Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation
Fukuda et al. Cardiovascular Diabetology
Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation
Shiro Fukuda 0
Ayumu Hirata 1
Hitoshi Nishizawa 0
Hirofumi Nagao 0
Susumu Kashine 0
Takekazu Kimura 0
Kana Inoue 0
Yuya Fujishima 0
Masaya Yamaoka 0
Junji Kozawa 0
Tetsuhiro Kitamura 0
Tetsuyuki Yasuda 0
Norikazu Maeda 0
Akihisa Imagawa 0
Tohru Funahashi 1
Iichiro Shimomura 0
0 Department of Metabolic Medicine, Graduate School of Medicine, Osaka University , 2-2 B-5, Yamada-oka, Suita, Osaka 565-0871 , Japan
1 Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University , 2-2-B, Yamada-oka, Suita, Osaka 565-0871 , Japan
Background: Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in 2 a considerable number of Japanese non-obese subjects (BMI <25 kg/m ). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation. Methods: The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 11.5 years, mean SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm2 using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity. Results: The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation () group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than () patients. Conclusions: Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.
Type 2 diabetes; Visceral fat accumulation; Adiponectin; Systemic arteriosclerosis; Vascular ultrasonography; Eating behavior
Type 2 diabetes mellitus accelerates the process of
arteriosclerosis and may result in severe cardiovascular events.
Since a variety of etiological factors seem to contribute to
type 2 diabetes mellitus, it is important to understand the
etiology in each patient and detect potential arteriosclerosis
at an early stage. In type 2 diabetes, arteriosclerosis is a
polyvascular and multifocal disease that can advance
without overt symptoms, making early prediction of
coronary artery diseases (CAD) important for the
prevention of cardiovascular events in these patients. We
have recently reported that quantification of the severity
of arteriosclerosis by vascular ultrasonography is a useful
tool for predicting CAD, and that the metabolic syndrome
was a significant determinant of total systemic vascular
score of 2 .
Recently, the prevalence of obesity-related type 2
diabetes mellitus has increased worldwide, especially in Asia
[2-5]. We reported previously that a considerable
proportion of non-obese (body mass index (BMI) <25 kg/m2)
Japanese subjects have visceral fat accumulation (visceral
fat area (VFA) 100 cm2), as well as multiple risk factors
of cardiovascular diseases, and that reduction of VFA
was significantly associated with a decrease in total
cardiovascular risk . Patients with visceral fat accumulation
also show dysregulation of adipocytokines, such as
hypoadiponectinemia, which is associated with type 2
diabetes mellitus and CAD [7-9]. Adiponectin is an
adipose-specific endocrine factor that exhibits
antidiabetic, anti-atherogenic, and anti-inflammatory
properties. It is therefore possible that type 2 diabetic patients
with visceral fat accumulation may be more affected by
arteriosclerosis, although there is little evidence to confirm
or deny this hypothesis.
In modifying the lifestyle of patients with obesity,
cognitive behavioral therapy is important in addition to diet and
exercise therapy , and research findings show a
relationship between eating behavior and obesity/weight gain .
It is therefore important to help each patient identify and
improve eating behavior problems. In the present study, we
investigated differences in the clinical features of Japanese
type 2 diabetic patients with and without visceral fat
accumulation, focusing on systemic arteriosclerosis, serum
adiponectin concentration, and eating behavior.
The study subjects were selected from April 2012 to
December 2012 among inpatients hospitalized for the
control type 2 diabetes at the Division of Endocrinology and
Metabolism of Osaka University Hospital, and
outpatients who visited the Diabetes & Metabolic Station
outpatient clinic of Osaka University Hospital. Written
consent was obtained from each subject after explaining
the purpose and possible complications of the study.
This study complied with the Guidelines of the Ethnical
Committees of Osaka University. Type 2 diabetes was
defined according to the World Health Organization
(WHO) national diabetic group criteria of 2006 and/or
treatment of diabetes. The following patients were
excluded: 1) patients in whom waist circumference (WC)
and estimated visceral fat area (eVFA; see Clinical
examination) was not measured, 2) patients who were not
clinically diagnosed with type 2 diabetes mellitus.
