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Diabetes and Risk of Parkinson’s
Disease
QUN XU,MD,PHD
1
YIKYUNG PARK,SCD
2
XUEMEI HUANG,MD,PHD
3
ALBERT HOLLENBECK,PHD
4
AARON BLAIR,PHD
5
ARTHUR SCHATZKIN,MD,PHD
2
HONGLEI CHEN,MD,PHD
1
OBJECTIVE—To investigate the relationship between diabetes and future risk of Parkinson’s
disease (PD) among older U.S. adults.
RESEARCH DESIGN AND METHODS—A prospective study of self-reported diabetes
in 1995 and 1996 in relation to PD diagnosed after 1995 among 288,662 participants of the
National Institutes of Health-AARP Diet and Health Study. Multivariate odds ratio ( OR) and 95%
CI were derived from logistic regression models.
RESULTS—A total of 1,565 participants with PD diagnosed after 1995 were included in the
analysis. After adjustment for potential confounders, PD risk was ;40% higher (OR = 1.41 [95%
CI 1.20–1.66]) among diabetic patients than among participants without diabetes. Further
analysis showed that the risk elevation was largely limited to individuals who had diabetes for
more than 10 years at the time of baseline survey (1.75 [1.36–2.25]). The association with
diabetes was seen for both participants with PD diagnosed between 1995 and 1999 and partic-
ipants with PD diagnosed after 2000. In addition, similar results were obtained after excluding
participants with stroke, heart disease, cancers, or poor or fair health status and in subgroup
analyses by age, sex, smoking status, and coffee consumption.
CONCLUSIONS—This large study showed that diabetes was associated with a higher future
risk of PD and the nature of this association warrants further investigation.
Diabetes Care 34:910–915, 2011
Over the past several decades, type 2
diabetes has become a significant
public health problem worldwide.
Around ;10% of middle-aged adults and
20% of the elderly in the U.S. have diabe-
tes (1), in part because of high prevalence
of inactive lifestyle and obesity. Diabetic
patients often suffer from a variety of neu-
rological consequences, ranging from pe-
ripheral neuropathy (2) to higher risk of
dementia (3) or Alzheimer’s disease (4). A
link between diabetes and Parkinson’s
disease (PD) has also been explored in
several epidemiological studies, but the
results are inconsistent (5–11), ranging
from a significant inverse association
to a significant positive association. These
studies often included few exposed cases
(PD participants with diabetes) and did
not have information on the duration of
diabetes. We therefore examined the his-
tory of diabetes in relation to PD risk in
the large prospective cohort of the Na-
tional Institutes of Health (NIH)-AARP
DietandHealthStudy.
RESEARCH DESIGN AND
METHODS
Study participants
The prospective NIH-AARP Diet and
Health study was established in 1995 and
1996 by the National Cancer Institute to
investigate etiologies of cancer and other
age-related chronic diseases (12). AARP,
formerly known as American Association
of Retired Persons, is a nonprofitand
membership-based interest organization
for U.S. adults aged 50 years or older.
AARP currently has over 40 million mem-
bers across the U.S. and thus represents a
wide range of older U.S. adults. The NIH-
AARP Diet and Health cohort is composed
of 566,401 AARP members (ages 50–71
years) from six U.S. states (California,
Florida, Pennsylvania, New Jersey, North
Carolina, and Louisiana) and two metro-
politan areas (Atlanta, GA and Detroit,
MI), and all participants completed a com-
prehensive survey on diet and lifestyle at
baseline (12). Between 2004 and 2006, a
follow-up questionnaire was mailed to
surviving participants of the cohort to up-
date lifestyle information and to ascertain
the occurrence of major chronic diseases,
including PD. A total of 187,499 (55.2%)
men and 130,761 (57.6%) women of the
baseline participants answered the follow-
up survey and were thus eligible for the
current study. Of those not in the follow-
up survey (n= 248,141), 58,192 (23.5%)
were deceased and 189,949 (76.6%) were
nonresponders. On the follow-up ques-
tionnaire, participants were asked to re-
port whether they had been diagnosed
by a doctor as having PD during the fol-
lowing periods: before 1985, 1985–1994,
1995–1999, or 2000 to present. Of the
2,432 self-reported PD patients, we ex-
cluded 459 who were diagnosed before
1995 to eliminate cases prevalent at the
time of cohort enrollment. Furthermore,
we excluded 293 patients whose diagnosis
was denied either by the patients them-
selves or by their treating physicians in
the diagnostic validation process as de-
scribed below and 115 patients with miss-
ing information on baseline diabetes status.
