□ ORIGINAL ARTICLE □Lipid Deposition in Various Sites of the Skeletal Muscles
and Liver Exhibits a Positive Correlation with Visceral Fat
Accumulation in Middle-aged Japanese Menwith Metabolic Syndrome
Shin-ichiro Taira 1, Michio Shimabukuro 2, Moritake Higa 3, Kouichi Yabiku 1,
Chisayo Kozuka 1, Rei Ueda 1, Sumito Sunagawa 1, Yuzuru Ohshiro 1, Mototsugu Doi 1,
Toyotaka Nanba 1, Eriko Kawamoto 1, Yoshiro Nakayama 1, Hideaki Nakamura 1, Takako Iha 1,
Sawako Nakachi 1, Takeaki Tomoyose 1, Tomomi Ikema 1,
Ken Yamakawa 1 and Hiroaki Masuzaki 1

Abstract
Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore
the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middleaged men with metabolic syndrome.
Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area
(VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver.
Results A significant inverse correlation was observed between the VFA and the CT HU values of theiliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestylemodification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated withthe levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment.
On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease
after Miglitol treatment.
Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and theliver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid
deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.
Key words: metabolic syndrome, diabetes, visceral fat, ectopic lipid deposition, computed tomography(Intern Med 52: 1561-1571, 2013)(DOI: 10.2169/internalmedicine.52.0521)

Introduction
In addition to visceral fat accumulation (1, 2), ectopic
lipid deposition, especially in the liver and skeletal muscle,

has been implicated in the pathophysiology of diabetes, insulin resistance and dyslipidemia (3). Of note, Japanese patients with metabolic syndrome exhibit a relatively lower degree of obesity than Caucasians (4). However, the prevalence of diabetes among the Japanese population is compa-

１

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Medicine), Graduate School of
Medicine, University of the Ryukyus, Japan, ２Department of Cardio-Diabetes Medicine, The University of Tokushima Graduate School of
Health Biosciences, Japan and ３Diabetes and Life-style Related Disease Center, Tomishiro Central Hospital, Japan
Received for publication March 5, 2013; Accepted for publication March 24, 2013
Correspondence to Dr. Hiroaki Masuzaki, hiroaki@med.u-ryukyu.ac.jp1561

Intern Med 52: 1561-1571, 2013

DOI: 10.2169/internalmedicine.52.0521

rable to that observed in the United States, thus leading to
the speculation that excessive energy intake by Japanese individuals may exaggerate ectopic lipid deposition due totheir limited capacity to store subcutaneous fat tissue (5).
Animal experiments have demonstrated that excess accumulation of lipids in pancreatic islets is associated with progressive beta cell apoptosis, which results in impaired secretion of insulin (6). When fed a high-fat diet, transgenic miceoverexpressing the leptin receptor (Ob-R) exclusively in adipose tissue under a genetically obese and diabetic db/db
background exhibit marked weight reduction compared to
db/db mice per se. In contrast, lipid deposition in the liver,cardiac muscle and pancreas is pronounced, which aggravates the severity of diabetes in transgenic animals (7). Agedependent declines in the mitochondrial function and increases in intramyocellular lipid content have also been reported (8). In humans, lifestyle modification markedly decreases intramyocellular lipid deposition in association withconcomitant increases in insulin-mediated glucose uptake inmuscles (9).
To the best of our knowledge, there are no reports describing the association between visceral fat accumulationand lipid deposition in the liver or skeletal muscle in a large
number of patients with metabolic syndrome. Therefore, thepresent study was designed to investigate the metabolic link
between lipid deposition, particularly in skeletal muscles andthe liver, and visceral fat accumulation in relation to lifestyle and pharmacological interventions. Recently, proton
magnetic resonance spectroscopy (1H-MRS) has been employed to precisely evaluate ectopic lipid accumulation. Because the technique is expensive and elaborate, however, its
use is not yet prevalent in clinics. In this context, we attempted to establish a concise method for evaluating ectopic
lipid deposition using abdominal computed tomography(CT) scanning.

Materials and Methods
Subjects
Our study included patients who visited Tomishiro Central Hospital (Okinawa prefecture, Japan) via self-referral orrecommendation for further checkup by local health care institutions. In the present study, we performed an ad hocanalysis using the pooled database of 332 men who agreed
to participate in interventional trials performed at Tomishiro
Central Hospital. The results of some parts of these interventional trials have recently been published (10), whileother parts are currently in the process of manuscript preparation. Subjects taking antidyslipidemic or antidiabetic drugs
were completely excluded. Furthermore, no drugs were administered to subjects recruited during the observation period. The convergence of metabolic abnormalities was evaluated during medical checkups. According to the current definition of metabolic syndrome in Japan (11, 12), the presenceof abdominal obesity (a waist circumference of !85 cm formen and !90 cm for women) is essential for making a diagnosis of metabolic syndrome. In the present study, metabolic
syndrome was defined according to the 2005 International
Diabetes Federation (IDF) guidelines (13), which include thepresence of at least two of the following four factors: (1)elevated triglycerides (TG) (!150 mg/dL (1.7 mmol/L)), (2)reduced high-density lipoprotein (HDL) cholesterol (<40mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women), (3) elevated blood pressure (a systolic bloodpressure of !130 mmHg or a diastolic blood pressure of !85
mmHg or both) and (4) elevated fasting plasma glucose(FPG) (!100 mg/dL (5.6 mmol/L)). The present study wasapproved by the ethical committee for human research at
Tomishiro Central Hospital (November 16, 2011. No. 104).
Study 1: Relationship between ectopic lipid deposition and metabolic parameters
Evidence regarding the association between excessive
lipid deposition in nonadipose tissue, also known as ectopic
lipid deposition, and metabolic derangement has been accumulating (14). In Study 1, we focused on ectopic lipid
deposition in the skeletal muscles and liver. We analyzed
105 men under 60 years of age who underwent abdominal
CT before receiving various types of clinical interventions.
The study included 105 middle-aged men (age: 49.0±8.0
years) with metabolic syndrome who were diagnosed using
the IDF criteria described above. At the umbilical level, theCT Hounsfield unit (HU) values of three different regions ofskeletal muscle (the iliopsoas muscle, back muscle and rectus abdominis muscle) and the visceral fat area (VFA) were
simultaneously measured using unenhanced CT. On the CT
slices obtained at the umbilical level, the adipose tissue area
located in the peritoneal cavity was defined as the VFA andthe adipose tissue area underlying the skin layer was definedas the subcutaneous fat area (SFA). Using the abdominal CT
images in the pooled database, we measured the CT valuesof the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. In the present study, the CT HU value wasused to assess the relative extent of ectopic lipid deposition,
as described below. Anthropometric and metabolic parameters were analyzed as previously reported (Table 1 (15)).
Study 2: Effects of lifestyle modification and pharmaceutical interventions on ectopic lipid deposition
and fuel metabolism
The impact of lifestyle modification and pharmacologicalinterventions on ectopic lipid deposition and glucose-lipid
metabolism was investigated by examining 68 men between
32 and 76 years of age. Before the intervention, all participants received guidance for lifestyle modification. The subjects followed a standard diet (25 kcaL/kg + 0-200 kcaL)and engaged in regular exercise by walking approximately
10,000 steps per day or approximately one hour per day forthree to five days per week during the study period. In
Study 2, we analyzed 181 subjects who received interventions with either lifestyle modification alone (104 cases),1562