Height, weight, and WC were measured in the standing
position (in inpatients, these data were measured on
admission). The bioelectrical impedance analysis method
was used to measure eVFA, which we showed previously to
correlate significantly with VFA determined by computed
tomography . The duration of diabetes was retrieved
through medical interview. Systolic/diastolic blood pressure
(BP) was measured with a standard mercury
sphygmomanometer on the right arm in the supine position after
at least 10 minutes of rest. Venous blood samples were
collected in the morning after overnight fasting for
measurements of glucose and HbA1c (National
Glycohemoglobin Standardization Program (NGSP)), serum
C-peptide, lipids, creatinine, and uric acid (UA). Estimated
glomerular filtration rate (eGFR) was calculated using the
simplified Modification of Diet in Renal Disease equation
modified by the appropriate coefficient for Japanese
populations by gender . The serum samples obtained
at baseline from each participant were stored promptly
at 20C. After thawing, serum levels of total adiponectin
in 62 patients were measured by enzyme-linked
immunosorbent assay (ELISA) (human adiponectin ELISA
kit, Otsuka Pharmaceutical Co. Tokushima, Japan), as
reported previously . Urinary albumin-creatinine
ratio (uACR) was calculated from a single spot urine
specimen collected in the morning. The maximum or mean
intima-media thickness (IMT) of the common carotid
artery was measured in supine position by echography
as described previously [15,16].
Definition of visceral fat accumulation, diabetic retinopathy,
diabetic nephropathy, hypertension, dyslipidemia, and
Visceral fat accumulation was defined as eVFA 100 cm2
[17,18]. Diabetic retinopathy was assessed by an
ophthalmologist, and based on this we divided patients into two
groups (NDR and SDR/PrePDR/PDR). Diabetic
nephropathy was diagnosed when the uACR was 30 mg/g
creatinine. Hypertension was defined by systolic BP 140 mmHg
and/or diastolic BP 90 mmHg. Dyslipidemia was defined
as low-density lipoprotein cholesterol (LDL-C)
concentrations 140 mg/dl, triglyceride (TG) concentrations 150
mg/dl, and/or high-density lipoprotein cholesterol (HDL-C)
concentrations 40 mg/dL. Patients were considered
positive for hypertension and/or dyslipidemia if they received
antihypertensive and/or anti-dyslipidemic medications,
respectively. Metabolic syndrome was defined as follows:
1) eVFA 100 cm2 and 2) positive for hypertension or
dyslipidemia (except for the criteria of LDL-C). This
definition was based on the Japanese guidelines for
metabolic syndrome , using eVFA instead of WC.
Questionnaire for eating behavior
Eating behavior was assessed in patients by using the
questionnaire of The Guideline For Obesity issued by the
Japan Society for the Study of Obesity, as in our previous
reports [20,21]. Briefly, this questionnaire comprises
55item questions of seven major scales as follows: 1)
recognition for weight and constitution, 2) external eating
behavior, 3) emotional eating behavior, 4) sense of hunger,
5) eating style, 6) food preference, and 7) regularity of
eating habits. All items were rated on a four-point scale
ranging from 1 (seldom) to 4 (very often).
Evaluation of systemic vascular score
Among all study patients, 67 subjects were scored as
having systemic arteriosclerosis by vascular ultrasonography,
as per our previous report . Briefly, we qualitatively
evaluated the presence of systemic arteriosclerosis by
systemic vascular ultrasonography using an ultrasound
scanner, evaluating the vessel interior of the following
four arteries: 1) common carotid arteries (for existence
of plaque, calcification), 2) renal arteries (stenosis), 3)
abdominal aorta between the diaphragm and bifurcation
of the common iliac arteries (plaque, calcification,
aneurysm), and 4) common iliac arteries (plaque,
calcification). Plaques in the aortic and common iliac artery
walls were considered present when the intimal surface
was not smooth and >1 mm in thickness. Renal arterial
stenosis was diagnosed by a peak systolic velocity of
more than 200 cm/sec with post-stenotic turbulence or
renal aortic flow velocity ratio. The score was set as 1
for an abnormality on either side in carotid, renal, and
common iliac arteries (0 to 4).
Data are presented as mean SD. First, Shapillo-Wilks W
test was used to determine the distribution of each
parameter. Next, the difference between groups in systolic BP,
diastolic BP, LDL-C, HDL-C, and UA (i.e., variables with
normal distribution) were analyzed with Welchs t-test.
