Journal of Parkinson’s Disease xx (20xx) x–xx 1

DOI 10.3233/JPD-181305
IOS Press

Research Report

High Prevalence of Undiagnosed

Insulin Resistance in Non-Diabetic
Subjects with Parkinson’s Disease

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Elliot Hogga , Kishore Athreyaa , Christina Basilea , Echo E. Tana , Jan Kaminskib
and Michele Tagliatia,∗
a Department of Neurology, Cedar-Sinai Medical Center, Los Angeles, CA, USA
b Department of Neurosurgery, Cedar-Sinai Medical Center, Los Angeles, CA, USA

Accepted 20 February 2018

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d
Abstract.
Background: Reduced glucose tolerance has been long recognized as a potential risk factor for Parkinson’s disease (PD), and
increasing scrutiny is currently being placed on insulin resistance (IR) as a pathologic driver of neurodegeneration. However,
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the prevalence of IR in PD is unknown.
Objective: To determine IR prevalence in non-diabetic patients with PD and to correlate IR with other metabolic indicators,
motor and non-motor symptoms (NMS) of PD, and quality of life (QoL).
Methods: Non-diabetic patients with a diagnosis of PD were identified and tested for fasting insulin, fasting glucose,
c

and HbA1c. Patients were also offered to take a battery of clinical tests (MoCA, NMSQ, and PDQ-39) and had their PD
medications, height, weight, and other demographic features recorded. IR was defined as HOMA-IR≥2.0 and/or HbA1c≥5.7.
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IR abnormalities were correlated with BMI and demographic features, in addition to motor and NMS.
Results: 154 subjects (109 M, 45F, mean age 67.7 ± 10.5) were included in this study. Mean HOMA-IR was 2.3 ± 1.8. Ninety
out of 154 (58.4%) subjects had abnormal IR. IR was more frequent in overweight and obese subjects (61.1% and 82.8%
respectively) than normal weight subjects (41.5%). Multivariate analysis showed that BMI was the only significant predictor
or

of IR (p < 0.0001). There was no significant correlation between HOMA-IR and MoCA, PDQ-39, and NMSQ scores.
Conclusions: IR is prevalent in PD and it correlates with BMI. A correlation between IR with cognitive and QoL measures
cannot be determined on the basis of this sample.

Keywords: Body mass index, cognition, insulin resistance, Parkinson’s disease

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INTRODUCTION indicated a high rate of abnormal glucose tolerance