Intern Med 52: 1561-1571, 2013
Table 1.

DOI: 10.2169/internalmedicine.52.0521

Patient Characteristics (Study 1)

Age (years)

49.0 ± 8.0

Body weight (kg)78.2 ± 9.9

BMI (kg/m2)

27.8 ± 3.4

Waist circumference (cm)

Next, we performed an ad hoc analysis of 68 men who
underwent abdominal CT before and after receiving various
types of clinical interventions, a group who underwent lifestyle modification alone (28 cases), a group who underwent
lifestyle modification with Pioglitazone treatment (24 cases)
and a group who underwent lifestyle modification with
Miglitol treatment (16 cases). Briefly, Group A (n=28; age:
55±11.4 years) maintained the lifestyle modifications forthree months. Group B (n=24; age: 55±9.0 years) received
treatment with Pioglitazone (30 mg/day) for three months.
Group C (n=16; age: 58±9.7 years) received treatment with
Miglitol (150 mg/day) for three months. Before and after
the treatment period, the amount of ectopic lipid deposition
and the anthropometric and metabolic parameters were analyzed, as in Study 1. The clinical characteristics of theStudy 2 participants are summarized in Table 2.

93.9 ± 7.4

VFA (cm2)

185.0 ± 58.3

SFA (cm2)

177.8 ± 66.6

FPG (mg/dL)

115.0 ± 23.0

Fasting insulin (ȝU/mL)

13.0 ± 6.8

HOMA-IR

3.6 ± 2.0

HOMA-ȕ

99.7 ± 58.7

HbA1c (%)

7.0 ± 1.3

T-Cho (mg/dL)

210.0 ± 35.8

HDL-C (mg/dL)

47.0 ± 10.9

TG (mg/dL)

213.0 ± 215.4

AST (IU/L)

30.0 ± 18.7

ALT (IU/L)

45.0 ± 29.5

Ȗ-GTP (IU/L)

82.0 ± 83.6

UA (mg/dL)

6.3 ± 1.3

CRP (mg/dL)

0.2 ± 0.2

FFA (mmol/L)

0.5 ± 0.2

SBP (mmHg)

140.0 ± 15.3

DBP (mmHg)

87.0 ± 9.7

Pulse (beats/min)

78.0 ± 12.2

CT HU value of iliopsoas muscle

44.2 ± 5.9

CT HU value of back muscle

41.8 ± 8.2

CT HU value of rectus abdominis muscle

28.2 ± 14.1

CT HU value of liver50.2 ± 11.3

CT HU value of spleen

Assessment of the CT HU values of the nonadipose
tissues(1) Assessment of the CT HU values of the three
types of skeletal muscles
CT scans of lipid deposition in skeletal muscle, including
the iliopsoas muscle, back muscle and rectus abdominismuscle, performed at the umbilical level usually result in thedetection of patchy or diffuse areas (16). Commonly, a region of interest (ROI) is determined to evaluate the average
CT HU value (17). Notably, skeletal muscles are known to
exhibit wide regional differences in the density of muscle fibers (16, 18), and the CT HU value of the muscle greatly
depends on the ROI location. Therefore, in the present
study, ROIs were not used. Instead, minor modifications
were made to a previously described method (19), according
to which cross sections of the iliopsoas muscle, back muscle
and rectus abdominis muscle were outlined at the umbilicallevel using a cursor. The CT HU value of the region surrounded by the line was employed as the average CT HU
value of the respective skeletal muscle, and the values obtained on each side were averaged to obtain the representative CT HU value. A lower CT HU value reflects increased
lipid deposition in each tissue.

47.8 ± 5.1
2

Iliopsoas muscle area (cm )1,322.3 ± 277.2

Back muscle area (cm2)2,775.4 ± 590.7
2

Rectus abdominis muscle area (cm )602.0 ± 149.7

The plus-minus values indicate the mean ± SD.
VFA : Visceral fat area, SFA : Subcutaneous fat area, FPG : Fasting plasma
glucose, HDL-C: High-density lipoprotein cholesterol, TG: Triglyceride,
AST: Aspartate 2-oxoglutarate aminotransferase, ALT: Alanine
2-oxoglutarate aminotransferase, UA: Uric acid, CRP: C-reactive protein,
HbA1c: Glycosylated hemoglobin, T-Cho: Total cholesterol, FFA: Free
fatty acid, Ȗ-GTP: Gamma-glutamyl transpeptidase, SBP: Systolic bloodpressure, DBP: Diastolic blood pressure, BMI: Body mass index
The body mass index is the weight in kilograms divided by the square of
the height in meters.
The value for HbA1c (%) is estimated as the NGSP equivalent value (%)
calculated according to the formula HbA1c (%) = HbA1c (JDS) (%) + 0.4%,
considering the relational expression of HbA1c (JDS)(%) measured basedon the previous Japanese standard substance and measurement methods andHbA1c (NGSP) (15).
JDS: Japan Diabetes Society, NGSP: National Glycohemoglobin
Standardization Program(2) Assessment of the CT HU values of the liver

lifestyle modification with Pioglitazone treatment (39 cases)or lifestyle modification with Miglitol treatment (38 cases).
The baseline characteristics were roughly similar between
the three groups.