For the other parameters (variables with skewed
distribution), Mann-Whitneys U test was used. We performed
the Cochran-Armitage trend test to analyze relationships
between the systemic vascular score groups. Fischers
exact test was used to compare gender, frequencies of
diabetic retinopathy, nephropathy, hypertension, and
dyslipidemia, and percentage of patients with systemic vascular
score exceeding 2. In all cases, probability (P) values
of <0.05 were considered statistically significant. All
analyses were performed with the JMP Pro 10.0.2 for
Windows (SAS Institute, Cary, NC).
We screened 92 Japanese patients with type 2 diabetes
(75 inpatients and 17 outpatients), excluded 17 patients
(they did not have eVFA data), and finally enrolled 75
patients in this study (58 inpatients and 17 outpatients; 41
males and 34 females; age, 64.8 11.5 years; BMI 26.4
5.8 kg/m2, WC; males 95 14.4 cm, females 93.3 11.9
cm; eVFA; males 151.4 73.0 cm2, females 118.9 55.5
cm2). The enrolled patients were divided into two groups
based on eVFA. We defined the 53 patients (32 males and
21 females, 42 inpatients and 11 outpatients) with an
eVFA 100 cm2 as the visceral fat accumulation (+) group,
and the 22 remaining patients (9 males and 13 females,
16 inpatients and 6 outpatients) as the visceral fat
accumulation () group. Table 1 summarizes the baseline
characteristics of the patients.
Compared with the visceral fat accumulation () group,
the (+) group had significantly shorter duration of
diabetes, higher serum C-peptide, higher TG, lower HDL-C,
higher UA levels, and higher percentage of dyslipidemia.
On the other hand, there were no significant differences
in age, sex, BP, glucose, HbA1c, T-Cho, LDL-C, Cr, eGFR,
uACR, max IMT, or mean IMT. Furthermore, there were
no significant differences between the two groups in the
prevalence of diabetic retinopathy, diabetic nephropathy,
hypertension, or medications.
Evaluation of systemic vascular score and serum adiponectin
Figure 1 shows the distribution of systemic vascular
scores and serum adiponectin levels in each group. We
evaluated systemic arteriosclerosis by ultrasonography in
67 subjects (46 of (+) group and 21 of () group). The
systemic vascular score was significantly higher in the
visceral fat accumulation (+) group than in the () group
(Figure 1A). Furthermore, the percentage of subjects with
a systemic vascular score 2 was significantly higher in
the (+) group than in the () group (Figure 1B). Serum
adiponectin levels were measured in 62 subjects (44 of (+)
group and 18 of () group). The visceral fat accumulation
(+) group had significantly lower serum adiponectin levels
(10.33 7.07 g/ml) than the () group (5.82 3.61 g/ml)
Assessment of eating behavior
Figure 2 shows a radar chart of eating behavior among all
study subjects, with the visceral fat accumulation (+) group
(continuous line) showing a significantly higher score than
the () group (dotted line) in total score, recognition for
weight and constitution, external eating behavior, sense
of hunger, food preference, and regularity of eating
habit (Figure 2A).
Finally, we examined eating behavior between males
(n = 41) and females (n = 34). The differences between
the (+) and () groups in males were similar to those in
all subjects. On the other hand, in females (Figure 2C),
only recognition for weight and constitution showed a
significant difference between (+) and () groups.
In this study, type 2 diabetic patients with visceral fat
accumulation showed 1) progression of systemic arteriosclerosis,
Table 1 Baseline characteristics (Continued)
n = 37 (49%)
n = 37 (49%)
Data are mean SD [minimum-maximum], or number of subjects (frequency (%)). eVFA; estimated visceral fat area, BP; blood pressure, NGSP; National
Glycohemoglobin Standardization Program, T-Cho; total cholesterol, TG; triglyceride, LDL-C; LDL cholesterol, HDL-C; HDL cholesterol, UA; uric acid, eGFR; estimated
glomerular filtration rate, uACR; urine albumin-to-creatinine ratio, CCA; common carotid artery, IMT; intima-media thickness, Alpha-GI; alpha-glucosidase inhibitor,
DPP-4; dipeptidyl peptidase-4, GLP-1; glucagon-like peptide-1, ACEI; angiotensin-converting enzyme inhibitor, ARB; angiotensin II receptor blocker. **Fishers exact
test (males vs females), +; Mann-Whitneys U test ((+) group vs () group), *Fishers exact test ((+) group vs () group), #; Welchs t-test ((+) group vs. () group).
