Norihito Moniwa, Daisuke Yoshida and Kazuaki Shimamoto

Masato Furuhashi, Nobuyuki Ura, Katsuhiro Higashiura, Hideyuki Murakami, Marenao Tanaka,
Patients With Essential Hypertension
Blockade of the Renin-Angiotensin System Increases Adiponectin Concentrations in
Print ISSN: 0194-911X. Online ISSN: 1524-4563
Copyright 2003 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Hypertension
doi: 10.1161/01.HYP.0000078490.59735.6E
2003;42:76-81; originally published online June 9, 2003; Hypertension.
http://hyper.ahajournals.org/content/42/1/76
World Wide Web at:
The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org//subscriptions/
is online at: Hypertension Information about subscribing to Subscriptions:

http://www.lww.com/reprints
Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information about
Office. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Hypertension in
Requests for permissions to reproduce figures, tables, or portions of articles originally published Permissions:
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
Blockade of the Renin-Angiotensin System Increases
Adiponectin Concentrations in Patients With
Essential Hypertension
Masato Furuhashi, Nobuyuki Ura, Katsuhiro Higashiura, Hideyuki Murakami, Marenao Tanaka,
Norihito Moniwa, Daisuke Yoshida, Kazuaki Shimamoto
AbstractAdiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity.
We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic
glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and
investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were
divided into 12 insulin-resistant EHT (EHT-R) and 18 noninsulin-resistant EHT (EHT-N) using mean1 SD of the M
value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly
higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher
levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin
concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI,
insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were
independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were
treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n9) or an angiotensin II receptor blocker
(candesartan, 8 mg/d; n7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood
pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These
results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade
increases adiponectin concentrations with improvement in insulin sensitivity. (Hypertension. 2003;42:76-81.)
Key Words: adiponectin

hypertension, essential

insulin resistance

renin-angiotensin system
A
dipose tissue was once thought to be simply a depot for
fuel storage in the form of triglyceride. However, it is
now known that adipocytes secrete a variety of proteins, such
as tumor necrosis factor (TNF)-, plasminogen activator
inhibitor-1, leptin, resistin, and adiponectin. These proteins
are implicated in a wide range of biological effects. Adi-
ponectin, an adipocyte-derived protein referred to as Acrp30,
apM1, AdipoQ, and GBP28, has been independently identi-
fied and characterized.
15
In contrast to other adipocyte-
derived proteins, the circulating levels of adiponectin are
reduced in patients with coronary artery disease and in states
of insulin resistance such as obesity and type 2 diabetes.
68
Adiponectin has been suggested to enhance insulin sensitivity
and prevent atherosclerosis.
9,10
Furthermore, thiazolidinedio-
nes, currently being used as insulin sensitizers in the treat-
ment of type 2 diabetes, have been shown to enhance the
mRNA levels and plasma levels of adiponectin in human
subjects and animal models of insulin resistance and type 2
diabetes.
1113
Insulin resistance and accompanying hyperinsulinemia
have been linked to the onset and progression of hypertension
and atherosclerosis. It has been shown that approximately
40% of essential hypertensives are insulin-resistant.
14,15
Al-
though there have been 2 recent studies on the concentrations
of adiponectin in patients with essential hypertension,
16,17
the
results are inconsistent. In those studies, some subjects had
been taking antihypertensive drugs, which might influence
insulin sensitivity, and a method for reliable and direct
assessment of insulin sensitivity such as the euglycemic-hy-
perinsulinemic glucose clamp method was not used. In
addition, antihypertenisve drugs such as angiotensin-
converting enzyme inhibitors and angiotensin II receptor
blockers have been reported to improve insulin sensitivi-
ty,
18,19
but there are no reports on the relationship between
adiponectin concentrations and blockade of the renin-angio-
tensin system (RAS).
We therefore examined the association between insulin
sensitivity assessed by the euglycemic-hyperinsulinemic glu-
cose clamp technique and adiponectin concentrations in
patients with essential hypertension as well as the effect of
RAS blockade on adiponectin concentrations in patients with
essential hypertension.