Similar to the results of the analyses of skeletal muscles,
lipid deposition in the liver is usually detected in a diffuse
or patchy pattern (20). Contrary to the evaluations of skeletal muscles, ROIs were employed to assess the CT HU values of the liver in this study. To carefully prevent contamination of blood vessels, ROIs broader than 100 mm2 were
measured in the liver parenchyma (two sites in the rightlobe and one site in the left lobe) (21). The average CT HU
value assessed according to this method exhibited a significant inverse correlation with the degree of fatty liver, as described in the Results section.

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Intern Med 52: 1561-1571, 2013
Table 2.

DOI: 10.2169/internalmedicine.52.0521

Clinical Parameters Measured before and after Three Months of Intervention
Group A
Lifestyle modification(n = 28)0M

Age (years)
Body weight (kg)BMI (kg/m2)
Waist circumference (cm)
VFA (cm2)
SFA (cm2)
CT HU value of iliopsoas muscle
CT HU value of back muscle
CT HU value of rectus abdominismuscleCT HU value of liver
FPG (mg/dL)
Fasting insulin (ȝU/mL)
HOMA-IR
HOMA-ȕ
HbA1c (%)
T-Cho (mg/dL)
HDL-C (mg/dL)
TG (mg/dL)
AST (IU/L)
ALT (IU/L)Ȗ-GTP (IU/L)
UA (mg/dL)
CRP (mg/dL)
FFA (mmol/L)
SBP (mmHg)
DBP (mmHg)
Pulse (beat/min)
CT HU value of spleenGroup B
Pioglitazone(n = 24)

Group C
Miglitol(n = 16)

3M

0M

3M

0M

3M

55 ±11.4
76.0 ± 10.2
27.1 ± 3.5
94.4 ± 6.1
187.0 ± 55.3
159.1 ± 60.9
43.0 ± 4.6
40.0 ± 9.3
24.6 ± 13.4

74.0 ± 10.0
26.7 ± 3.6
92.3 ± 8.2
174.0 ± 58.8
154.4 ± 63.1
46.2 ± 4.9
42.8 ± 9.6
26.4 ± 17.5

55 ± 9.0
74.0 ± 12.1
27.0 ± 3.9
93.9 ± 8.7
200.0 ± 61.0
164.2 ± 72.9
44.0 ± 5.4
41.1 ± 7.9
29.3 ± 9.5

73.0 ± 12.6
26.7 ± 4.1
90.4 ± 8.4
176.0 ± 63.1
167 ± 84.6
42.9 ± 4.9
39.4 ± 8.3
27.6 ± 13.3

58 ± 9.7
76.0 ± 8.0
28.5 ± 2.7
94.3 ± 5.9
207.0 ± 48.2
171.0 ± 46.5
42.0 ± 3.3
37.6 ± 5.9
23.0 ± 17.6

73.0 ± 7.1
27.3 ± 2.3
90.7 ± 4.9
171.0 ± 40.3
152.0 ± 37.9
43.0 ± 3.1
39.6 ± 3.8
25.6 ± 14.3

51.7 ± 11.0
114.0 ± 12.9
11.0 ± 5.3
3.1 ± 1.5
84.1 ± 44.4
5.9 ± 0.7
199.4 ± 41.5
43.9 ± 9.5
178.8 ± 96.5
28.2 ± 12.6
43.7 ± 35.8
68.0 ± 73.6
6.5 ± 1.3
0 ± 0.18
0 ± 0.15
135.0 ± 15.1
82.0 ± 12.0
78.0 ± 14.8
50.0 ± 4.6

55.0 ± 8.8
111.9 ± 11.3
11.3 ± 6.9
3.1 ± 1.9
87.8 ± 54.2
5.9 ± 0.5
189.9 ± 37.3
56.5 ± 33.8
146.7 ± 84.5
22.1 ± 7.2
28.4 ± 18.1
55.4 ± 66.8
6.3 ± 1.2
0.3 ± 0.63
0.5 ± 0.55
131.0 ± 14.2
80.0 ± 10.0
75.0 ± 11.2
50.2 ± 7.6

52.0± 11.5
122.0 ± 18.8
12.0 ± 8.6
3.6 ± 2.2
88.0 ± 55.2
6.3 ± 0.9
209.6 ± 37.7
50.8 ± 14.3
257.3 ± 353.5
24.5 ± 7.1
38.9 ± 20.1
79.5 ± 55.8
6.5 ± 1.4
0.2 ± 0.3
0.5 ± 0.2
144.0 ± 13.4
87.0 ± 12.7
78.0 ± 15.4
50.8 ± 4.1

57.3 ± 8.9
115.6 ± 19.4
9.0 ± 5.3
2.6 ± 2.0
67.0 ± 34.7
6.1 ± 0.7
204.8 ± 44.3
54.5 ± 12.4
142.7 ± 59.7
21.3 ± 6.5
21.2 ± 7.1
45.2 ± 34.0
5.9 ± 1.5
0.1 ±0.1
0.4 ± 0.2
132.0 ± 13.7
83.0 ± 8.9
77.0 ± 14.5
48.0 ± 5.4

50.5 ± 12.3
113.0 ± 16.1
14.0 ± 6.3
4.0 ± 1.9
111.2 ± 59.0
5.9 ± 0.6
201.8 ± 33.3
48.2 ± 10.0
171.6 ± 79.6
32.6 ± 13.7
44.0 ± 24.2
95.0 ± 120.5
6.7 ± 1.4
0.24 ± 0.3
0.46 ± 0.2
143.0 ± 12.2
89.0 ± 7.5
76.0 ± 11.7
45.6 ± 4.3

51.6 ± 9.5
108.0 ± 14.2
11.0 ± 3.4
3.1 ± 1.2
96.0 ± 39.0
5.7 ± 0.5
193.8 ± 41.7
47.9 ± 10.5
136.9 ± 66.9
30.8 ± 15.2
40.9 ± 19.1
94.4 ± 162.6
6.4 ± 1.2
0.15 ± 0.2
0.38 ± 0.2
133.0 ± 12.4
82.0 ± 7.0
72.0 ± 11.9
45.1 ± 2.2