Figure 1 Visceral fat accumulation and (A) number of subjects,
(B) percentage of subjects with systemic vascular score 2, (C)
serum total adiponectin levels. Each P value is calculated with:
(A); Cochran-Armitage trend test, (B); Fischers exact test, (C);
Mann-Whitneys U test. Data are mean SD.
2) low serum adiponectin levels, and 3) different eating
behaviors from those without visceral fat accumulation.
Systemic arteriosclerosis and serum adiponectin levels in
type 2 diabetic patients with visceral fat accumulation
We have shown that systemic arteriosclerosis predicts
CAD development in patients with type 2 diabetes ,
and that metabolic syndrome is a determinant of systemic
arteriosclerosis . Moreover, hypoadiponectinemia
correlates with visceral fat accumulation  and predicts the
risk of CAD in Japanese type 2 diabetic patients .
Adiponectin is an adipocyte-derived plasma protein, which
our group identified through a human cDNA project
targeting adipose tissue  and which shows various
anti-atherogenic effects in vascular endothelial cells,
smooth muscle cells, and macrophages in cell culture
[24-26]. Furthermore, administration of adiponectin with
adenovirus vector suppressed the progression of
arteriosclerosis in apolipoprotein E-knockout mouse, which is
the animal model for arteriosclerosis .
Although several research groups reported that
adiponectin correlates with diabetes mellitus and/or
arteriosclerosis, few studies have compared serum adiponectin
levels between type 2 diabetic patients with visceral fat
accumulation and those without. The present study
therefore provides the first evidence to clarify the state of
hypoadiponectinemia in type 2 diabetic patients with visceral fat
accumulation, and to suggest that these states together
could be associated with the progression of systemic
arteriosclerosis. Hypoadiponectinemia is associated with type
2 diabetes, metabolic syndrome, and atherosclerosis .
Recently, we reported that C1q-binding adiponectin levels
were high in patients with ACS, suggesting the possibility
of a protective role of adiponectin against
activatedcomplement system in ACS patients. On the other hand, it
is reported that high serum adiponectin is correlated with
cardiovascular mortality . The patients with heart
failure or renal failure had also high plasma
adiponectin levels [30,31]. It is possible that the plasma
adiponectin levels were affected by various pathophysiological
conditions. Further studies are needed to clarify the
association between plasma adiponectin levels and
Figure 2 Comparisons of eating behavior between (+) group (the subjects with visceral fat accumulation, solid line) and () group
(those without, dotted line), (A) in all subjects, (B) in male subjects, (C) in female subjects. *; P < 0.05, **; P < 0.01, (+) group versus ()
group, calculated with Mann-Whitneys U test.
In the present study, we found that 45% of the non-obese
(BMI <25 kg/m2) subjects had visceral fat accumulation
(eVFA 100 cm2) and that the frequency of two or more as
a vascular score is significantly higher in such patients than
in non-obese patients without visceral fat accumulation
(BMI <25 kg/m2 and eVFA <100 cm2) (87.5% vs. 42.9%,
respectively), while their serum adiponectin levels tended to
be lower (5.96 1.9 vs. 10.23 7.14 g/ml, P = 0.09). Thus,
the type 2 diabetic patients with visceral fat accumulation,
even if they are not obese, might still develop systemic
arteriosclerosis and dysregulation of adipocytokines, and
are considered to be at high risk of cardiovascular diseases.
Asian and Japanese populations could be easily affected
with type 2 diabetes mellitus, including those with relatively
low BMIs, compared to Caucasians , and since many
such patients are non-obese, assessment of visceral fat
accumulation is important to identify the patients with
multiple risk factors of cardiovascular diseases [6,33], and
particularly to identify patients who could possibly improve
their diabetes and prevent arteriosclerosis through
decreasing multiple cardiovascular risk factors by reduction of
accumulated visceral fat.
This study found no association between visceral fat
accumulation and diabetic microangiopathies, such as
retinopathy and nephropathy. Several research groups
have reported that glycemic control and the duration of
diabetes significantly influence the onset and progression
of diabetic microangiopathy [34-36], and herein, the
duration of diabetes was significantly shorter in subjects
with visceral fat accumulation than in those without,
whereas HbA1c levels were not different. Dirani M et al.
demonstrated in prospective study that obese diabetic
patients were more likely to have diabetic retinopathy ,
while a recent paper reported no significant association
between obesity and diabetic retinopathy , suggesting
that the association between obesity and diabetic
microangiopathy seems to be still unclear. Thus, evaluation of
microangiopathies should also be carried out, regardless of
the patients visceral fat accumulation status.
