High prevalence of gastroesophageal reflux symptoms in type 2 diabetics with hypoadiponectinemia and metabolic syndrome.

Abstract

The prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide. Abdominal obesity or visceral fat accumulation rather than simple obesity is associated with GERD. Previous reports demonstrated the association between GERD and type 2 diabetes mellitus (T2DM). Signification of visceral fat accumulation and adiponectin in T2DM patients with GERD remains unclear. The present study investigated the relationships between GERD symptoms, visceral fat accumulation and adiponectin in subjects with T2DM.
The study (ADMIT study) subjects were 66 Japanese T2DM outpatients, who answered the questionnaire regarding GERD symptoms in Frequency Scale for the Symptoms of GERD (FSSG), and were measured visceral fat area by bioelectrical impedance analysis. Patients with FSSG scores of more than 8 were considered as positive. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with the metabolic syndrome (Mets) were significantly higher compared to those without Mets. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with low levels of serum adiponectin were significantly higher compared to those with high levels of serum adiponectin. Moreover, the combination of Mets and hypoadiponectinemia had a multiplicative effect on GERD symptom score (p = 0.047).
Our study showed that the coexistence of MetS and low levels of serum adiponectin was associated with the higher prevalence of FSSG score ≥ 8 and the higher scores of GERD symptom in subjects with T2DM.
UMIN 000002271.

Full text

Page 1

BRIEF COMMUNICATIONOpen Access
High prevalence of gastroesophageal reflux
symptoms in type 2 diabetics with
hypoadiponectinemia and metabolic syndrome
Ayumu Hirata1, Ken Kishida1,2*, Hideaki Nakatsuji1, Kana Inoue1, Aki Hiuge-Shimizu1, Tohru Funahashi1,2and
Iichiro Shimomura1
Abstract
Background: The prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide.
Abdominal obesity or visceral fat accumulation rather than simple obesity is associated with GERD. Previous reports
demonstrated the association between GERD and type 2 diabetes mellitus (T2DM). Signification of visceral fat
accumulation and adiponectin in T2DM patients with GERD remains unclear. The present study investigated the
relationships between GERD symptoms, visceral fat accumulation and adiponectin in subjects with T2DM.
Findings: The study (ADMIT study) subjects were 66 Japanese T2DM outpatients, who answered the questionnaire
regarding GERD symptoms in Frequency Scale for the Symptoms of GERD (FSSG), and were measured visceral fat
area by bioelectrical impedance analysis. Patients with FSSG scores of more than 8 were considered as positive.
The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with the metabolic syndrome (Mets)
were significantly higher compared to those without Mets. The prevalence of FSSG score ≥ 8 and average FSSG
score in T2DM subjects with low levels of serum adiponectin were significantly higher compared to those with
high levels of serum adiponectin. Moreover, the combination of Mets and hypoadiponectinemia had a
multiplicative effect on GERD symptom score (p = 0.047).
Conclusions: Our study showed that the coexistence of MetS and low levels of serum adiponectin was associated
with the higher prevalence of FSSG score ≥ 8 and the higher scores of GERD symptom in subjects with T2DM.
Trial Registration
UMIN 000002271.
Keywords: gastroesophageal reflux symptom, metabolic syndrome, visceral fat, adiponectin
Background
The prevalence of gastroesophageal reflux disease
(GERD) has been increasing worldwide [1], and is asso-
ciated with impairment of quality of life (QOL), Barrett’s
esophagus, esophageal carcinogenesis and lifestyle-
related diseases including sleep dysfunction, metabolic
disorders and heart disease [2]. This increase is likely
associated with the increased prevalence of obesity [2].
Obesity is shown to be an independent risk factor of
GERD [3], through increased transient lower esophageal
sphincter relaxation, which is an important mechanism
of GERD [4]. Abdominal obesity or visceral fat accumu-
lation rather than simple obesity is associated with
GERD [5,6]. With accumulation of visceral fat, circulat-
ing levels of adiponectin, a potential anti-inflammatory
adipocytokine, are decreased, whereas circulating levels
of proinflammatory cytokines, such as interleukin-6 (IL-
6), are increased. Low serum adiponectin levels were
reported in subjects with esophago-gastro-duodeno-
scopic erosive esophagitis [7] or obese patients with
GERD [8,9]. Visceral fat accumulation and dysregulated
production of adipocytokines could exacerbate local
inflammation at the esophagogastric junction.