**
**
**
**
**
**

**
*
**
**

**

**
*
**
**
*
*

*
**
**
**

**
*

**
**
**
**
*

*
*

**
**

The plus-minus values indicate the mean ± SD.
The body mass index is the weight in kilograms divided by the square of the height in meters.
* p < 0.05, ** p < 0.01 vs. 0M
VFA: Visceral fat area, SFA: Subcutaneous fat area, FPG: Fasting plasma glucose, HDL-C: High-density lipoprotein cholesterol, TG: Triglyceride, AST:
Aspartate 2-oxoglutarate aminotransferase, ALT: Alanine 2-oxoglutarate aminotransferase, UA: Uric acid, CRP: C-reactive protein, HbA1c: Glycosylated
hemoglobin, T-Cho: Total cholesterol, FFA: Free fatty acid, Ȗ-GTP: Gamma-glutamyl transpeptidase, SBP: Systolic blood pressure, DBP: Diastolic bloodpressure, BMI: Body mass index

Statistical analyses
The values are expressed as the mean ± standard deviation (SD). The differences were analyzed using paired Student’s t-test or the Wilcoxon signed-rank test as appropriate.
Pearson’s correlation coefficients and Spearman’s correlation
coefficients were used where applicable. Values that were
not distributed normally were transformed into logarithms(base e) (log) and subsequently analyzed using Pearson’s
correlation coefficients. Values that were not distributed normally even after being transformed into logarithms (base e)(log) were analyzed using Spearman’s correlation coefficients. Multiple regression analyses were applied to determine whether a line of variables was significantly associatedwith glucose-lipid metabolic markers. Due to the crosssectional nature of the analysis, the associations do not nec-

essarily indicate causality. Therefore, we attempted to investigate the potential associations between the changes in the
CT HU values of the three skeletal muscles (delta value: 3months (3M)-0 month (0M)) and changes in the other variables, including VFA (delta value: 3 months (3M)-0 month(0M)), during the observation period. A p value of <0.05
was considered to be statistically significant.

Results
Study 1
A total of 105 men (age: 49.0±8.0 years; BMI: 27.8±3.4kg/m2; waist circumference: 93.9±7.4 cm; body weight:
78.2±9.9 kg) were included in the present study. The CT
HU values of each muscle were as follows: iliopsoas mus-1564

Intern Med 52: 1561-1571, 2013

DOI: 10.2169/internalmedicine.52.0521

(a)

50
(c)
40

70

30

60

R=0
p = 0.90
n = 105

20

0
0
(b)

10

20

30

40

50

60

70

80

CT HU value (Liver)

70
60

CT HU value (back muscle)

R = 0.023
p = 0.78
n = 105

50

10

50
40

CT HU value (rectus abdominis muscle)

CT HU value (iliopsoas muscle)

60

40
30
20
10
0
0

10

20

30

40

50

60

70

80

-10
-20

30
R = 0.0076
p = 0.44
n = 105

20

-30
-40

10

CT HU value (Liver)

0
0

20

40

60

80

CT HU value (Liver)

Figure 1. A comparison of the computed tomography (CT) Hounsfield unit (HU) values of the liver and skeletal muscles. No correlations were observed between the CT HU values of the iliopsoas
muscle and liver (a), between the CT HU values of the back muscle and liver (b) and between the CT
HU values of the rectus abdominis muscle and liver (c). Overall, the CT HU values of the liver exhibited greater variability than those of the skeletal muscles. Among the three skeletal muscles, theCT HU values of the rectus abdominis muscle exhibited the widest variation.

cle: 44.2±5.9 HU (95% confidence interval (CI), 43.1-45.3);
back muscle: 41.8±8.2 HU (95% CI, 40.2-43.4); and rectus
abdominis muscle: 28.2±14.1 HU (95% CI, 25.5-30.9). The
intrasubject coefficients of variation of the CT HU values of
the iliopsoas muscle, back muscle, rectus abdominis muscle
and liver were 1.6%, 1.1%, 4.4% and 0.7%, respectively (n=10). The intersubject coefficients of variation of the CT HU
values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver were 8.7%, 5.1%, 36.0% and 25.8%,
respectively (n=5).
Notably, there were no correlations between the CT HU
values of the three types of skeletal muscles and those of
the liver. Overall, the CT HU values of the liver exhibited
greater variability than those of the skeletal muscles (Fig. 1).
Among the three skeletal muscles, the CT HU values of therectus abdominis exhibited greater variation (Fig. 1). Importantly, significant inverse correlations were observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle (r=-0.27, r=-0.47
and r=-0.37, respectively; p<0.01) and liver (r=-0.23, p<0.05) (Fig. 2). Furthermore, significant inverse correlations
were observed between age and the CT HU values of theiliopsoas muscle, back muscle and rectus abdominis muscle(r=-0.45, r=-0.45 and r=-0.41, respectively; p<0.01). In contrast, no correlations were observed between the CT HU
values of the three skeletal muscles and body weight, waist
circumference, SFA, the levels of hepatic enzymes or thelevels of glucose-lipid metabolic markers.
Significant positive correlations were observed between
the iliopsoas muscle area and BMI, waist circumference andSFA (r=0.54, r=0.40 and r=0.38, respectively; p<0.01).
Similarly, significant positive correlations were observed between the rectus abdominis muscle area and BMI, waist circumference and SFA (r=0.47, r=0.44 and r=0.29, respectively; p<0.01). The iliopsoas muscle area was correlatedwith the levels of fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), aspartate 2oxoglutarate aminotransferase (AST) and alanine 2oxoglutarate aminotransferase (ALT) (r=0.38, r=0.38, r=
0.32, p<0.01; r=0.30, p<0.05). Inverse correlations were observed between the back muscle area and HDL-C and freefatty acid (FFA) (r=-0.31 and r=-0.36, respectively; p<0.01).
However, no correlations were observed between the backmuscle area and BMI, waist circumference or SFA.
A significant positive correlation was observed between
the iliopsoas muscle area and the CT HU value of the iliopsoas muscle (r=0.30, p<0.01). Similarly, a significant positive correlation was observed between the back muscle area
and the CT HU value of the back muscle (r=0.28, p<0.01).
On the other hand, no correlations were observed between
the rectus abdominis muscle area and the CT HU value ofthe rectus abdominis muscle (r=0.17, p=0.07).
We next explored the possible associations between the
CT HU values and the levels of glucose-lipid metabolic

