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The Association Between Diabetic Complications and Exercise Capacity in

NIDDM Patients

Article  in  Diabetes Care · February 1998

DOI: 10.2337/diacare.21.2.291 · Source: PubMed

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Pathophysiology/Complications
N A L A R T I C L E

The Association Between Diabetic

Complications and Exercise Capacity in
NIDDM Patients
RAYMOND O. ESTACIO, MD BARRETT JEFFERS, PHD peripheral vascular disease in this popula-
JUDITH G. REGENSTEINER, PHD MATTHEW DICKENSON, MD tion, with the leading cause of mortality
EUGENE E. WOLFEL, MD ROBERT W. SCHRIER, MD
being cardiovascular disease (3,4). These
end-organ complications not only influence
morbidity and mortality but also may have
a major impact on the diabetic patients abil-
ity to perform normal daily activities.
OBJECTIVE — Exercise capacity has been used as a noninvasive parameter for predicting A number of studies in nondiabetic
cardiovascular events. It has been demonstrated previously in NIDDM patients that several risk
populations have evaluated the association
factors (i.e., obesity, smoking, hypertension, and African-American race) are associated with
an impaired exercise capacity. We studied 265 male and 154 female NIDDM patients who between exercise capacity and cardiovas-
underwent graded exercise testing with expired gas analyses to determine the possible influ- cular disease. Studies involving healthy
ences of diabetic neuropathy, nephropathy, and retinopathy on exercise capacity. populations (5,6), patients with coronary
artery disease (7), and patients with con-
RESEARCH DESIGN A N D METHODS — Univariate and multiple linear regression gestive heart failure (8) have revealed that a
analyses were performed to determine the relationship between diabetic neuropathy, urinary decrease in exercise capacity was associated
albumin excretion (UAE), and retinopathy with respect to peak oxygen consumption (Vo2). with future cardiac events in those popula-
Neuropathy was assessed by neurological symptom and disability scores, autonomic function tions. Previous studies on exercise capacity
testing, and quantitative sensory exams involving thermal and vibratory sensation. Three cat- involving NIDDM patients have included
egories of UAE were used: normal albuminuria (<20 ug/min), microalbuminuria (20-200
ug/min), and overt albuminuria (>200 ug/min). Retinopathy was assessed by stereoscopic fun-
only a small number of subjects, with the
dus photographs. Multiple linear regression analyses were then performed controlling for age, vast majority involving only male subjects
sex, length of diagnosed diabetes, duration of hypertension, race and ethnicity, GHb, BMI, and (9,10). Regensteiner et al. (10) demon-
smoking to determine whether there was an independent effect of these diabetic complications strated that male and female NIDDM
on exercise capacity. patients, in the absence of known compli-
cations, have a reduced exercise capacity
RESULTS — Univariate analyses revealed that the presence of diabetic retinopathy (P = compared with age- and activity-matched
0.03), neuropathy (P = 0.002), microalbuminuria (P = 0.04), and overt albuminuria (P = 0.06) normal subjects. Rubier et al. (11) also
were associated with a lower peak Vo2. Multiple linear regression analyses were performed to observed that a decrease in exercise per-
determine independent relationships with peak Vo2. The results revealed that increasing formance may signal coronary artery dis-
retinopathy stage (Parameter estimate [PE] = —0.59 ± 0.3 ml • kg" 1 • min"1; P = 0.026) and ease in NIDDM patients. Previously we
increasing UAE stage (PE = —0.62 ± 0.3 ml kg" 1 • min"1; P = 0.044) were associated with a described various risk factors that inde-
decrease in peak Vo2.
pendently impacted exercise capacity in an
CONCLUSIONS— In the present study of NIDDM subjects, a significant independent NIDDM population (12). These risk factors
association was demonstrated between diabetic nephropathy and retinopathy with exercise included African-American race, age, sex,
capacity. These results were obtained controlling for age, sex, length of diagnosed diabetes, BMI, systolic blood pressure, and number
hypertension, race, and BMI. Thus the findings in this large NIDDM population without a his- of pack-years having smoked. The rela-
tory of coronary artery disease indicate a potential pathogenic relationship between microvas- tionship between diabetic complications
cular disease and exercise capacity. and exercise capacity in NIDDM patients
has not been well delineated.
In the present study, we examined the