Received February 26, 2003; first decision March 19, 2003; revision accepted May 14, 2003.
From the Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Correspondence to Masato Furuhashi, M.D., Ph.D., Second Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1,
W-16, Chuo-ku, Sapporo 0608543, Japan. E-mail furuhasi@sapmed.ac.jp
2003 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000078490.59735.6E
76 by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
Methods
Study Protocol 1
Two groups of subjects were enrolled in this study: 30 mild-to-
moderate essential hypertensive patients (EHT, mean age:
46.410.6 years) and 20 body mass index (BMI)-matched normo-
tensive subjects (NT, mean age: 45.613.9 years). The subjects had
been taking no medication or had stopped taking all drugs that may
affect insulin sensitivity at least 2 weeks before the start of the study.
None of the subjects had any evidence of complications such as
endocrine or metabolic disturbances, cerebrovascular or cardiovas-
cular disease, or renal disease. All of the subjects were hospitalized
and were put on a regular diet (2000 kcal/d) that included 310 g of
carbohydrate, 50 g of fat, 80 g of protein, 120 mmol of sodium, and
75 mmol of potassium for more than 1 week. Insulin sensitivity was
evaluated as the M value (metabolic clearance of glucose, mg m
2
min
1
) by the euglycemic-hyperinsulinemic glucose clamp tech-
nique. Mean1 SD of the M value in the NT was chosen as the
cutoff point for insulin resistance. On the basis of this value, the EHT
were divided into two groups: one group of insulin-resistant EHT
(EHT-R) and one of noninsulin-resistant EHT (EHT-N). Before the
clamp study, blood pressure was measured and blood samples were
obtained from all of the subjects. The concentrations of adiponectin,
glucose, insulin, and lipid variables were measured. This study was
performed with the approval of the ethics committee of our institu-
tion, and informed consent was obtained from all of the subjects.
Study Protocol 2
We also examined the effect of RAS blockade on insulin resistance
and serum adiponectin concentrations in patients with essential
hypertension. Sixteen patients with essential hypertension were
recruited from the EHT in study protocol 1 and treated with an
angiotensin-converting enzyme inhibitor, temocapril (4 mg/d, n9),
or an angiotensin II receptor blocker, candesartan (8 mg/d, n7), for
2 weeks in hospital. Insulin sensitivity was evaluated by glucose
clamp study before and after treatment. Blood samples were obtained
before the clamp study.
Euglycemic-Hyperinsulinemic Glucose
Clamp Technique
A 2-hour euglycemic-hyperinsulinemic glucose clamp was per-
formed according to the method described by DeFronzo et al.
20
A
vein in a forearm was cannulated for blood glucose monitoring.
During the glucose clamp, blood was continuously withdrawn at 2.0
mL/h through a catheter. In addition, a contralateral antecubital vein
was cannulated with a plastic cannula for the infusion of insulin and
glucose. Continuous insulin infusion, monitoring of glucose concen-
tration, and infusion of various amounts of glucose in order to clamp
glucose levels in the basal state were performed with a model
STG-22 artificial endocrine pancreas (Nikkiso Corp). The infusion
rate of insulin (humalin R U-40, Shionogi Pharmaceutical Co) was
40 mU m
2
min
1
. During insulin infusion, euglycemia was
maintained by infusion of a 20% glucose solution. The mean rate of
glucose infusion for the last 30 minutes of the clamp was used as an
index of insulin sensitivity (M value). The M value was expressed as
milligrams of glucose per square meter of body surface area.
Laboratory Investigations
Serum adiponectin level was measured using a commercially avail-
able sandwich enzyme-linked immunosorbent assay kit (Otsuka
Pharmaceuticals Co, Ltd) as previously reported.
5
Fasting plasma
glucose was determined by the glucose oxidase method. Fasting
plasma insulin was measured by a radioimmunoassay method
(Insulin RIA bead, Dianabot). Serum lipid profiles, including total
cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride,
and free fatty acid (FFA), were estimated by enzymatic methods.