A relationship between Parkinson’s disease (PD)
and diabetes mellitus type II (DM2) has been
described for several decades, predating the introduc-
tion of levodopa therapy [1]. Multiple studies have
∗ Correspondence
to: Michele Tagliati, MD, Department of
Neurology, Cedar-Sinai Medical Center, 127 S. San Vicente Ave.,
A6600, Los Angeles, CA 90048, USA. Tel.: +1 310 248 6704;
Fax: +1 310 967 0601; E-mail: Michele.Tagliati@cshs.org.
ISSN 1877-7171/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
in PD patients, ranging between 50 to 80% depend-
ing on the source [2–4]. DM2 is associated with more
severe motor and non-motor features of PD [5] and
appears to increase the risk of developing PD [6, 7],
although evidence is controversial [8].
The key link between DM2 and PD appears to
be insulin resistance (IR), a condition defined by a
reduced biological effect for any given concentration
of insulin, which is common in aging [9]. Peripheral
2 E. Hogg et al. / Insulin Resistance is Prevalent in PD
IR can be measured using the glucose clamp tech-
nique or by a less cumbersome method provided by
the Homeostatic Model Assessment (HOMA) equa-
tion [10]. Peripheral IR is a reversible condition that
not only predisposes to DM2 but is associated with
central IR [11]. Importantly, central IR can be a either
a cause [12] or a consequence [13] of neurodegener-
ation.
While peripheral IR is a reversible condition and
may be a target for pharmacologic and lifestyle man-
agement therapies, the prevalence of peripheral IR in
PD is currently unknown, hampering interventions in
this area. Complicating matters is that there is little
oo
consensus as to what constitutes normal and abnor-
mal insulin sensitivity with significant variation in
reported measures of peripheral IR in different pop-
ulations [14, 15]. We conducted a study to determine
the prevalence of peripheral IR in a population of non-
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diabetic PD patients and its correlation to quality of
life, cognitive decline and other non-motor features.
METHODS
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One hundred and sixty idiopathic PD people
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attending the movement disorders clinic at Cedars-
Sinai Medical Center in Los Angeles were offered
testing for fasting plasma insulin (FPI), fasting
plasma glucose (FPG) and glycated hemoglobin
c
(HbA1c). HOMA index was calculated by the for-
mula: HOMA-IR = (FPI x FPG)/405 [10, 16]. The
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study obtained local Institutional Review Board
(IRB) approval.
To meet inclusion criteria, individuals had to be age
18 and above with a clinical diagnosis of PD accord-
or
ing to the UK Brain Bank criteria. Exclusion criteria
included a diagnosis of DM2, as well as an inability
to undergo blood draws. Results were obtained and
recorded with the date of the sample noted. Demo-
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graphic information collected included age, gender,
ethnicity, PD subtype (i.e. tremor-predominant,
akinetic-rigid, mixed), age at PD symptom onset,
duration of PD symptoms, height and weight. Motor
severity and progression were assessed using the
Movement Disorder Society Unified Parkinson’s
Disease Rating Scale (MDS-UPDRS) and Hoehn
and Yahr Scale (H&Y) collected as part of routine
clinic visits. Body mass index (BMI) was calculated
according to the formula weight (Kg)/height2 (m)
and subjects were subdivided in obese (BMI>30),
non-obese overweight (BMI>25) and lean (BMI<25)
[17]. Additional testing of non-motor symptoms
was performed in a subgroup of 71 subjects for
later analysis. This included Montreal Cognitive
Assessment (MOCA), Non-Motor Symptoms Scale
(NMSQ), and Parkinson’s Disease Questionnaire –
39 (PDQ-39) to assess health related quality of life.
Dopaminergic medications were recorded including
type and dose, to enable levodopa-equivalent dose
(LED) calculation [18].
Impaired fasting glucose (IFG), the intermediate
state of abnormal blood sugar between normal and
diabetes was defined by FPG concentration ≥100
and <126 mg/dl [19]. A cutoff HOMA index of 2.0,
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equivalent to <50% sensitivity, was used to define IR.
Subjects were considered to have IR if they either had
a HOMA≥2.0 and/or HbA1c≥5.7. We classified par-
ticipants as overweight if their BMI was 25 or greater,
and obese if BMI was 30 or greater [20]. MoCA≤22
was considered consistent with dementia.
Pearson R coefficient was used to determine the
strength of observed correlations between HOMA-
IR index, demographic (age, BMI) and clinical
data including LED, MoCA, NMSQ, PDQ-39, and
HbA1c. Student t-test analysis was used for group
comparisons. Multivariate linear regression analysis
was performed to identify variables that indepen-
dently contributed to IR. A probability value of
p < 0.05 was considered statistically significant.
RESULTS
One hundred and sixty people were initially
recruited. Six subjects were excluded from further
analysis as they were found to have fasting plasma
glucose (FPG) concentration (≥126 mg/dl) or HbA1c
levels (>6.5 mmol/mol) in the diabetic range. The
remaining 154 subjects (109M, 45F) were included
in the final analysis. Mean age was 67.7 ± 10.5, with
a mean PD duration of 6.5 ± 5.5 years at time of
study, and a mean H&Y of 2.2 ± 0.7. Mean BMI was
26.8 ± 4.8 and mean LED was 491.5 ± 537.2. 17/154
subjects (11.0%) had undergone deep brain stimula-
tion (DBS). For additional demographic data please
see Table 1.
Mean fasting glucose levels for this population was
95.8 ± 10.2. Fifty-two subjects (33.7%) had IFG, of
which 32 (61.5%) also had abnormal HOMA-IR.
Mean HOMA-IR was 2.3 ± 1.8 and mean HbA1c
was 5.5 ± 0.4 (n = 118). 70 subjects (45.5%) had an
abnormal HOMA index, consistent with IR. In addi-
tion, 39 (33.1%) subjects had HbA1c data in the
pre-diabetic range (≥5.7). Of these 39, 20 had a
 E. Hogg et al. / Insulin Resistance is Prevalent in PD 3