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DOI: 10.2169/internalmedicine.52.0521

(a)

(b)
R = - 0.27
p < 0.01
n = 105

350
300

400
Visceral fat area (cm2)

Visceral fat area (cm2)

400

250
200
150
100
50
0
0

20

40

350
300
250
200
R = - 0.47
p < 0.01
n = 105

150
100
50
0

60

0

CT HU value (iliopsoas muscle)

(c)

20
40
60
CT HU value (back muscle)

80

(d)

350
300

R = - 0.37
p < 0.01
n = 105

400
Visceral fat area (cm2)

Visceral fat area (cm2)

400

250
200
150
100
50

300
250
200
150
100
50

0
-40

R = - 0.23
p < 0.05
n = 105

350

0

-20
0
20
40
60
CT HU value (rectus abdominis muscle)

80

0

20

40

60

80

CT HU value (Liver)

Figure 2. A comparison between the visceral fat area and the CT HU values of the liver and skeletal muscles. Significant inverse correlations were observed between the visceral fat area and the CT
HU values of the iliopsoas muscle (a), back muscle (b), rectus abdominis muscle (c) and liver (d).

markers in groups stratified according to BMI. Inverse correlations were observed between the CT HU value of theiliopsoas muscle and the levels of triglycerides and HOMAβ in subjects with a BMI of less than 25 kg/m2 (r=-0.46, p<
0.05, r=-0.58, p<0.01). Inverse correlations were observed
between the level of uric acid and the CT HU values of theiliopsoas muscle and the rectus abdominis muscle in subjects with a BMI ranging from 25 to 30 kg/m2 (r=-0.33, p<
0.05, r=-0.35, p<0.01). Positive correlations were observed
between the level of ALT and the CT HU values of theiliopsoas muscle, back muscle and rectus abdominis muscle
in subjects with a BMI ranging from 25 to 30 kg/m2 (r=0.29, r=0.28 and r=0.29, respectively; p<0.05). Positive correlations were observed between the level of triglycerides
and the CT HU values of the back muscle and rectus abdominis muscle in subjects with a BMI higher than 30 kg/
m2 (r=0.45, p<0.01; r=0.40, p<0.05).
Of note, inverse correlations were observed between theliver CT HU value and the levels of liver enzymes (ASTand ALT) (r=-0.42 and r=-0.49) and glucose-lipid metabolic
markers (fasting insulin, HOMA-IR, HOMA-β and glycosylated hemoglobin) (r=-0.52, r=-0.51, r=-0.41 and r=-0.30,
respectively; p<0.01), confirming that lipid deposition in theliver is indicative of hepatic dysfunction and glucose dyshomeostasis.
In a multiple regression analysis, the CT HU values of
the three kinds of skeletal muscles were found to have nosignificant impact on the levels of glucose-lipid metabolic
markers (Table 3).

Study 2
Group A (Lifestyle modification)
A total of 28 men (age: 55±11.4 years; body weight:
76.0±10.2 kg; BMI: 27.1±3.5 kg/m2; waist circumference:
94.4±6.1 cm) were included in this study. All participants
adopted lifestyle modifications, including walking (approximately 10,000 steps per day or approximately one hour per
day for three to five days per week) and a specific diet (25kcaL/kg + 0~200 kcaL), for three months. After this threemonth period, significant decreases in body weight (from76.0±10.2 to 74.0±10.0 kg, p<0.01), BMI (from 27.1±3.5 to
26.7±3.6 kg/m2, p<0.01) and waist circumference (from94.4±6.1 to 92.3±8.2 cm, p<0.01) were observed. The VFA
values also significantly decreased (from 187.0±55.3 to174.0±58.8 cm2, p<0.01). On the other hand, no significant
changes were observed in SFA. After the interventions, significant increases in the CT HU values of the iliopsoas muscle (from 43.0±4.6 to 46.2±4.9 HU, p<0.01) and back muscle (from 40.0±9.3 to 42.8±9.6 HU, p<0.01) were detected.
In contrast, no changes were observed in the CT HU valuesof the rectus abdominis muscle. Although the differenceswere not significant, there was a trend toward improvementin the CT HU values of the liver (from 51.7±11 to 55.0±8.8
HU, p=0.4). No changes were observed in the tested fuelmetabolism markers.

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Table 3. Potential Associations between the CT HU Values of Each Tissue and the Levels of Glucose-lipid Metabolic
Markers in a Multiple Regression Analysis

Predictor variable

FPG (mg/dL)

CT HU value of
iliopsoas muscle

CT HU value ofback muscle

CT HU value of
rectus abdominismuscleCT HU value of
liver

VFA

F value

F value

F value

F value

F value

0.459986

1.514525

0.310999

0.095170.022875

Fasting insulin (ȝU/mL)

0.016163

0.269931

0.372145

28.75759**

6.411355**

HOMA-IR

0.024614

0.19633

1.271732

26.29663**

8.971085****

4.258011*

HOMA-ȕ

1.337558

2.450484

0.104022

12.38965

HbA1c (%)

0.000122

0.055566

0.343369

0.786111

0.738849

T-Cho (mg/dL)

2.807251

0.52064

2.110077

0.62340.702938

HDL-C (mg/dL)

0.480973

0.005649

0.741931

0.042927

0.376761

TG (mg/dL)

0.046872

0.069886

0.042644

0.516454

0.361545

AST (IU/L)

0.056663

0.296184

5.598727

0.000453

0.710747

ALT (IU/L)

0.285036

0.417567

2.133421

0.799271

1.506195

Ȗ-GTP (IU/L)

0.136143

0.56958

0.020191

0.506694

0.059505

FFA (mmol/L)

