian Diabetes and
Exercise Study ODES). PLoS One. 2012;7:
E49297.
51 Fritschi C, Quinn L, Hacker ED, et al.
Fatigue in women with type 2 diabetes.
Diabetes Educ. 2012;38:662-672.
52 Balducci S, Zanuso S, Cardelli P, et al.
Changes in physical fitness predict
improvements in modifiable cardiovascu
lar risk factors independently of body
weight loss in subjects with type 2 diabe
tes participating in the Italian Diabetes and
Exercise Study ODES). Diabetes Care.
2012;35:1347-1354.

54 Reusch JE, Bridenstine M, Regensteiner

JG. Type 2 diabetes mellitus and exercise
impairment. Rev Endocr Metab Disord.
2013;14:77-86.
55 Bauer TA, Reusch JE, Levi M. Regensteiner
JG. Skeletal muscle deoxygenation after
the onset of moderate exercise suggests
slowed microvascular blood flow kinetics
in type 2 diabetes. Diabetes Care. 2007;
30:2880-2885.
56 Kwon HR, Min KW, Alin HJ, et al. Effects
of aerobic exercise vs. resistance training
on endothelial function in women with
type 2 diabetes mellitus. Diabetes Metab J.
2011;35:364-373.
57 Maiorana A, O'Driscoll G, Cheetham C,
et al. The effect of combined aerobic and
resistance exercise training on vascular
function in type 2 d iabetes./Am Coll Car
diol. 2001;38:860-866.
58 Gohel MG, Chacko AN. Serum GGT activ
ity and hsCRP level in patients with type 2
diabetes mellitus with good and poor glycemic control: an evidence linking oxida
tive stress, inflammation and glycemic
control. J Diabetes Metab Disord. 2013;
12:56.
59 Thomas DE, Elliott EJ, Naughton GA. Exer
cise for type 2 diabetes mellitus. Cochrane
Database Syst Rev. 2006;3:CD002968.

53 Schmidt ME, Chang-Claude J, Seibold P,

et al. Determinants of long-term fatigue in
breast cancer survivors: results of a pro
spective patient cohort study. Psychoon
cology. 2014 May 17 [Epub ahead of
print], doi: 10.1002/pon.3581.

Num ber 2

February 2 0 1 5

Copyright of Physical Therapy is the property of American Physical Therapy Association and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.