Of those who did not report a PDdiagnosis,
we excluded 28,731 participants with
missing data on diabetes (n=20,607)or
PD status (n= 8,124). Therefore the final
analyses included 1,565 self-reported PD
participants diagnosed in or after 1995
and 287,097 participants without PD.
We conducted diagnostic validations
for surviving self-reported PD patients,
ccccccccccccccccccccccccccccccccccccccccccccccccc
From the
1
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle
Park, North Carolina; the
2
Nutritional Epidemiology Branch, National Cancer Institute, Rockville,
Maryland; the
3
Department of Neurology, Pennsylvania State University-Milton S. Hershey Medical
Center, Hershey, Pennsylvania;
4
AARP, Washington, District of Columbia; and the
5
Occupational and
Environmental Epidemiology Branch, National Cancer Institute, Rockville, Maryland.
Corresponding author: Honglei Chen, chenh2@niehs.nih.gov.
Received 7 October 2010 and accepted 30 January 2011.
DOI: 10.2337/dc10-1922
Q.X. is currently affiliated with the Department of Epidemiology and Health Statistics, Institute of Basic
Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educa tional and not for profit, and the work is not alte red. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
910 DIABETES CARE,VOLUME 34, APRIL 2011 care.diabetesjournals.org
Epidemiology/Health Services Research
ORIGINAL ARTICLE
described in detail previously (13).
Briefly, with permission from patients,
we asked their treating physicians (mostly
neurologists) to complete a diagnostic
questionnaire and to send us a copy of
relevant medical records that were sub-
sequently reviewed by a movement
disorder specialist (X.H.). A case was con-
firmed if the diagnosis was considered
clinically definitive or probable by the
treating neurologist or if the medical re-
cord included a final PD diagnosis or ev-
idence of two or more cardinal signs with
one being rest tremor or bradykinesia, a
progressive course, responsiveness to do-
paminergic treatments, and absence of
features that suggest an alternative diag-
nosis. To date, we have received a total of
1,069 responses from the treating physi-
cians and 940 (87.9%) confirmed the di-
agnosis. The average age at diagnosis of
confirmed PD patients was 66.7 67.3
years.
Exposure assessment
At baseline in 1995 and 1996, partici-
pants were asked whether they had ever
been told by a doctor that they had
diabetes. We did not differentiate type 2
from type 1 diabetes. However, because
;90–95% of all diagnosed diabetes in
adults is type 2 diabetes (14), we believe
most patients in our cohort have type 2
diabetes. A similar question was also
asked in the follow-up questionnaire
along with the calendar year of diabetes
diagnosis: before 1985, 1985–1994,
1995–1999, and 2000 to present. With
these two questions, we defined the ana-
lytic variables for the presence of diabetes
and the duration of diabetes at baseline.
Because the baseline survey was con-
ducted in 1995 and 1996, diabetic patients
who reported diagnoses before 1985
were considered as having $10 years of
diabetes before baseline and those diag-
nosed between 1985 and 1994 as having
,10 years of diabetes at baseline. The
analysis on diabetes duration included
fewer participants because 922 eligible di-
abetic patients did not report the year of
diagnosis on the follow-up questionnaire.