0.679677

0.034012

0.161059

0.148468

0.020256** p < 0.05, ** p < 0.01
VFA: Visceral fat area, FPG: Fasting plasma glucose, HDL-C: High-density lipoprotein cholesterol, TG: Triglyceride, AST: Aspartate 2-oxoglutarate
aminotransferase, ALT: Alanine 2-oxoglutarate aminotransferase, HbA1c: Glycosylated hemoglobin, T-Cho: Total cholesterol, FFA: Free fatty acid,Ȗ-GTP: Gamma-glutamyl transpeptidase

Group B (Pioglitazone treatment)
A total of 24 men (age: 55±9.0 years; body weight: 74.0±
12.1 kg; BMI: 27.0±3.9 kg/m2; waist circumference: 93.9±
8.7 cm) were included. The subjects were treated with Pioglitazone (30 mg/day) for three months. After treatment, nochanges were observed in body weight, BMI or waist circumference. A significant decrease was observed in VFA(from 200.0±61.0 to 176.0±63.1 cm2, p<0.01). In contrast,
no significant changes were detected in SFA. No changes
were observed in the CT HU values of the iliopsoas muscle,back muscle or rectus abdominis muscle. At the end oftreatment, significant increases in the CT HU values of theliver were observed (from 52.0±11.5 to 57.3±8.9 HU, p<0.01) (Fig. 3) accompanied by significant improvements inthe liver function. Significant decreases were also observedin the levels of FPG (from 122.0±18.8 to 115.6±19.4 mg/
dL, p<0.05), fasting insulin (from 12.0±8.6 to 9.0±5.3 μU/
mL, p<0.01), HOMA-IR (from 3.6±2.2 to 2.6±2.0, p<0.01)
and triglycerides (from 257.3±353.5 to 142.7±59.7 mg/dL, p<0.05).
Group C (Miglitol treatment)
A total of 16 men (age: 58±9.7 years; body weight: 76.0±
8.0 kg; BMI: 28.5±2.7 kg/m2; waist circumference: 94.3±5.9cm) were included in this section of the study. The participants were treated with Miglitol (150 mg/day) for threemonths. At the end of the treatment period, significant decreases in body weight (from 76.0±8.0 to 73.0±7.1 kg, p<0.01), BMI (from 28.5±2.7 to 27.3±2.3 kg/m2, p<0.01) andwaist circumference (from 94.3±5.9 to 90.7±4.9 cm, p<0.01)
were observed. Significant decreases in VFA (from 207.0±
48.2 to 171.0±40.3 cm2, p<0.01) and SFA (from 171.0±46.5
to 152.0±37.9 cm2, p<0.05) were also observed. No changes
in the CT values of the iliopsoas muscle, back muscle, rectus abdominis muscle or liver were observed (Fig. 3). Significant decreases in the levels of fasting insulin (from 14.0±
6.3 to 11.0±3.4 μU/mL, p<0.05) and HOMA-IR (from 4.0±
1.9 to 3.1±1.2, p<0.05) were observed. No changes wereobserved in the FPG levels or lipid metabolism.
Potential associations between the changes in the
CT HU values of the three skeletal muscles andchanges in the other variables
Due to the cross-sectional nature of the analysis, the associations do not necessarily indicate causality. Therefore, we
attempted to investigate the potential associations between
the changes in the CT HU values of the three skeletal muscles (delta value: 3 months (3M)-0 month (0M)) andchanges in the other variables, including VFA (delta value: 3months (3M)-0 month (0M)), during the observation period.
The results were newly appended in Table 4. Overall, withthe exception of some of the delta values in the metabolic
parameters, the changes in the CT HU values of the threeskeletal muscles did not exhibit any significant correlations
with the changes in the other variables, including VFA.

1567

Discussion
Using abdominal CT scan analyses, we herein attempted

Intern Med 52: 1561-1571, 2013

DOI: 10.2169/internalmedicine.52.0521
(b)

(a)
70

55

P = 0.14

CT HU value (iliopsoas muscle)

P < 0.01

CT HU value (Liver)

65
60
55
50
45
40

45
40
35
30

0M

3M

0M

3M

(d)

(c)
70

55
CT HU value (Iliopsoas muscle)

P = 0.47

65
CT HU value (Liver)

50

60
55
50
45

P = 0.30

50
45
40
35
30

40
0M

0M

3M

3M

Figure 3. Changes in the CT HU values of the liver and skeletal muscles in the patients receiving
pharmacological treatments. (a) The Pioglitazone-treated patients (n=24) exhibited significant increases in the CT HU values of the liver. (b) The Pioglitazone-treated patients (n=24) exhibited nochanges in the CT HU values of the skeletal muscles before and after the three-month treatment. (c)The Miglitol-treated patients (n=16) exhibited no changes in the CT HU values of the liver before
and after the three-month treatment. (d) The Miglitol-treated patients (n=16) exhibited no changes
in the CT HU values of the skeletal muscles before and after the three-month treatment.

to establish a concise, comprehensive evaluation method ofassessing ectopic lipid deposition in conjunction with visceral fat accumulation. The major findings of the present
study of middle-aged, mildly obese Japanese men are summarized as follows. In patients with metabolic syndrome, (1)visceral fat accumulation is correlated with lipid depositionin the iliopsoas muscle, back muscle, rectus abdominis muscle and liver, (2) lifestyle modifications and treatment withantidiabetic drugs, including Pioglitazone and Miglitol, significantly attenuate visceral fat accumulation and (3) liver
lipid deposition is strongly correlated with biochemicalmarkers of glucose-lipid metabolism.
A limited number of reports have explored the potential
association between ectopic lipid deposition and visceral fat
accumulation using the 1H-MRS method (22, 23). Recent
studies using 1H-MRS in healthy, young populations havereported significant positive correlations (1) between the extent of intramyocellular lipid deposition in the soleus muscle
and the VFA and (2) between the extent of intrahepatic lipid
deposition and the VFA. Moreover, these studies reported
positive correlations between the extent of intramyocellularlipid deposition in the soleus muscle and intrahepatic lipid
deposition (22, 23). However, no correlations have been observed between the extent of intramyocellular lipid deposition in the tibialis anterior muscle and intrahepatic lipid

deposition. Overall, there have been no reports addressing
the association between visceral fat mass and skeletal muscle and liver lipid deposition in patients with metabolic syndrome. In this context, the present study demonstrated significant correlations (1) between the CT HU values of threedifferent skeletal muscle lipid depots and the VFA and (2)between the CT HU value of the liver and the VFA. In contrast, there were no correlations between the CT HU valuesof the skeletal muscles and liver. In previous studies using
1
H-MRS, the intramyocellular lipid content was measured
exclusively in the lower thigh in healthy, young populations (22, 23). In the present study, however, the skeletal
muscle CT HU value was measured using the trunk muscles. Although the CT HU values of the liver and skeletal
muscles may not necessarily reflect the intramyocellular andintrahepatic lipid content (24), the present study describes aconcise, comprehensive method of evaluating ectopic lipid
deposition that may be beneficial for assessing the metabolicstatus and the impact of therapy in patients with metabolic
syndrome.
In the present study, lifestyle modifications caused significant decreases in lipid deposition in the iliopsoas and backmuscles, whereas the amount of lipids in the rectus abdominis muscle did not change. Although the differences were
not significant, there was a trend toward improvement in the1568