normal HOMA-IR, bringing the total subjects with values, with 65.8% overall overweight subjects and
undiagnosed IR to 90, or 58.4% of the study popula- 19% in obesity range. HOMA or HbA1c values con-
tion. BMI distribution was skewed toward overweight sistent with IR were found in 24/29 (82.8%) obese,
44/72 (61.1%) overweight, and 22/53 (41.5%) normal
Table 1 weight subjects (Fig. 1).
Demographic data
In the full study cohort, HOMA-IR positively cor-
Mean ± STD related with BMI (Pearson R = 0.42, p < 0.0001) and
Age 67.7 ± 10.5 years HbA1c (Pearson R = 0.19, p < 0.05), while it showed
PD Duration 6.5 ± 5.5 years
LED 491.5 ± 537.2 mg
a negative correlation with age (Pearson R = –0.19,
LED/Weight 7.9 ± 6.8 mg/kg p = 0.01). There was no significant difference in
BMI 26.8 ± 4.8 kg/m2 HOMA-IR between male and female subjects. Obese
FPG 95.8 ± 10.2 mmol/L subjects had significantly higher mean HOMA-

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FPI 9.4 ± 6.7 ␮U/ml
2.2 ± 0.7
IR (3.3 ± 1.7 vs. 2.03 ± 1.7, p < 0.0005) and were

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H&Y
MDS-UPDRS ON (n = 112) 17.3 ± 9.5 significantly younger (63.6 ± 11.5 years old vs.
MDS-UPDRS OFF (n = 49) 20.4 ± 13.1 68.7 ± 10.1, p < 0.05) than non-obese subjects. Sim-
HOMA-IR 2.3 ± 1.8 ilarly, non-obese overweight subjects (BMI >25
Male (n = 109) 2.4 ± 1.9
Female (n = 45) 2.0 ± 1.2 and <30) had significantly higher mean HOMA-IR
5.5 ± 0.4% (2.5 ± 2.0 vs. 1.4 ± 0.6, p < 0.001) and were signifi-

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HbA1c (n = 118)
MoCA (n = 71) 26.4 ± 3.0 cantly younger (67.3 ± 11.1 years old vs. 71.4 ± 7.9,
NMSQ (n = 71) 11.3 ± 5.1 p < 0.05) than lean subjects. Mean weight-adjusted
PDQ39 (n = 71) 157.2 ± 103.5
LED was 7.9 ± 6.8 mg/kg. HOMA-IR did not signif-
LED: Levodopa equivalent dose, LED/Weight: body weight (kg)
adjusted LED, BMI: Body Mass Index, HOMA-IR: Homeostatic
icantly correlate with weight-adjusted LED, as well
model assessment, FPG: fasting plasma glucose, FPI: fasting as with PD duration, LED, MDS-UPDRS and HY
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plasma insulin, H&Y: Hoehn & Yahr Disease severity scale, MDS- scores. Multivariate analysis showed that BMI was
UPDRS: Movement Disorder Society Unified PD Disease Rating the only resulting independent variable correlated
Scale in ON and OFF medication states (11 subjects had both
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with IR (p < 0.0001).
ON and OFF scores available from the same date for analysis),
HbA1c: glycated hemoglobin, MoCA: Montreal Cognitive Assess-
Mean H&Y scores were virtually identical
ment, NMSQ: Non-Motor Symptoms Scale, PDQ-39 Parkinson’s between IR and non-IR subjects (Table 2) and there
Disease Questionnaire–39. was no significant trend in HOMA-IR by disease
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or
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Fig. 1. Insulin Resistance distribution by body-type. Stacked bar chart describing the relationship between insulin resistance (IR) and body
type. Percentage of subjects who met criteria for IR (see text for definition) is represented on the vertical axis, and it is grouped by body-type,
as determined by body mass index (BMI, kg/m2 ). Normal weight was defined as BMI less than 25, non-obese overweight as BMI greater
than 25 but less than 30, and obese as BMI greater than 30.
4 E. Hogg et al. / Insulin Resistance is Prevalent in PD