In addition to diabetes status, the baseline
survey also asked participants to report
their age, sex, race, education, cigarette
smoking, body weight and height, physi-
cal activity, general health status, diagno-
sis of stroke or heart disease, and cancers
(12). BMI was calculated as weight in kilo-
grams divided by height squared in me-
ters. For physical activity, we asked how
often they did activities at work or home
that lasted at least 20 min or increased
breath or heart rate or caused sweat, and
six categorical answers were allowed
(never, rarely, times/week: ,1, 1–2, 3–
4, and $5).
Statistical analysis
We derived multivariate odds ratios (OR)
and 95% CI from unconditional logistic
regression models, adjusting for baseline
age (in 5-year groups), sex, race (white vs.
nonwhite), education (,8years,8–11
years, 12 years or completed high school,
post-high school or some college, and col-
lege and post graduate), smoking status
(never, past smokers [years since last
smoking: $35, 30–34, 20–29, 10–19,
1–9], and current smokers [number of
cigarettes per day: 1–10, 11–20, .20]),
cups of coffee per day (none, ,1, 1, 2–3,
.3), BMI (kg/m
2
,22.5, 22.5–24.9,
25.0–27.4, 27.5–29.9, and $30.0), and
physical activity (never or rarely, times/
week: ,1, 1–2, 3–4, 5). Analysis was first
conducted with all PD participants diag-
nosed since 1995 and then separately for
PD participants diagnosed between 1995
and 1999 and diagnosed after 2000. For
the later group, PD diagnoses were made
at least 4 or 5 years after baseline ascertain-
ment of diabetes and therefore reverse
causality was less likely.
Certain types of cancers have been
linked to both PD and diabetes; further-
more, because diabetic patients often
have vascular changes that might compli-
cate PD diagnosis (e.g., vascular parkin-
sonism) and participants with these
chronic diseases or poorer health at base-
line might have frequent clinical visits and
thus introduce identification bias, we
conducted sensitivity analyses by exclud-
ing participants with stroke, heart disease,
cancers, or poor or fair health from the
analysis. Finally, we conducted subgroup
analyses according to selected key factors
that are known to be associated with PD
risk, including baseline age (,65 years
and $65 years), sex (men and women),
smoking status (never and ever [current
and past smokers]), and coffee drinking
(,2 cups per day and $2 cups per day).
The statistical significance for linear trend
of PD with diabetes duration was tested
by assigning a value to each duration cat-
egory (5 for ,10 years and 12 for $10
years) and including it as a continuous
variable in the regression model. All sta-
tistical analyses were conducted using
SAS software (Version 9.1, Cary, NC),
and the significance tests were two-tailed
with a= 0.05.
RESULTS—Table 1 shows population
characteristics according to baseline dia-
betes status. When compared with partic-
ipants without diabetes, diabetic patients
were older and were more likely to be
men, nonwhite, and past smokers. They
were also more likely to report lower edu-
cation; higher BMI; less exercise; poorer
health status; and a history of heart dis-
ease, stroke, or cancers.
The primary analysis included a total
of 1,565 PD patients diagnosed in or after
1995. After adjustment for potential con-
founders, baseline diabetes was associ-
ated with a 41% (OR 1.41 [95% CI 1.20–
1.66]) higher risk of PD (Table 2). The
risk elevation was higher among individ-
uals who had diabetes for more than
10 years at baseline (1.75 [1.36–2.25])
than among diabetic patients with ,10
years of the disease at baseline (1.11
[0.89–1.38]). Excluding participants
with heart disease, stroke, cancers or
fair/poor health status attenuated the
slightly higher risk for patients with ,10
years of diabetes but made little difference
to patients with more than 10 years of di-
abetes at baseline. Generally, similar re-
sults were obtained when we further
analyzed the data according to year of
PD diagnosis (1995–1999 vs. after
2000). Finally, the association between
diabetes and PD was observed in each
subgroup analysis according to age, sex,
smoking status, and coffee consumption
(Fig. 1).
CONCLUSIONS—In this large popu-
lation of older adults in the U.S., we found
that diabetes was associated with a mod-
est increase of PD risk. Further analysis
suggested that the higher risk was pri-
marily limited to study participants who
had had diabetes for more than 10 years
before the baseline survey. Multivariate
and stratified analyses suggest that these
results were not confounded or modified
by known or suspected PD risk factors,
nor could they be accounted for by poorer
baseline health status or the presence of
vascular diseases or cancers as shown in
the sensitivity analyses.