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DOI: 10.2169/internalmedicine.52.0521

Table 4. Associations between the Changes in the CT HU Values of the Three Skeletal Muscles and the Changes in the Other
Variables during the Observation Period
Group A
Lifestyle modification(n = 28)
ǻCT HUvalue ofiliopsoasmuscle

ǻCT
HU
value
of back
musclerǻBody weight (kg)ǻWaist circumference(cm)ǻVFA (cm2)ǻSFA (cm2)ǻCT HU value of
iliopsoas muscle
ǻCT HU value of backmuscleǻCT HU value of
rectus abdominismuscleǻCT HU value of liverǻFPG (mg/dL)ǻFasting insulin
ȝ8mL)
ǻHOMA-IRǻHOMA-ȕǻHbA1c (%)ǻT-Cho (mg/dL)
ǻHDL-C (mg/dL)
ǻTG (mg/dL)ǻAST (IU/L)ǻALT (IU/L)ǻȖ-GTP (IU/L)ǻUA (mg/dL)ǻCRP (mg/dL)ǻFFA (mmol/L)ǻSBP (mmHg)
ǻDBP (mmHg)
ǻPulse (beat/min)ǻCT HU value of
spleenǻCT HUvalue ofrectusabdominis
muscler-0.183-0.291-0.413-0.445-0.287-0.033-0.304-0.406
0.534

0.534

**

0.491

*

Group B
Pioglitazone(n = 24)****

ǻCT HUvalue ofiliopsoasmuscle

ǻCT
HU
value
of back
muscleGroup C
Miglitol(n = 16)
ǻCT HUvalue ofrectusabdominis
musclerr

r-0.282-0.214-0.0200.071-0.173-0.036-0.4530.036-0.124-0.1690.491

0.257-0.290-0.063-0.3440.796

0.031-0.348
0.646

**

0.642

**

*

0.354
0.354

0.796

**

0.646

**

0.642

r

**

0.009
0.039
-0.310-0.108-0.3390.015

0.287-0.0640.283

0.306-0.0450.276

0.079-0.478-0.244-0.038-0.059-0.123
0.298
0.134
0.068
0.001
0.115
0.240
-0.4070.142-0.643-0.427-0.232-0.0910.624-0.302-0.285-0.137
0.153
0.284
0.210
0.022
0.142
0.406
-0.170-0.270-0.643-0.426-0.218-0.0470.370-0.0320.136-0.3090.025
0.030-0.067
0.205
0.229
0.127
-0.269-0.094-0.714-0.211-0.241-0.124
0.470

0.261
0.390
-0.1050.160
0.252-0.019-0.013
0.173
0.399
0.144
-0.036-0.133
0.116
0.507
0.297
0.419

0.217
0.390
-0.2890.117
0.083-0.018-0.049
0.187
0.394
0.252
-0.029-0.191
0.088
0.415
0.508
0.493

0.167
0.166
0.199
-0.2430.241-0.217-0.2200.254-0.151-0.0020.168-0.065-0.116
0.138
0.395
0.433

*

**

*

**

*

*
*

*

**

-0.140-0.052-0.051*

ǻCT HUvalue ofiliopsoasmuscle

*
*
*

*

*

ǻCT
HU
value
of back
muscleǻCT HUvalue ofrectusabdominis
musclerr-0.153-0.303-0.294-0.379-0.3680.104

0.395-0.431-0.181-0.4000.627-0.197-0.335
0.124

0.627

r

**

**

0.256

0.124

0.256

0.138
0.221
0.515

0.494
-0.0770.163-0.1910.150-0.138

0.110
0.227
0.143
0.083
0.261
-0.035-0.002
0.014
0.169
0.147
-0.241
0.016
0.192-0.195-0.071
0.508-0.032-0.1320.504-0.188-0.0290.132
0.135-0.1590.010-0.1560.162-0.433
0.488
0.042
0.018
-0.009

0.474
0.350
0.257
0.516
-0.005-0.012-0.046
0.060
0.011
0.103
-0.2540.359
0.046-0.221-0.176
0.556

*

*

*

*

r: correlation coefficient* p < 0.05, ** p < 0.01
VFA: Visceral fat area, SFA: Subcutaneous fat area, FPG: Fasting plasma glucose, HDL-C: High-density lipoprotein cholesterol, TG: Triglycerides, AST: Aspartate 2-oxoglutarate
aminotransferase, ALT: Alanine 2-oxoglutarate aminotransferase, UA: Uric acid, CRP: C-reactive protein, HbA1c: Glycosylated hemoglobin, T-Cho: Total cholesterol, FFA: Free fatty acid,Ȗ-GTP: Gamma-glutamyl transpeptidase, SBP: Systolic blood pressure, DBP: Diastolic blood pressure