N
IDDM accounts for 90% of diabetic cations that are associated with significant hypothesis that certain microvascular com-
cases in the U.S. (1) and is responsible morbidity and mortality. Complications plications of NIDDM are associated with
for greater than $90 billion of health specific to diabetes include retinopathy, impairment in exercise capacity. The study
care costs today (2). It is a disease accom- nephropathy and neuropathy There is also was conducted with 265 male and 154
panied by characteristic long-term compli- an increased prevalence of cardiac and female NIDDM patients who underwent a
screening exercise test for the Appropriate
From the Divisions of General Internal Medicine (R.O.E., J.G.R) and Cardiology (E.E.W), the Internal Med- Blood Pressure Control in Diabetes (ABCD)
icine Residency Program (M.D.), and the Division of Renal Diseases and Hypertension (B.J., R.WS.), Depart- Trial (13) to determine if complications
ment of Medicine, Denver Health and University of Colorado Health Sciences Center, Denver, Colorado. specific to diabetes are related to impaired
Address correspondence and reprint requests to Robert W Schrier, MD, Division of Renal Diseases and exercise capacity. The population study had
Hypertension, Department of Medicine, 4200 East Ninth Ave., B178, Denver, CO 80262.
Received for publication 31 January 1997 and accepted in revised form 16 October 1997. no previous diagnosis of cardiovascular dis-
Abbreviations: ABCD Trial, Appropriate Blood Pressure Control in Diabetes Trial; PE, parameter estimate; ease. Peak oxygen consumption (Vc"h) was
RER, respiratory exchange ratio; UAE, urinary albumin excretion. analyzed with respect to neuropathy