Table 2 Table 3
Motor, cognitive, other non-motor symptoms, and health related Non-motor symptoms and health related quality of life sub-
quality of life scores in PD subjects with and without Insulin categorical scores in 71 PD subjects with and without insulin
Resistance resistance
IR+ (n = 95) IR- (n = 66) IR- IR+
MDS-UPDRS III (ON) 17 ± 7.8 18 ± 12.0 NS NMSQ
MDS-UPDRS III (OFF) 20 ± 12.7 21 ± 13.7 NS Gastrointestinal 3.2 ± 2.0 2.6 ± 2.0 NS
H&Y 2.2 ± 0.6 2.3 ± 0.8 NS Urinary 1.4 ± 0.8 1.4 ± 0.7 NS
IR+ (n = 27) IR- (n = 44) Pain 0.3 ± 0.5 0.2 ± 0.4 NS
Cognitive 1.8 ± 0.9 1.3 ± 1.2 NS
MoCA 26.3 ± 3.3 26.6 ± 2.7 NS
Psych 0.3 ± 0.5 0.1 ± 0.4 NS
NMSQ 10.6 ± 4.9 12.6 ± 5.3 NS
Mood 0.8 ± 0.8 1.0 ± 0.8 NS
PDQ-39 156.7 ± 102.6 158.0 ± 106.9 NS
Sexual 1.0 ± 0.8 0.9 ± 0.8 NS
MDS-UPDRS III: Movement Disorder Society Unified Parkin- Cardiovascular 0.7 ± 0.8 0.7 ± 0.7 NS

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son’s Disease Rating Scale part III, H&Y: Hoehn and Yahr scale. Sleep/Fatigue 2.5 ± 1.4 2.1 ± 1.3 NS
0.5 ± 0.6 0.5 ± 0.7

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MoCA: Montreal Cognitive Assessment, NMSQ: Non-Motor Miscellaneous NS
Symptoms Scale, PDQ-39 Parkinson’s Disease Questionnaire – PDQ-39
39, IR: Insulin Resistant based on HOMA≥2.0 and/or HbA1c≥5.7, Mobility 21.2 ± 24.4 22.9 ± 20.9 NS
NS: non-significant. ADLs 23.9 ± 19.6 20.7 ± 18.6 NS
Emotional 21.6 ± 17.6 22.5 ± 16.6 NS
Stigma 17.8 ± 14.0 17.7 ± 18.5 NS

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severity between stages of the H&Y (data not shown). Social support 4.8 ± 10.0 6.3 ± 14.6 NS
Similarly, mean MDS-UPDRS measured either in Cognitive 23.6 ± 18.7 19.2 ± 19.2 NS
Communication 20.2 ± 18.1 22.2 ± 25.7 NS
ON or OFF state did not differ between IR and Bodily discomfort 25.0 ± 21.9 25.2 ± 21.6 NS
non-IR subjects (Table 2). The prevalence of chronic NMSQ: Non-Motor Symptoms Questionnaire; PDQ-39: Parkin-
renal disease was quite low overall and did not dif- son’s Disease Questionnaire – 39, IR: Insulin Resistant based on
fer between IR (4.4%) and non-IR subjects (3.1%). HOMA≥2.0 and/or HbA1c≥5.7, NS: non-significant.
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Chronic cardiac disease, including coronary artery
disease, atrial fibrillation, chronic heart failure and
The DBS subgroup (n = 17) had a significantly
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cardiomyopathy, was also relatively infrequent both
higher mean PD duration (11.9 ± 5.3 years versus
in IR (18.9%) and non-IR subjects (10.9%), while
5.8 ± 5.1 in non-DBS subjects, p < 0.0005) and a
the prevalence of hypertension was higher, affecting
significantly higher NMSQ than non-DBS subjects
35.6% of subjects with IR and 25% of subjects with-
c