Statistical Analysis
Numeric variables are expressed as meanSD in protocol 1 and as
median (range) in protocol 2. Group statistical comparisons were
assessed by one-way analysis of variance and
2
test. Linear
regression analysis was used to determine the correlation between 2
variables. Multiple linear regression analysis was performed by
using serum adiponectin level as a dependent variable and age,
gender, BMI, mean blood pressure, M value, HDL cholesterol,
triglycerides, and FFA as independent variables. Stepwise regression
analysis was also performed in a forward direction with F for the
entry set to 4, showing the percentage of variance in the adiponectin
concentration that significant independent variables explained (r
2
).
The difference between 2 paired variables in protocol 2 was analyzed
by Wilcoxon signed rank test. A probability value of 0.05 was
considered statistically significant.
Results
Study Protocol 1
The EHT showed a significantly higher mean blood pressure
and a lower M value than did the NT. Using a cutoff point of
mean1 SD of the M value in the NT, the EHT were divided
into two groups: one group of 12 EHT-R and one group of 18
EHT-N. As shown in Table 1, there were no intergroup
differences in age, gender, and BMI. Mean blood pressures in
the EHT-R and EHT-N were comparable. The EHT-R had
significantly higher levels of fasting insulin and triglyceride
than did the NT and EHT-N. The EHT-R had higher levels of
FFA and lower levels of HDL cholesterol than did the
EHT-N. The levels of fasting plasma glucose and total
cholesterol in the three groups were similar. No significant
differences were found between lipid variables in the NT and
EHT-N. In all of the subjects, the M value was negatively
correlated with the levels of fasting insulin (r0.57,
P0.01) and FFA (r0.44, P0.01).
The EHT-R had significantly lower levels of serum adi-
ponectin concentrations than did the NT and EHT-N (Table
1). Although adiponectin concentrations were significantly
higher in women than in men (6.32.0 versus 4.82.0
g/mL, P0.01), serum adiponectin concentrations in the
TABLE 1. Basal Characteristics and Metabolic Variables of
Study Subjects
Variables
NT
(n20)
EHT-N
(n18)
EHT-R
(n12)
Age, y 45.613.9 46.39.7 46.312.1
Men/Women, n 10/10 9/9 5/7
Body mass index, kg/m
2
24.52.7 24.72.9 25.32.5
Mean blood pressure, mm Hg 93.410.7 111.513.9* 106.321.0*
M value, mg m
2
min
1
184.646.5 197.941.2 120.313.9*
Fasting plasma glucose, mmol/L 4.90.5 4.80.4 4.90.6
Fasting insulin, pmol/L 29.213.9 23.78.7 48.528.7*
Total cholesterol, mmol/L 4.90.9 4.71.0 4.61.0
HDL cholesterol, mmol/L 1.10.3 1.10.3 0.90.1
Triglyceride, mmol/L 0.90.4 0.90.4 1.31.0*
Free fatty acid, mmol/L 0.510.26 0.340.17 0.620.39
Adiponectin, g/mL 5.72.3 6.02.1 4.21.4*
Values are expressed as number (n) or meanSD. NT indicates normoten-
sive subjects; EHT-N, essential hypertensive patients with no insulin resistance;
EHT-R, essential hypertensive patients with insulin resistance; and M value,
metabolic clearance rate of glucose as an index of insulin sensitivity. Group
comparisons were assessed by one-way analysis of variance and the
2
test.
*P0.01 vs NT; P0.01 vs EHT-N.