DIABETES CARE, VOLUME 21, NUMBER 2, FEBRUARY 1998 291

Exercise capacity and NIDDM complications
nephropathy, and retinopathy while con-
trolling for the known risk factors for
diminished exercise performance in these
NIDDM patients.
RESEARCH DESIGN AND
METHODS
Study population
The ABCD Trial is a large, prospective, ran-
domized, blinded clinical trial designed to
determine the effects of moderate versus
intensive antihypertensive control on the
outcome of NIDDM complications. This
trial has been described in detail previously
(12). Participants in the ABCD Trial, ages
40-74 years, were identified based on diag-
nosis-related groups and pharmacy and
billing lists from participating hospitals
during the period March 1991 to January
1993. Individuals found to be eligible after
an initial phone screen and eligibility visit
were enrolled.
NIDDM diagnosis for all patients
enrolled in the ABCD Trial was made
according to criteria based on the World
Health Organization report of 1985 (14),
which followed the National Diabetes
Group criteria of 1979. Institutional Review
Board approval was obtained for the con-
duct of all aspects of the ABCD Trial, and all
eligible patients gave informed consent to
be studied.
During the prerandomization period
of the trial, participants were tapered off
preexisting antihypertensive agents, and
placebo was prescribed for a minimum of 7
and a maximum of 11 weeks. During this
time, all baseline examinations were per-
formed. A structured interview with
detailed questions regarding medications
and history of cardiovascular disease was
also done. Patients on beta-blockers or
digoxin were excluded (17). During this
prerandomization period, 524 consecutive
patients completed a graded exercise tread-
mill test with respiratory gas analysis along
with the neuropathy testing, retinal pho-
tographs, and urine collections. Patients
with a history of coronary artery disease or
congestive heart failure (68 of the 524
patients) as determined by self-history, a
positive Rose questionnaire (15), or Q-
wave criteria on the baseline electrocardio-
gram were excluded in the analyses.
Procedures
Exercise testing. An exercise treadmill test
was administered during the prerandom-
ization period using a Half Bruce protocol
292
(16). The electrocardiogram was monitored min during recovery from exercise, 4) sys-
continuously (Q5000 Exercise Monitor; tolic hypotension with exercise (systolic
Quinton, Seattle, WA) and blood pressure blood pressure falling during exercise to lev-
was measured at the end of each stage by an els lower than rest), or 5) ventricular tachy-
automated blood pressure cuff (model 412 cardia (>5 consecutive beats) with exercise.
automated blood pressure cuff; Quinton). Neuropathy staging. Neuropathy was
Patients exercised until symptoms forced assessed and staged according to the rec-
them to stop. Measurements of oxygen con- ommendations made by the American Dia-
sumption and CO2 production with calcula- betes Association and American Academy of
tions of the respiratory exchange ratios were Neurology at the San Antonio Conference
continuously performed using an automated on Diabetic Neuropathy (19). Staging of
gas exchange measuring system (Q-Plex neuropathy was based on the following: 1)
Metabolic Cart; Quinton). Values were neurological symptom score (includes sub-
recorded at 15-s intervals. The respiratory categories of sensory, motor, and autonomic
exchange ratio (RER; the ratio of carbon symptoms), 2) neurological disability score
dioxide production to oxygen consump- (scored neurological examination with sub-