* Correspondence: kkishida@imed2.med.osaka-u.ac.jp
1Department of Metabolic Medicine, Graduate School of Medicine, Osaka
University, Suita, Osaka 565-0871, Japan
Full list of author information is available at the end of the article
Hirata et al. Nutrition & Metabolism 2012, 9:4
http://www.nutritionandmetabolism.com/content/9/1/4
© 2012 Hirata et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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Previous reports demonstrated the association
between GERD and type 2 diabetes mellitus (T2DM) in
Japanese [10-12]. Signification of visceral fat accumula-
tion and adiponectin in T2DM patients with GERD
remains unclear. Ambulatory 24-h pH test-monitoring is
the gold standard for diagnosing GERD [13]. This
method, however, places pressure on patients. A ques-
tionnaire for the diagnosis of reflex disease (QUEST)
was introduced and its usefulness for GERD diagnosis
has been evaluated in Western countries [14]. However,
QUEST have several problems that it was not easy to
complete the questionnaire and evaluate therapeutic
response of GERD in Japanese [15], and therefore, a
new questionnaire for Japanese (FSSG; Frequency Scale
for the Symptoms of GERD) was developed [16]. The
present study investigated the relationships between
GERD symptom score using FSSG, visceral fat accumu-
lation and adiponectin in Japanese T2DM patients.
Table 1 Baseline characteristics of type 2 diabetic patients in the present study (n = 66)
Metabolic syndrome (-)
(n = 38)
Metabolic syndrome (+)
(n = 28)
p value
Gender, male/female
Age, years
Body mass index, kg/m2
Waist circumference, cm
Estimated visceral fat area, cm2
Estimated glomerular filtration rate, mL/min
Blood glucose, mg/dL
Fasting immunoreactive insulin, μIU/mL (n = 50)
HbA1c (NGSP), %
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Triglyceride, mg/dL
High-density lipoprotein cholesterol, mg/dL
Low-density lipoprotein cholesterol, mg/dL
Smoking (none/ex-/current-smoker)
Brinkman index
Duration of diabetes, years
Diabetic neuropathy
Diabetic retinopathy (NDR/SDR/PDR)
Diabetic nephropathy (stage I/II/III)
Hypertension
Dyslipidemia
Medications for hypertension (CA/ACEIorARB/b/diuretics/a)
Medications for diabetes
(SU/BG/aGI/glinide/Insulin)
Medications for dyslipidemia (statins/fibrate)
Serum adiponectin, μg/mL (all; n = 66)
adiponectin, μg/mL (males)
adiponectin, μg/mL (females)
Serum interleukin-6 (IL-6), pg/mL (all; n = 66)
IL-6, pg/mL (males)
IL-6, pg/mL (females)
Serum TBARS, nmol/mL (all, n = 66)
TBARS, nmol/mL (males)
TBARS, nmol/mL (females)
FSSG scores
< 8/≥ 8
18/20
63 ± 1 (36-78)
23.2 ± 0.53 (19.1-32.7)
84.1 ± 1.3 (69-104)
97 ± 7 (34-192)
74.4 ± 2.9 (34.4-114)
131 ± 46 (83-261)
8.6 ± 0.9 (2.9-15.0)
7.1 ± 0.1 (5.9-10.6)
130 ± 2 (105-180)
74 ± 1 (60-100)
109 ± 9 (41-260)
59 ± 2 (34-97)
111 ± 5 (57-208)
15/13/10
531 ± 106 (0-3000)
10 ± 1 (1-38)
7
31/3/4
25/8/5
11
21
7/12/3/1/1
15/8/7/2/11
9/19
67 ± 2 (40-88)
25.9 ± 0.62 (20.9-36.4)
91.4 ± 1.3 (65-109)
154 ± 8 (101-226)
64.8 ± 3.3 (28.8-97.3)
130 ± 7 (84-196)
9.0 ± 1.1 (2.9-26.2)
7.2 ± 0.2 (5.6-9.6)
134 ± 3 (110-160)
76 ± 1 (60-91)
150 ± 12 (78-396)
54 ± 2 (38-93)
116 ± 6 (57-203)
9/13/6
538 ± 124 (0-1800)
11 ± 1 (1-38)
10
18/6/4
16/5/7
22
21
15/18/3/2/1
11/11/8/0/5
0.210
0.101
0.016
0.002
< 0.0001
0.039
0.823
0.860
0.702
0.708
0.423
0.011
0.181
0.550
0.604
0.622
0.529
0.104
0.314
0.359
0.009
0.100
0.309
0.157
16/0
9.8 ± 0.9 (2.3-33.5)
8.5 ± 1.1 (2.3-23.0)
11.2 ± 1.5 (3.9-33.5)
3.37 ± 0.39 (0.33-13.75)
3.92 ± 0.59 (0.81-13.75)
2.71 ± 0.46 (0.33-5.59)
4.49 ± 0.15 (2.68-7.30)
4.45 ± 0.20 (2.68-6.10)
4.53 ± 0.24 (3.24-7.30)
2.5 ± 1.4 (0-24)
33/5
16/0
8.4 ± 1.1 (2.2-21.5)
7.6 ± 1.2 (2.2-21.5)
9.8 ± 1.9 (4.2-11.5)
2.36 ± 0.45 (0.33-5.4)
2.16 ± 0.63 (0.33-5.4)
2.73 ± 0.60 (0.81-4.75)
4.68 ± 0.18 (3.01-6.56)
4.44 ± 0.21 (3.01-6.56)
5.23 ± 0.35 (4.00-6.20)
8.6 ± 1.8 (0-24)
18/10
0.125
0.235
0.583
0.576
0.286
0.075
0.582
0.423
0.958
0.112
0.015
0.031