Eating behaviors and visceral fat accumulation
We also demonstrated different eating behaviors in type 2
diabetic patients with visceral fat accumulation compared
to those without visceral fat accumulation, including food
preference, eating style, and sense of hunger, and
these result were more obvious in male patients. Kozuka
et al.  reported that hypothalamic endoplasmic
reticulum stress was associated with preference for high
fat food, which is one of the eating behaviors assessed.
Studies from our group have also shown that treatment
with liraglutide, a glucagon-like peptide-1 (GLP-1)
analogue, improved not only glycemic control, but also
obesity, possibly through affecting eating behavior (especially
sense of hunger and eating style) in Japanese type 2
diabetic patients, using the radar chart [20,21].
Glucagonlike peptides have both peripheral effects, such as gastric
motility, and central effects, such as inhibition of appetite,
through targeting the arcuate nucleus and other
hypothalamic lesions . Accordingly, body weight reduction is
effective for the treatment of type 2 diabetes with visceral
fat accumulation , and the reduction of visceral and
subcutaneous fat was reported to correlate with the
elevation of adiponectin levels . Body weight reduction
can be achieved through conventional diet and exercise
therapy as well as cognitive therapy . A
questionnairebased radar chart of eating behaviors could therefore be a
useful tool for the treatment of type 2 diabetic patients
with visceral fat accumulation, by helping patients to
visually recognize their eating behaviors and to modify their
own eating behaviors by themselves. Although it is
possible that there is gender difference in the assessment of
eating behaviors using the questionnaire, its etiology
remains unclear in the present study.
Taken together, the present results demonstrated the
importance of evaluating VFA in type 2 diabetic patients,
and for those with visceral fat accumulation, physicians
may need to screen for systemic arteriosclerosis more
intensively and consider support for patients in modifying
their eating behaviors.
This study has several limitations. The study was not
prospective in design, included a relatively small population,
and was performed in a single institution. The influence of
gender, ethnicities, and other residual or unmeasured
factors which affect several cardiometabolic factors and eating
behaviors cannot be fully excluded. Further prospective
studies of larger populations are needed in the future.
In conclusion, type 2 diabetic patients with visceral fat
accumulation showed more advanced systemic arteriosclerosis,
lower serum adiponectin levels, and differences in eating
behavior, compared to those without visceral fat accumulation.
ACS: Acute coronary syndrome; BMI: Body mass index; BP: Blood pressure;
CAD: Coronary artery diseases; eGFR: Estimated glomerular filtration rate;
ELISA: Enzyme-linked immunosorbent assay; eVFA: Estimated visceral fat area;
GLP-1: Glucagon-like peptide-1; HDL-C: High-density lipoprotein cholesterol;
IMT: Intima-media thickness; LDL-C: Low-density lipoprotein cholesterol;
NDR: No diabetic retinopathy; NGSP: National Glycohemoglobin Standardization
Program; PDR: Proliferative diabetic retinopathy; PrePDR: Preproliferative
diabetic retinopathy; SDR: Simple diabetic retinopathy; TG: Triglyceride;
UA: Uric acid; uACR: Urinary albumin-creatinine ratio; VFA: Visceral fat area;
WC: Waist circumference.
The authors declare that they have no competing interests.
SF and AH acquired and analyzed the data, and wrote the manuscript. HN
conceived the study, analyzed data, and wrote the manuscript. HN, SK, TK, KI,
YF, MY, JK, TK, TY, NM, and AI acquired and researched the data. TF and IS
reviewed the manuscript. All authors read and approved the final manuscript.
We thank all members of the Adiposcience Laboratory at the Department of
Metabolic Medicine, Graduate School of Medicine, Osaka University for the
helpful discussion and suggestions. We also thank Chie Tokuzawa, Naoko
Nagai and Yoko Yasui from the Division of Nutritional Management, Osaka
University Hospital, for data acquisition. This work was supported in part by
Grants-in-Aid for Scientific Research (C) no. 24591351 (to HN), and no.
22590979 (to NM), Scientific Research on Innovative Areas no. 22126008
(to TF), and Pfizer Health Research Foundation (to HN).
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