tion) was used as a measure of exercise categories of cranial nerve, sensory, motor,
intensity Peak Vo2 was defined as oxygen and reflex function), 3) autonomic function
consumption (ml kg"1 • min"1) at peak testing (heart rate responses to deep breath-
exercise and was calculated as the mean of ing), and 4) quantitative sensory examina-
values during the last minute of exercise. To tion (computerized examination involving
ensure an adequate effort, only patients who thermal and vibratory sensation). The stages
reached an RER >1.0 were used for analy- were defined as follows: stage 0, no neu-
sis; 35 of the 456 patients who did not have ropathy (fewer than two abnormalities
a previous diagnosis of coronary artery dis- among the above tests); stage 1, asympto-
ease did not reach a peak RER of 1.0 and matic neuropathy (more than two abnor-
were excluded. Also, because we felt that malities among neurological disability score,
disabling neuropathy could affect exercise autonomic function testing, or quantitative
tolerance, we excluded these patients (n = 2) sensory examination, but no abnormality
from the analyses. Thus the following analy- on the neurological symptom score); stage
ses were performed on the remaining 419 2, symptomatic neuropathy (more than two
NIDDM patients. abnormalities among neurological disability
During the exercise test, patients were score, autonomic function testing, quanti-
asked to report their degree of exertion tative sensory examination, or neurological
according to the Borg Scale (18). Exercise symptom score but no disabling neuro-
treadmill results were categorized as 1) non- pathic symptoms as assessed by the neuro-
ischemic, 2) positive or strongly positive for logical symptom score); and stage 3,
ischemia, or 3) nondiagnostic. A nondiag- disabling neuropathy (more than two
nostic treadmill test was defined by 1) an abnormalities among neurological disability
inadequate heart rate response that was score, autonomic function testing, quanti-
<85% of the predicted maximum heart rate, tative sensory examination, or neurological
or 2) the presence of a left bundle branch symptom score accompanied by disabling
block on resting electrocardiogram (ECG). neuropathic symptoms as assessed by the
The predicted maximum heart rate was neurological symptom score).
determined by 220 — age of subject. A pos- Urinary albumin excretion. Urinary albu-
itive treadmill test was defined by J) ^1.0 min excretion (UAE) was measured from a
mm ST-segment depression (horizontal or 24-h collection using radioimmunoassay
down sloping >0.08 s from the J-point) techniques (Double Antibody Albumin
with progressive exercise with or without #KHD2; Diagnostic Products, Los Angeles,
angina, and 2) normal blood pressure CA). During thefirst8 months of the study,
response and signs and symptoms of angina UAE was initially measured by the neph-
occurring in the second stage of exercise or elometric method (20). The correlation 2
beyond and then resolving within 7 min coefficient for the two methods was r =
into the recovery period. A strongly positive 0.99. UAE was classified into one of the fol-
treadmill test was defined by 1) >1.0 mm lowing categories: 1) normal albuminuria
ST-segment depression with or without (<20 ug/min), 2) microalbuminuria
angina in thefirststage of the protocol in one (20-200 ug/min), or 3) overt albuminuria
or more leads, 2) >2.0 mm ST-segment (>200 ug/min) (21).
depression in more than five ECG leads, 3) Retinopathy staging. Stereoscopic fundus
persistent ST-segment depression for >7 photographs with pupillary dilation were
DIABETES CARE, VOLUME 21, NUMBER 2, FEBRUARY 1998
 Estacio and Associates