(16 ± 4.5 vs. 10.3 ± 4.7, p < 0.005). Weight distribu-

out IR. All these differences failed to reach statistical
tion in the DBS subgroup was similar to the general
significance.
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study population, with 5/17(29.4%) DBS subjects

In the subgroup undergoing more detailed clinical
in the normal weight range, 7/17(41.2%) non-obese
testing (n = 71), mean MoCA score was 26.4 ± 3.0,
overweight, and 5/17(29.4%) obese. Age, BMI,
with 23/71 (32.4%) abnormal values (25 or less)
HOMA-IR, Hb1ac, MoCA, and PDQ-39 were not
and 5/71 (7.0%) values consistent with demen-
or

significantly different between DBS and non-DBS

tia. HOMA-IR, BMI, PD duration, LED, Hb1ac,
subjects.
PDQ-39, NMSQ, and age were not significantly
different between demented and non-demented sub-
DISCUSSION
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jects. MoCA showed a significant inverse correlation

with age (Pearson R = –0.38, p < 0.001) but did not
correlate with PD duration, or HoMA-IR. Mean
NMSQ score was 11.3 ± 5.1. Mean study PDQ-39
was 157.2 ± 103.5. There was no significant differ-
ence between IR and non-IR subjects in sub-section
scores of either PDQ-39 or NMSQ (Table 3). Like-
wise, there was no significant correlation between
BMI subgroups and HbA1c, PD duration, LED,
MoCA, PDQ-39, and NMSQ. Multivariate analy-
sis including HOMA IR and age, disease duration,
MoCA scores, HY stage and weight-adjusted LED in
this subgroup failed to reveal significant predictors of
cognitive decline.
Despite the growing interest in the use of incretin
mimetics in the treatment of PD [21, 22], there is lit-
tle information regarding the prevalence of IR in PD,
with available data limited to a small study show-
ing significantly elevated HOMA index scores in PD
patients as compared to healthy controls [23]. Our
study indicates that almost two thirds of non-diabetic
people with PD may be insulin resistant, despite
normal fasting glucose and, in many cases, normal
HbA1c. These figures suggest that IR in PD is a preva-
lent and largely undetected problem, especially in
those patients who are overweight or obese, a feature
 E. Hogg et al. / Insulin Resistance is Prevalent in PD
reported in the early stages of PD [24]. While our
data confirms previous studies showing that HOMA-
IR is more than double in obese than in lean subjects
[25], we also found a substantially higher percent-
age (41%) of lean PD patients with IR than reported
in healthy adults [26]. This finding may be related
to the abnormal fat distribution in subjects with PD,
which show, on average, a higher visceral to subcuta-
neous fat ratio [27], a feature that correlates with IR
[28]. We were unable to characterize fat distribution
in this study, and therefore the role of abnormal fat
distribution in the high prevalence of IR in PD will
need further evaluation. Nevertheless, we propose
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that HOMA-IR may be a more relevant marker of
metabolic health than BMI in patients with PD, as
BMI does not capture weight distribution. Interest-
ingly, the subgroup of PD patients who underwent
DBS, a treatment frequently associated with weight
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gain [29], had metabolic measures largely similar to
the rest of our PD cohort.
While other dementing neurodegenerative dis-
eases, including Alzheimer’s disease [30], dementia
with subcortical features [31], and Huntington’s dis-
d
ease [32] have been associated with IR, we found
no correlation between HOMA-IR and cognitive
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decline. Mean MoCA scores were virtually iden-
tical in subjects with and without IR. This is in
contrast to prior reports describing elevated HOMA-
IR in subjects with PD-Dementia [33], but in line
c
with other investigations showing an inverse corre-
lation between IR and incidence of dementia [34].
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As expected, advancing age predicted lower MoCA
scores, however PD duration or severity did not. The
unanticipated demographic composition of our study
population affected the relationship between IR and
or
MoCA, as BMI – the most powerful predictor of
IR – inversely correlated with age – a predictor of
cognitive decline. Furthermore, the low incidence
of dementia in our study cohort and the use of a
C
screening test, as opposed to a formal neurocogni-
tive battery, may have limited the sensitivity of our