Over the past decade, diabetes has
been reported to be associated with in-
creased risk of dementia (3) and Alzhei-
mer’s disease (4), suggesting a potential
role of diabetes or insulin dysregulation
in neurodegeneration. Several lines of ev-
idence also indicate a link between dia-
betes and PD. Insulin receptors are
expressed in the substantia nigra (15).
Thedopamineagonistbromocriptine
care.diabetesjournals.org DIABETE S CARE,VOLUME 34, APRIL 2011 911
Xu and Associates
improves glycemic control (16) and was
recently approved for adjunctive treat-
ment of diabetes. Conversely, the insulin
sensitizer rosiglitazone protects dopami-
nergic neurons in animal models of PD
(17). From an etiologic perspective, it is
also important to point out that both di-
abetes and PD are age-related chronic dis-
eases and some pathogenic processes may
underlie both conditions. For example,
systemic chronic inflammation, which
increases the risk of diabetes, was also
found to be associated with higher risk
of PD (18,19). Furthermore, oxidative
stress and mitochondria abnormalities
have been implicated in both diseases
(20–22).
A few epidemiological studies have
investigated the association between di-
abetes and PD. Several case-control stud-
ies (6–8,23), but not all (5,24), reported
that PD patients were less likely to report
diabetes. A closer examination of these
studies revealed further uncertainties.
For example, the diabetes-PD association
did not persist in the multivariate analysis
of one study (7) and another study
showed different results across subgroups
(6). Despite these uncertainties, it has
been hypothesized that the lower preva-
lence of diabetes among PD patients is a
result of impaired autonomic functions
and fewer cardiovascular risk factors
among PD patients (7,8). However, alter-
native explanations such as chance or bias
could not be excluded since these studies
were often based on small sample sizes,
prevalent cases of patients with PD, and
retrospective exposure assessment. For
example, a spurious inverse association
between diabetes and PD could arise
in a case-control study with prevalent
cases if PD adversely affects the survival
of diabetic patients or vice versa. Finally,
case-control studies were not ideal to ad-
dress the temporal relationships between
diabetes and PD because of the use of
prevalent cases and sometimes unspeci-
fied time window of exposure assessment.
Unlike case-control studies, prospec-
tive studies collect exposure data before
outcome identification and therefore are
less prone to recall and selection biases.
To the best of our knowledge, three
prospective studies to date have exam-
ined diabetes in relation to future risk of
PD (9–11). In contrast with case-control
studies, none of the prospective studies
found lower PD risk among diabetic pa-
tients. The Health Professionals Follow-
up and Nurses Health Studies reported
similar risk of PD between individuals
with and without diabetes (RR = 1.04)
(11). On the other hand, the Finnish
study reported an 83% higher risk of PD
among diabetic patients than participants
without PD (10). Cases in this study were
identified from the Finnish nationwide
drug register without further diagnostic
validation and therefore some caution is
needed in interpreting the result. The
third study was conducted in the Physi-
cians Health Study and was the only one
that took into account the duration of di-
abetes in the analyses (9). This study also
reported a higher PD risk (RR = 1.34)
among diabetic patients, but further anal-
ysis showed that the increment was limited
to diabetic patients with ,10 years of
the disease. Therefore, the authors attrib-
uted this finding to potential ascertain-
ment bias, reverse causality, or common
mechanisms that underlie both diabetes
and PD (9).