mean ± SEM or n (range), NDR: non-diabetic retinopathy, SDR; simple diabetic retinopathy, PDR; proliferative diabetic retinopathy, SU; sulfonyl urea, BG;
biguanide, aGI; alpha glucosidase inhibitor, CA; calcium channel antagonist, ACEI; angiotensin converting enzyme inhibitor, ARB; angiotensin receptor blocker, b;
b blockade, a; a blockade, TBARS; thiobarbituric acid reactive substance.
Estimated glomerular filtration rate = 194 × creatinine-1.094x age-0.287.
Significant level was set at p value < 0.05 (bold type).
Hirata et al. Nutrition & Metabolism 2012, 9:4
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Methods and Procedures
Study population
Subjects were recruited from consecutive Japanese
T2DM outpatients, who answered the questionnaire
regarding GERD symptoms in FSSG, and were measured
visceral fat area by bioelectrical impedance analysis
(BIA) [17], in the “Diabetes & Metabolic Station”, Osaka
University Hospital, between September 2009 and
November 2011. Exclusion criteria included patients
that were pregnant, a nursing mother, or a shift worker.
Disease-related exclusion criteria included the following;
malignant diseases, active peptic ulcer disease, or a past
history of upper gastrointestinal surgery. Patients were
also ineligible if they had received continuously acid-
suppression drugs (histamine-2 blockers and proton-
pump inhibitors). The study subjects comprised 66 Japa-
nese excluding subjects who were treated with pioglita-
zone (n = 4), which is known to increase serum
adiponectin levels in T2DM [18]. This study approved
by the Medical Ethics Committee of Osaka University.
All participants were Japanese and each gave a written
informed consent. This study (ADMIT study) is regis-
tered under number UMIN 000002271.
https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?func-
tion=brows&action=brows&type=summary&recptno=
R000002777&language=E
GERD score
The FSSG consisted of 12 questions, which were scored
to indicate the frequency of symptoms as follows: never
= 0; occasionally = 1; sometimes = 2; often = 3; and
always = 4. Patients with FSSG scores of more than 8
were considered as positive (When the cut-off score was
set at 8 points, this test shows a sensitivity of 62%, a
specificity of 59%, and an accuracy of 60% [16]). Based
upon 80% power to detect statistically significant differ-
ences (p = 0.05; two-sided), a sample size of at least 25
patients in each group was required to demonstrate
(total sample size = 50), according to previous reports
[9,10].
Anthropometry and laboratory measurements
Venous blood samples were collected in the morning
after overnight fast for measurements of each parameter
and adiponectin (Otsuka Pharmaceutical Co., Tokush-
ima, Japan, intra-coefficient of variation (CV); < 10%,
inter-CV < 10%), IL-6 (Human IL-6 Quantikine ELISA
Kit, R&D Systems, USA, intra-CV; 7.3%, inter-CV 7.7%),
as we previously reported [18,19]. Serum concentration
of thiobarbituric acid-reacting substance (TBARS), an
important biomarker of systemic oxidative stress reflect-
ing serum lipid peroxidation products, was determined
by the method of Yagi (Japan Institute for the Control
of Aging, Nikken SEIL Co., Shizuoka, Japan), as reported
previously by our group [18]. Diabetic retinopathy,
nephropathy and peripheral neuropathy were diagnosed,
as we previously reported [20]. The metabolic syndrome
(Mets) was diagnosed according to the Japanese guide-
lines for Mets based on VFA ≥ 100 cm2[21]. Briefly, the
voltage recorded at the flank to the flow of current
between the umbilicus and the back correlates signifi-
cantly with visceral fat area (VFA) and is not influenced
by subcutaneous fat. We reported previously that VFA
estimated by BIA (eVFA) correlates significantly with
that determined by computed tomography (CT) (r =
0.88, p < 0.0001) [17]. The CV of BIA with the value of
CT was 0.89% in the standing position and late exhala-
tion. A cutoff value for BIA-measured eVFA was 100
cm2for both males and females as criteria to screen
coming multiple obesity-related cardiovascular risk fac-
tors [22].