sample. In the end, the lack of longitudinal sampling
prevents any firm conclusion in regard to a possible
link between IR and cognitive decline.
IR did not appear to affect the prevalence of any
non-motor symptom, as mean NMSQ scores in our
study were comparable to NMSQ data in similar pop-
ulations of PD patients [35]. Likewise, mean PDQ-39
scores in our cohort were consistent with other studies
[36]. IR was not associated with changes in health-
related QoL sub-categories (Table 3). Finally, no
correlation was found between IR and LED, even
5
when adjusted for weight, in line with prior research
showing that levodopa does not affect glucose
tolerance in PD [37].
Despite some controversy [38], HOMA-IR
appears to be a reliable indicator of IR [39] and a more
sensitive and responsive measurement to changes in
body metabolism than other traditional measures,
such as fasting glucose [40]. An optimal cutoff for
HOMA-IR has yet to be determined and may vary
regionally [14, 15, 41] and by age [42]. We used
a cut-off HOMA of 2.0 given that this represents
50% beta cell function, but a lower set point may
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increase sensitivity. IR is an important predictor of
metabolically linked conditions such as DM2 [43]
and cardiovascular disease [44]. The risk of IR is
known to increase with obesity, aging, physical inac-
tivity, and genetic predisposition [45], risk factors
also associated with the diagnosis of PD [46]. Inter-
estingly, IR did not positively correlate with age or
disease duration in our study population, suggest-
ing that IR may be an independent process in PD.
While insulin resistance in aging has been associ-
ated to abdominal obesity in the general population
[47], other authors have suggested that changes in adi-
posity may not fully explain age related increases in
insulin resistance [48]. While we did find a strong
positive correlation between obesity and IR, age
negatively correlated with obesity in our popula-
tion. PD patients tend to initially gain weight [24]
and then lose weight over time, although they may
actually increase caloric intake as weight decreases,
suggesting a complex metabolic picture [49]. Longi-
tudinal data are therefore needed to understand how
weight changes in PD may impact IR status over
time [50].
The generalizability of these results may be lim-
ited, as this study was performed at a single center,
with a largely affluent population who generally has
access to good medical insurance coverage. Two-
thirds of our study population was overweight, a bias
that might have resulted in higher incidence of IR.
In addition, both insulin sensitivity and HOMA may
vary by ethnicity [51], with our cohort including a
caucasian majority. We cannot rule out self-selection
bias of patient at greater risk for IR due to diet, weight,
or other lifestyle factors. Additionally, given the high
prevalence of pre-diabetes or undiagnosed diabetes
in the general population of California [52], the rel-
evance of our findings has to be assessed against a
backdrop of pervasive metabolic disease present in
our region. We did not find a particularly high preva-
lence of diseases characterized by association with
6 E. Hogg et al. / Insulin Resistance is Prevalent in PD
IR in non-PD adults, such as chronic cardiovascular
disease and chronic renal failure [53], with the
possible exception of hypertension. However, the
distribution of hypertension was not significantly
different between IR and non-IR subjects. Finally,
although this study was not intended to address
metabolic syndrome in PD, it is worth noting that
we did not collect lipid and cholesterol data for this
population.
We conclude that peripheral IR is prevalent in PD
and may be an under-diagnosed problem in a large
proportion of PD patients, especially in those who
are overweight or obese. Given the early occurrence
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of weight gain in PD and the putative role of IR in
accelerating the progression of motor and non-motor
features of PD, we believe that these data will deserve
further attention and research.
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ACKNOWLEDGMENTS
Financial support for this research was solely
through internal departmental funding, including the
Caron and Steven D. Broidy Chair in Movement
d
Disorders.
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CONFLICT OF INTEREST
The authors have no conflict of interest to report.
c
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