Table 1—Population characteristics according to diabetes status at baseline*
Variable Nondiabetes Diabetes
N267,051 21,611
Age (years) 61.4 65.4 62.1 65.1
Male (%) 57.5 66.6
Race (%)
White 93.2 87.3
Nonwhite 5.9 11.3
Education (%)
,8 years 4.0 6.5
8–11 years 17.1 20.4
12 years or completed high school 9.4 10.2
Post-high school or some college 22.7 23.9
College and postgraduate 44.6 36.2
Smokers (%)
Never 38.6 34.1
Past 50.5 56.7
Current 10.0 7.9
Coffee consumption (%)
None 10.3 10.6
,1 cup/day 16.2 17.6
1 cup/day 16.1 17.4
2 to 3 cups/day 41.4 39.2
.3 cups/day 15.5 14.6
BMI (kg/m
2
)26.764.8 29.8 65.8
Physical activity (%)
Never or rarely 15.1 22.1
,1 time/week 13.5 13.6
1 to 2 times/week 22.1 20.8
3 to 4 times/week 28.3 25.0
$5 times/week 20.3 17.4
Health status (%)
Excellent/very good 59.0 22.8
Good 32.5 47.4
Fair or poor 7.8 28.6
Heart disease (%)
No 88.1 75.6
Yes 11.6 24.0
Stroke (%)
No 98.2 96.1
Yes 1.4 3.4
Cancers
No 88.6 86.2
Yes 7.9 9.1
*Data are means 6SD for continuous variables and proportions for categorical variables. Participants
without diabetes (4,923 or 1.8%) and participants with diabetes (476 or 2.2%) had missing data on BMI; for
categorical variables, percentage may not add up to 100% because of missing values.
912 DIABETES CARE,VOLUME 34, APRIL 2011 care.diabetesjournals.org
Diabetes and PD
In addition to some design differ-
ences, all previous studies had fewer than
60 exposed cases (PD participants with
diabetes), which may have contributed to
the heterogeneous results. In comparison,
the current study was substantially larger
with 172 PD participants with diabetes
and 1,393 PD participants without di-
abetes. Furthermore, in data analysis, we
controlled for or stratified by known or
suspected PD risk factors to examine the
robustness of our result, and similar
results were found across subgroups.
Like the Finnish and the Physicians
Health studies, we observed a modestly
higher risk of PD among individuals with
baseline diabetes. In contrast with the
Physicians Health Study, we found the
higher risk was largely limited to diabetic
patients who had been diagnosed more
than 10 years before baseline. This asso-
ciation was evident for both PD partic-
ipants diagnosed between 1995 and 1999
and participants diagnosed after 2000; PD
diagnoses in the latter group were at least
4 to 5 years after the report of baseline
diabetes status. Finally, neither vascular
conditions or cancers nor poorer health
status at baseline accounted for the asso-
ciation of diabetes with PD risk. Taken
together, our results are consistent with
the hypothesis that diabetic patients had
higher risk of PD, which could not be
explained by reverse causality.
The higher PD risk among diabetic
patients could potentially be explained by
two intertwined possibilities. It is possible
that common pathogenic processes such
as chronic inflammation or oxidative
stress may first lead to diabetes and then
years later to a higher risk of PD. Alterna-
tively, one can speculate that diabetes and
insulin dysregulation or other aspects of
diabetes may themselves increase the risk
of PD. In either case, the evidence to date
is indirect and the relevance of these
speculations to our observed diabetes-
PD association needs to be evaluated in
future studies.
Our study has several limitations. In
such a large population, we had to rely on
self-reports to identify PD participants cost
effectively. This might have led to diagnos-
tic and reporting errors, particularly under-
reports since some PD patients might not
report their diagnoses on the follow-up
questionnaire. However, we were able to
confirm ;88% of diagnoses among self-
reported patients whose medical infor-
mation was available. Furthermore, we
excluded from analyses patients in the
case group with erroneous reports identi-
fied in the validation study. Diabetes was
also self-identified; however, previous
studies showed satisfactory agreement
(k= 0.76) between self-reports of diabetes
and medical records despite a modest sen-
sitivity (66%) (25). The lack of annual
glucose tolerance screening in the cohort
also resulted in underreports and under-
diagnosis of diabetes. Nevertheless, be-
cause diabetes status was assessed before
PD case ascertainment, inaccurate report-
ing of diabetes should be nondifferential
and thus might have underestimated the
true association between diabetes and PD.