Statistical analysis
Data are mean ± SEM, and compared by the c2and
Mann-Whitney U-test in experiments of two groups. In all
cases, a p value < 0.05 was considered statistically signifi-
cant. All analyses were performed with the JMP Statistical
Discovery Software 9.0 (SAS Institute, Cary, NC).
Results
Characteristics of subjects enrolled in the present study
The baseline characteristics of the patients are listed in
Table 1. The prevalence of FSSG score ≥ 8 in subjects
with T2DM was 23% (n = 15/66).
Contribution of the metabolic syndrome and adiponectin
on GERD symptoms
To investigate the contribution of Mets on GERD symp-
toms, the subjects were divided into two groups, those
without and with Mets. The prevalence of FSSG score ≥
8 and average FSSG score in T2DM subjects with Mets
were significantly higher compared to those without
Mets (Figure 1A). Next, to investigate the contribution
of adiponectin on GERD symptoms, the subjects were
divided into two groups, those with low and high circu-
lating levels of adiponectin (cutoff value 6.31 μg/mL for
men, 8.62 μg/mL for women, median value, respec-
tively). The prevalence of FSSG score ≥ 8 and average
FSSG score in T2DM subjects with low levels of serum
adiponectin were significantly higher compared to those
with high levels of serum adiponectin (Figure 1A). How-
ever, there was no significant difference of the preva-
lence of FSSG score ≥ 8 and average FSSG score in
between T2DM subjects with low and high levels of
serum IL-6 (cutoff value 2.02 pg/mL for men, 2.65 pg/
mL for women, median value, respectively) (Figure 1A).
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There was also no significant difference of the preva-
lence of FSSG score ≥ 8 and average FSSG score in
between T2DM subjects with low and high levels of
serum TBARS (cutoff value 4.24 nmol/mL for men, 4.90
nmol/mL for women, median value) (27% versus 21%; p
= 0.565, 6.0 ± 1.7 versus 4.9 ± 1.7; p = 0.648, data no
shown).
Finally, multiple regression analysis (adopted factors;
age, sex, Mets, adiponectin, Mets × adiponectin) identi-
fied interaction term (Mets × adiponectin) as a signifi-
cant determinant of GERD symptom score (p = 0.047,
Figure 1B). These results indicated that the combination
of Mets and hypoadiponectinemia had a multiplicative
effect on GERD symptom score.
Discussion
The study of Japanese T2DM patients demonstrated for
the first time that 1) the prevalence of T2DM with
FSSG score ≥ 8 was 23% (n = 15/66), 2) the coexistence
of Mets and low levels of serum adiponectin was asso-
ciated with GERD symptoms. We have demonstrated
that adiponectin suppresses inflammation in various
organs, such as the heart, lung, aorta, kidney, liver,
colon and pancreas [23]. Adiponectin may also play a
protective role of erosive esophagitis. To clarify the pro-
tective effect of adiponectin on GERD, further experi-
mental studies are required. On the other hand,
increased systemic IL-6 concentrations are associated
with the pathophysiology of T2DM, with adipose tissue
being the major source of this cytokine [24]. Exposure
to components of the gastric refluxate is sufficient to
stimulate esophageal cells to release a pro-inflammatory
cytokine, IL-6, with the potential to mediate the esopha-
geal motor abnormalities associated with GERD-induced
esophagitis [25]. However, the present study show
serum IL-6 levels are not associated with GERD symp-
toms in T2DM. Taken together, the results suggest that
decreased anti-inflammatory cytokines rather than
increased pro-inflammatory cytokines may be associated
with the development of GERD-induced erosive esopha-
gitis. We described here the prevalence and characteris-
tics of Japanese diabetics with GERD symptoms, and it
may be therefore necessary to diagnose a treatable
GERD from the standpoint of prevention of lifestyle-
related diseases as well as improvement of QOL in
T2DM patients. Large-scale interventional trials, such as
weight reduction, intensive anti-GERD and anti-diabetes
(especially thiazolidinedione which is known to increase
serum adiponectin) drugs or combinations of these
therapies, should be provided to assess the effects of
appropriate treatment on the outcome of T2DM
patients with GERD symptoms.