Table 1—Clinical characteristics ojpatients

Selected patient characteristics Present Absent P value

Male 23.7 ± 0.3 (265) 18.6 ±0.4 (154) 0.0001
Hypertension 21.8 ±0.4 (274) 21.9 ±0.4 (145) NS
African-American 19.4 ± 0.7 (46) 22.1 ±0.3 (373) 0.0005
LVH 18.4 ±0.7 (95) 22.2 ± 0.3 (324) 0.0001
Age (years) — — 0.0001 -0.22
Duration of diabetes (years) — — NS -0.03
Duration of hypertension (years) — — 0.0002 -0.18
GHb (%) — — NS -0.09
Pack-years smoking — — NS 0.01
BMI (kg/m2) — — 0.0001 -0.37
Systolic blood pressure (mmHg) — — 0.0001 -0.18
Diastolic blood pressure (mmHg) — — NS -0.001
Data are means ± SE. LVH, left ventricular hypertrophy by Estes, Cornell, or Sokolow criteria; r, correlation coefficient with peak Vo2; NS, P > 0.05.

obtained at the study site by a trained retinal
technician. Blind to the treatment regimen,
technicians at the Wisconsin Retinal Reading
Center interpreted and graded the retinal
films using the modified Airlie House classi-
fication (22). For the analyses, fundus pho-
tographs were categorized according to the
presence or absence of retinopathy.
Statistical analysis
Univariate analyses were performed relat-
ing peak oxygen consumption with various
clinical factors and diabetic complications.
The complications were categorized as 1)
no neuropathy versus asymptomatic neu-
ropathy, 2) UAE stages, and 3) no retinopa-
thy versus presence of retinopathy. Linear
regressions were performed in the case of
continuous independent variables, and x2
tests were used with discrete variables.
Multiple regression analyses were then per-
formed controlling for age, sex, duration of
diabetes, hypertension, race, and BMI. All
results were reported as means ± SE.
RESULTS — Data from a total of 419
patients (265 men and 154 women) were
used for the final analyses. Patient charac-
teristics and their univariate association with
peak Vo2 are reported in Table 1. Of all sub-
jects participating in the study, 65% had
hypertension (defined as a systolic blood
pressure >140 mmHg or diastolic blood
pressure >90 mmHg at the time of ran-
domization). Male subjects had a signifi-
cantly higher peak Vo2 than female subjects.
The presence of electrocardiographic left
ventricular hypertrophy, increasing age,
duration of hypertension, BMI, and increas-
ing systolic blood pressure was associated
with a decrease in peak Vo2.
Exercise treadmill results
Patients with a nondiagnostic test result
had a significantly lower peak Vo2 (18.0 ±
0.7 ml • kg" 1 • mirr 1 ; n = 42) than the
patients with a diagnostic result: nonis-
chemic, 22.2 ± 0.3 ml • kg" 1 • min"1, n =
305, P = 0.0001; strong positive, 22.8 ±
1.3 ml • kg" 1 • min"1, n = 14, P = 0.002;
and positive, 21.9 ± 0.7 ml • kg"1 • min"1,
n = 58, P = 0.0001. The average maxi-
mum heart rate was 156 ± 14 bpm. The
average maximum systolic blood pressure
was 210 ± 25 mmHg. The average maxi-
mum perceived effort (Borg scale) was
16.4 ± 1.8, and the averaged peak respi-
ratory exchange ratio was 1.13 ± 0.08. In
all, 330 patients stopped secondary to
overall or leg fatigue and 86 stopped sec-
ondary to dyspnea.
Diabetic complications
The presence of retinopathy and neuropa-
thy were univariately associated with a
decrease in exercise capacity (Table 2). Sub-
jects with normal albuminuria had a signifi-
cantly higher peak Vo2 than patients with
microalbuminuria or overt albuminuria.
Table 2—Univariate correlations between diabetic complications and peak Vo2
Complication
Retinopathy
Neuropathy
UAE
Normal (n = 270) vs.
microalbuminuria (n = 95)
Normal vs. overt albuminuria (n = 54)
Data are means ± SE.
Multiple regression analyses
The results of the multiple regression
analyses are given in Table 3. Increasing
retinopathy stage (PE = —0.59 ± 0.3 ml •
kg"1 • min""1; P = 0.026) and increasing
UAE stage (PE = -0.62 ± 0.3 ml • k g 1 •
min"1; P = 0.044) were both associated
with a decrease in peak Vo2.
CONCLUSIONS— Previous studies
have demonstrated that N1DDM subjects
and possibly their relatives (23) have a
lower peak Vo2 than nondiabetic subjects.
In the present study, an assessment of dia-
betic complications with regard to exercise
capacity was undertaken in an NIDDM
population. We found that increasing dia-
betic retinopathy and UAE were both asso-
ciated with a decrease in exercise capacity as
measured by peak Vo2. These micro vascu-
lar diabetic complications were associated
with exercise performance independent of
age, sex, race, length of diagnosed diabetes,
duration of hypertension, BMI, and GHb
level. No independent association was
found between exercise capacity and dia-
betic neuropathy.
Present (n) Absent (n) P value
21.3 ±0.3 (217) 22.4 ± 0.4 (204) 0.03
20.7 ±0.7 (161) 22.5±0.3(253) 0.002
22.3 ±0.3 21.1 ± 0 . 5 0.04
22.3 ±0.3 20.9 ± 0 . 7 0.06