Another limitation on diabetes assessment
was the lack of information on diabetes
complications and treatments. We there-
fore could not evaluate the possibility that
diabetes medications and treatments or di-
abetes complications might have contrib-
uted to higher risk of PD, particularly
among long-term diabetic patients. It was
also possible that diabetic patients might
have more frequent physician visits than
individuals without diabetes. Although
we conducted sensitivity analysis by ex-
cluding participants with poor/fair health
or several chronic diseases, we could not
Table 2—ORs and 95% CI of PD according to baseline diabetes status and disease duration*
Diabetes Diabetes duration (years)
No Yes None ,10 $10 Pfor trend
All Parkinson diagnoses since 1995
All participants
Number of PD patients 1,393 172 1,393 88 66
OR (95% CI) 1.0 1.41 (1.20–1.66) 1.0 1.11 (0.89–1.38) 1.75 (1.36–2.25) ,0.0001
Excluding participants with stroke, heart disease, cancers, and poor/fair health
Number of PD patients 952 79 952 40 30
OR (95% CI) 1.0 1.34 (1.06–1.69) 1.0 1.00 (0.73–1.38) 1.80 (1.25–2.60) 0.008
Parkinson diagnoses between 1995 and 1999
All participants
Number of PD patients 465 52 465 25 23
OR (95% CI) 1.0 1.31 (0.97–1.75) 1.0 0.97 (0.64–1.45) 1.85 (1.21–2.83) 0.02
Excluding participants with stroke, heart disease, cancers, and poor/fair health
Number of PD patients 328 27 328 12 12
OR (95% CI) 1.0 1.34 (0.90–2.00) 1.0 0.87 (0.49–1.56) 2.12 (1.18–3.78) 0.05
Parkinson diagnosis after 2000
All participants
Number of PD patients 928 120 928 63 43
OR (95% CI) 1.0 1.46 (1.20–1.77) 1.0 1.18 (0.91–1.53) 1.70 (1.25–2.31) 0.001
Excluding participants with stroke, heart disease, cancers, and poor/fair health
Number of PD patients 624 52 624 28 18
OR (95% CI) 1.0 1.33 (1.00–1.78) 1.0 1.07 (0.73–1.56) 1.64 (1.02–2.63) 0.06
*Adjusting for age, sex, race, education, smoking, coffee, BMI, and physical activity. The numbers of participants without PD for the overall analyses were 265,658
(no diabetes), 21,439 ( diabetes), 14,280 (diabetes ,10 years), and 6, 255 (diabetes duration $10 years). For the analysi s excluding stroke, heart disease, cancers, and
poor/fair health, the numbers were 203,299, 11,393, 7,878, and 3,030, respectively.
care.diabetesjournals.org DIABETE S CARE,VOLUME 34, APRIL 2011 913
Xu and Associates
exclude the possibility of identification bias
from this source. Finally, the current anal-
yses were limited to participants of the fol-
low-up survey. A spurious association
might be induced if more diabetic patients
with PD survived and participated in the
follow-up survey than diabetic patients
without PD.
In conclusion, this study showed
higher PD risk among diabetic patients
in a large cohort of older adults. The
nature of this association should be eval-
uated in future studies.
Acknowledgments—This study was sup-
ported by the intramural research program of
the NIH, the National Institute of Environ-
mental Health Sciences (Z01-ES-101986),
and the National Cancer Institute (Z01-CP-
010196-02).
No potential conflicts of interest relevant to
this article were reported.
Q.X. researched data and wrote the manu-
script. Y.P., X.H., A.H., A.B., and A.S. con-
tributed to data collection and discussion and
reviewed and edited the manuscript. H.C.
developed the study concept, researched data,
wrote the manuscript, contributed to discus-
sion, and reviewed and edited the manuscript.
The authors thank the participants of the
NIH-AARP Diet and Health study for their
important contributions and Dr. Xuguang
Guo (Westat) for analytical help.
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