CT HU values of the liver. Noteworthy is the finding that
the CT HU value of the rectus abdominis muscle exhibited
significantly larger variation among individuals than the values of the iliopsoas and back muscles (Fig. 1). The greaterinterindividual variation observed in lipid deposition in therectus abdominis may be linked to unique properties in the
response to lifestyle modifications. Site-specific differencesin muscle fiber components or sensitivity to stretch or exercise may also be involved. In this context, further studies
are warranted to clarify which sites in human skeletal muscles are more susceptible to lipid deposition under conditions of overnutrition or decreased physical activity. Interestingly, in Study 1, a positive correlation was found between
the iliopsoas muscle area and insulin resistance and an inverse correlation was observed between the back muscle
area and the level of HDL-C. These findings suggest thatthe degree of muscular lipid deposition in each tissue is notnecessarily correlated with muscular size.
The examination of the potential relationships between
ectopic lipid deposition and metabolic parameters conductedin Study 1 revealed strong correlations between liver lipid
deposition and the levels of glucose-lipid metabolic markers.
Furthermore, treatment with Pioglitazone (Study 2) resulted
in decreases in liver lipid deposition with concomitant improvements in the levels of glucose-lipid metabolic markers.
These results are consistent with those of a previous study
showing that the administration of Pioglitazone leads to improvement of hepatic insulin sensitivity and attenuation ofliver lipid deposition in patients with nonalcoholic steatohepatitis (25). In this context, our data showing that Pioglitazone treatment improves insulin resistance and decreases
lipid deposition in the liver validate the clinical setting of

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DOI: 10.2169/internalmedicine.52.0521

the present study. It is, therefore, tempting to speculate thatliver lipid overload may have a greater impact on glucoselipid metabolic markers than skeletal muscle lipid overload.
The present study demonstrated that visceral and subcutaneous adipose tissue mass is reduced during treatment with
Miglitol. On the other hand, ectopic lipid accumulation did
not improve significantly in the patients treated with Miglitol. To our knowledge, there have so far been no reports addressing the mechanisms whereby Miglitol reduces visceraland subcutaneous adipose tissue mass (10). Further studies
are warranted to clarify these underlying mechanisms.
The present study showed that lipid deposition in theiliopsoas muscle, back muscle and rectus abdominis muscle
increases with age. This finding is in agreement with the results of a previous study that showed that age-related decreases in mitochondrial activity are closely associated withskeletal muscle lipid deposition (8). Furthermore, it is noteworthy that the extent of the decreases observed in lipid
deposition in the skeletal muscles and liver exhibited wide
variation among the three kinds of studies (Fig. 3). Therefore, it is possible that depot-specific susceptibility to lipid
deposition exists. These findings lead to the speculation thatchanges in ectopic lipid deposition reflect responsiveness toantidiabetic drugs. Further studies are therefore warranted totest the hypothesis that depot-specific susceptibility to ectopic lipid deposition is associated with therapeutic effectiveness in patients with metabolic syndrome.
The use of proton 1H-MRS to evaluate tissue lipid content
is not yet prevalent in clinics because the technique is expensive and elaborate. In line with this notion, we did not
obtain our own data regarding a comparison between the
MRS and CT HU values. However, a previous work reported that the liver fat content, as assessed by MRS, in patients with nonalcoholic fatty liver disease exhibits goodcorrelation with the CT HU values (26). Therefore, futurestudies are warranted to verify that such a correlation would
also be reproduced in a variety of skeletal muscles in humans.
In summary, the present study is the first to show thatvisceral fat accumulation is correlated with lipid depositionin the iliopsoas muscle, back muscle, rectus abdominis muscle and liver in middle-aged men with metabolic syndrome.
CT-based simultaneous evaluations of ectopic lipid deposition and visceral fat accumulation may provide unique information for assessing cardiometabolic risks and therapeutic
impact.
Study limitations
There were some limitations associated with this study.
First, we did not measure the tissue lipid content directly using 1H-MRS. The CT HU values of the liver and skeletal
muscles may not necessarily reflect the intramyocellular or
intrahepatocellular lipid content, although they do reflect theextent of relative lipid deposition in each tissue.
Second, the correlations between the CT HU values of thetruncal muscles and body weight, waist circumference, thelevels of hepatic enzymes and the levels of glucose-lipid
metabolic markers were negligible. Therefore, it remains unclear in the present study whether changes in the CT HU
values of the truncal muscles reflect whole body glucoselipid metabolism.
Third, there is a limitation of a β error (type 2 error) in
our analysis due to the inclusion of 105 patients.
Indeed, we performed a post hoc power calculation to
analyze whether the study was adequately powered to detectassociations between these variables and the CT HU valuesof the three skeletal muscles. In our samples, given a total
sample size of 105 at the 5% level of significance, thepower (1-β error probability) of the associations between the
CT HU values of the iliopsoas, back and rectus abdominismuscles and the visceral fat area was calculated to be 0.78,
0.99 and 0.99, respectively, showing enough power to detectsignificant associations. Meanwhile, the power of the associations between the CT HU values of the iliopsoas, backand rectus abdominis muscles and the levels of FPG, fasting
insulin, HOMA-IR, HOMA-β, HDL-C, total cholesterol (TCho), triglyceride (TG), AST, ALT, glycosylated hemoglobin(HbA1c), FFA and γ-GTP in our 105 samples was quite low(power=0.05 to 0.07), except for the association between the
CT HU value of the rectus abdominis muscle and the levelof AST (power=0.79). Since at least 200 subjects are required to detect mild associations (r>0.20) with 80% powerat the 5% level of significance, there is a limitation to commit a β error (type 2 error) in our analysis.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
This work was supported in part by the Special AccountBudget for Education and Research granted by the MEXT JAPAN, The Takeda Science Foundation, Specified Research Grant,
Grants-in-Aid (MEXT, JAPAN) (Category C) (No.22591014 andNo. 225921059), the Okinawa Medical Science Research Foundation and a Research Promotion Grant of the University of the
Ryukyus Foundation and the project to “Establish a research hub
toward the development of an intellectual cluster,” Okinawa Prefecture, Japan.
M.S. and H.M. designed the studies. S.T., M.S., M.H., K.Y.,
C.K., R.U., S.S., M.D., T.N., E.K., Y.N., H.N., T.I., S.N., T.T., T.
I. and K.Y. conducted the data collection. S.T., M.S., M.H., K.Y.,
C.K., R.U., S.S., Y.O., K.Y. and H.M. contributed to the discussion. S.T. and H.M. wrote, reviewed and edited the manuscript.
We are grateful to Ms. N. Yamamoto, M. Katayanagi, M.
Hirata, I. Asato and C. Noguchi for their secretarial assistance.
We also thank Ms. K. Iwabuchi, K. Nakamoto and A. Ohshiro
for their technical assistance.

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