DIABETES CARE, VOLUME 21, NUMBER 2, FEBRUARY 1998 293

Exercise capacity and NIDDM complications
Table 3—Multiple logistic regression analy-
sis
Parameter estimate
Variable (ml • kg"1 • min"1) P value
Intercept 45.8 ± 2 . 0 0.0001
Retinopathy -0.59 ±0.3 0.026
stage
UAH -0.62 ±0.3 0.044
Daia are means ± SE. Unit for each variable equals
1 for calculation of parameter estimate.
In the present study, we chose to
include patients with a test positive for
ischemia in the analyses, since the predic-
tive value for screening asymptomatic indi-
viduals with an exercise treadmill test is
poor (24). Thus we may have included
some patients with coronary artery disease
in the analysis.
Previous studies involving IDDM
patients have demonstrated impaired car-
diovascular responses in patients with dia-
betic autonomic neuropathy (25-27).
However, this association has not been
demonstrated in NIDDM patients. In the
present study with NIDDM subjects, uni-
variate analyses revealed a strong associa-
tion between neuropathy and exercise
capacity (Table 2). But when neuropathy
was placed in a multivariate model that also
included retinopathy and nephropathy, no
independent association between neuropa-
thy and exercise capacity was demon-
strated. This suggests that there was a
strong correlation or interaction between
neuropathy and the other two NIDDM
complications, a correlation that Savage et
al. (28) previously demonstrated.
Microalbuminuria in European NIDDM
patients has been associated with future car-
diovascular events (29,30). Schneider et al.
(31) previously demonstrated a univariate
association between resting overt albumin-
uria and impaired exercise capacity in IDDM
and NIDDM subjects. Similar to Schneiders
findings, we found in the univariate and
multivariate analyses that the presence of
micro- or overt albuminuria was associated
with a decrease in exercise capacity. Further-
more, studies in IDDM subjects without
coronary artery disease have demonstrated
that increasing UAE is associated with left
ventricular dysfunction (32,33). Thus it can
be postulated, but not proven, that the
NIDDM subjects in the present study with
micro- or overt albuminuria may also have
an impairment in left ventricular function
294
that was manifested as an impairment in sensitivity and glucose utilization and
exercise capacity. This association of peak improving blood pressure control (37).
Vo2 with increased UAE is intriguing and Another possible explanation for this
may suggest a clinical link or possible com- association between retinopathy and exer-
mon pathogenic mechanism for microvas- cise capacity may be related to left ventric-
cular derangements in the kidney and heart. ular function. Although Pauwels et al. (38)
Kimball et al. (34) demonstrated an increase demonstrated no association between
in left ventricular mass with increasing uri- severe proliferative retinopathy and left
nary albumin in young IDDM subjects. This ventricular function in young IDDM male
observation may further support the possi- patients, work from Takahashi et al. (39) in
bility that changes in the heart and kidney a middle-aged population of NIDDM
may be related, and thus support the Japanese subjects suggested that retinopa-
hypothesis that abnormalities in these two thy is associated with impaired left ventric-
organ systems may develop in parallel with ular function.
NIDDM, especially with exposure to addi- In conclusion, the present study of
tional factors such as hypertension. In the NIDDM subjects demonstrated a signifi-
present study, electrocardiographic left ven- cant independent association of diabetic
tricular hypertrophy was univariately but nephropathy and retinopathy with exercise
not multivariately associated with a decrease capacity. Because the results obtained from
in peak Vo2. this study were from cross-sectional data, it
Another important complication of is beyond the scope of this study to deter-
diabetes is retinopathy. As with dia- mine if these associations were causally
betic nephropathy, this complication is related. The results suggest that a common
also considered to result from micro- pathogenic link may be present to explain
vascular disease. It is well known that these associations. Because the subjects
poor glycemic control, hypertension, and included in the study had no history of
length of diagnosed diabetes contribute to macro vascular disease, it is plausible that
the development and progression of dia- the findings may be attributed to microvas-
betic retinopathy (35). In the present study cular disease. We have demonstrated in
of NIDDM subjects, we found that increas- previous studies that several risk factors
ing severity of retinopathy was associated (i.e., smoking, hypertension, increasing
with decreasing peak Vo2. A possible expla- BMI, diabetes duration, and GHb), some
nation for this association is that NIDDM of which are reversible, were associated
patients with diabetic retinopathy are with these microvascular complications
involved in less physical activity than their (12,40). Thus the presence of diabetic
counterparts without retinopathy, which nephropathy and retinopathy in NIDDM
then results in a decrease in exercise capac- subjects in conjunction with other cardio-
ity. Unfortunately, physical activity ques- vascular risk factors may decrease exercise
tionnaires were not obtained from an capacity The diminished exercise perfor-
adequate number of subjects to ascertain mance in association with diabetic
the amount of physical activity involved in retinopathy and nephropathy has possible
their daily routine. In this regard, it is not implications for NIDDM patients' ability to
uncommon for caretakers of patients with perform normal daily activities and may be
diabetic retinopathy, especially proliferative associated with an increased cardiac mor-
retinopathy, to recommend abstinence bidity and mortality.
from vigorous exercise to avoid vitreoreti-
nal hemorrhage. Albert et al. (36) has
demonstrated that patients with prolif- Acknowledgments — This work was funded
erative retinopathy have an impaired in part by Bayer Pharmaceutical Company and
autoregulatory response to blood pres- the National Institutes of Health.
sure increases during exercise. The resul-
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