Several limitations of this study must be considered.
First, this is a cross-sectional study, making it difficult
to establish a cause-effect relationship. Further prospec-
tive studies should be conducted in the future to analyze
this relationship. Second, the results may not be applic-
able to females or non-Japanese populations. Third, the
current study did not include the effects of alcohol
intake, smoking habits, mental status, dietary habit and
use of pharmacotherapy (such as nonsteroidal anti-
inflammatory drugs; NSAIDs). The current study found
that the prevalence of FSSG score ≥ 8 and average FSSG
score were not influenced by smoking habits and use of
NSAIDs. Finally, further replication studies of larger
sample need to be designed including these confounding
variables, such as potential factors to be influenced
Figure 1
Prevalence of
FFSG Score ?8
(%)
-
+
0
2
4
6
10
8
p=0.015
n
38 28
Mean FFSG
Score
Adiponectin
p=0.015
33
High
33
Low
A
Metabolic syndrome
25
50
0
p=0.031 p=0.006
-
+
B
0
2
4
6
8
10
12
14
Mean FFSG
Score
IL-6
p=0.372
p=0.497
33
High
33
Low
n=22
n=11
n=16
n=17
Figure 1 A. Mean FSSG score in relation to the metabolic
syndrome (Mets), serum adiponectin levels (serum adiponectin
levels; cutoff value 6.31 μg/mL for men, 8.62 μg/mL for
women, median value, respectively), and serum interleukin-6
(IL-6) (cutoff value 2.02 pg/mL for men, 2.65 pg/mL for
women, median value, respectively). B. Comparison of
prevalence of GERD symptoms (FSSG score ≥ 8) and FSSG
score between T2DM without and with Mets, and with low and
high levels of serum adiponectin. Data are mean ± SEM, and
compared by the c2and Mann-Whitney U-test in experiments of
two groups. All analyses were performed with the JMP Statistical
Discovery Software 9.0 (SAS Institute, Cary, NC).
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serum adiponectin levels, such as smoking status, use of
pharmacotherapy (ACE-I/ARB, statin), in the future.
In conclusion, the coexistence of MetS and low levels
of serum adiponectin was associated with the higher
prevalence of GERD symptom in subjects with T2DM.
List of Abbreviations
BIA: bioelectrical impedance analysis; CV: coefficient of variation; eVFA:
estimated visceral fat area; FSSG: Frequency Scale for the Symptoms of
GERD; GERD: gastroesophageal reflux disease; IL-6: interleukin-6; Mets:
metabolic syndrome; QOL: quality of life; TBARS: thiobarbituric acid-reacting
substance; T2DM: type 2 diabetes mellitus.
Acknowledgements and funding
We thank all staff at “Diabetes & Metabolic Station” for the excellent medical
care, and Mrs. Miyuki Nakamura and Mr. Takeshi Nishimura for the excellent
technical assistance. This research was supported in part by a Grant-in-Aid
for Scientific Research on Innovative Areas (Research in a proposed research
area) “Molecular Basis and Disorders of Control of Appetite and Fat
Accumulation” (#22126008, to T.F. and K.K.).
Author details
1Department of Metabolic Medicine, Graduate School of Medicine, Osaka
University, Suita, Osaka 565-0871, Japan.2Department of Metabolism and
Atherosclerosis, Graduate School of Medicine, Osaka University, Suita, Osaka
565-0871, Japan.
Authors’ contributions
A.H. and K.K. researched and analyzed data. K.K. also participated in the
concept and design of the study, interpretation of data and reviewed/edited
the manuscript. H.N., K.I. and A.H-S. recruited the patients and collected the
data. T.F. and I.S. contributed to discussion and wrote the manuscript. All
authors read and approved the final version of the manuscript.
Competing interests
K.K. and T.F. are members of the “Department of Metabolism and
Atherosclerosis”, a sponsored course endowed by Kowa Co. Ltd. and a
company researcher is dispatched to the course. All other authors declare
no competing interests.
Received: 21 December 2011 Accepted: 25 January 2012
Published: 25 January 2012
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