Furuhashi et al Adiponectin and Renin-Angiotensin System Blockade 77
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
EHT-R were lower than those in the NT and EHT-N
regardless of gender. In all of the subjects, serum adiponectin
levels were positively correlated with the M value (r0.44,
P0.01) and HDL cholesterol levels (r0.51, P0.01) and
negatively with BMI (r0.62, P0.01) and levels of
fasting insulin (r0.39, P0.01), FFA (r0.29,
P0.05), and triglyceride (r0.33, P0.05) but not cor-
related with mean blood pressure. Multiple regression anal-
ysis showed that gender, the M value, BMI, and HDL
cholesterol levels were independently correlated with the
serum adiponectin concentrations. Stepwise regression anal-
ysis also revealed that gender, the M value, BMI, and HDL
cholesterol levels were independent determinants of adi-
ponectin concentrations, explaining a total of 67% of the
variance in this measure (r
2
0.67).
Study Protocol 2
Treatment with temocapril or candesartan significantly de-
creased mean blood pressure and FFA levels and increased
the M value (Table 2). Fasting insulin levels were decreased,
but not significantly, by treatment with temocapril (P0.06)
or candesartan (P0.08). There were no significant changes
in BMI and levels of fasting plasma glucose, total cholesterol,
HDL cholesterol, and triglyceride. Both temocapril and can-
desartan significantly increased adiponectin concentrations
(Figure). There were mean 15% and 30% increases in
adiponectin levels after treatment with temocapril and can-
desartan, respectively. Adiponectin concentrations were in-
creased in 15 of the 16 patients. The change in M value was
significantly correlated with that in adiponectin concentra-
tions (r0.59, P0.05). There was no significant difference
between the changes in adiponectin levels by treatment in
men and women.
Discussion
Four notable findings were obtained in the present study.
First, adiponectin concentrations in insulin-resistant essential
hypertensives were lower than those in normotensives and
noninsulin-resistant hypertensives, suggesting that hypoadi-
ponectinemia in essential hypertensives is attributable to
insulin resistance. This finding is in accordance with previous
findings that adiponectin levels are reduced in states of
insulin resistance such as obesity and type 2 diabetes.
7,8
Second, adiponectin levels were significantly correlated with
the degree of insulin sensitivity in the whole body (M value)
estimated by glucose clamp study, and the M value was an
independent predictor of adiponectin concentration. Third,
our findings are generally consistent with previous findings in
Japanese women of a positive association between adiponec-
tin concentrations and HDL cholesterol levels.
21
This rela-
tionship was independent of obesity and insulin sensitivity in
the present study. Finally, RAS blocking agents such as
temocapril and candesartan increased adiponectin levels with
accompanying improvement in insulin sensitivity but did not
affect the degree of adiposity. To the best of our knowledge,
TABLE 2. Change of the Metabolic Variables by Treatment
Variables
Temocapril (n9) Candesartan (n7)
Before After Before After
Age, y 54 (3466) 51 (3078)
Men/Women, n 6/3 3/4
Body mass index, kg/m
2
26.4 (20.529.6) 26.0 (20.628.9) 22.5 (20.528.5) 22.9 (20.627.8)
Mean blood pressure, mm Hg 121.0 (95.7144.0) 103.7 (100.3137.3)* 101.5 (79.1116.7) 91.8 (70.2109.8)*
M value, mg m
2
min
1
156.8 (100.5277.5) 179.1 (127.7312.2)* 151.9 (125.9196.2) 219.9 (140.8307.8)*
Fasting plasma glucose, mmol/L 4.6 (4.25.9) 4.7 (4.35.7) 4.7 (4.29.6) 4.7 (4.28.3)
Fasting insulin, pmol/L 24.6 (16.871.4) 20.4 (18.044.4) 26.4 (18.044.4) 19.2 (18.031.2)
Total cholesterol, mmol/L 5.3 (2.97.2) 5.3 (3.18.2) 4.2 (3.46.4) 4.5 (3.56.6)
HDL cholesterol, mmol/L 1.0 (0.71.8) 1.2 (0.62.0) 1.0 (0.81.9) 1.1 (0.71.8)
Triglyceride, mmol/L 0.9 (0.52.6) 0.8 (0.43.7) 1.0 (0.62.3) 0.7 (0.51.5)
Free fatty acid, mmol/L 0.38 (0.250.88) 0.32 (0.190.78)* 0.34 (0.220.59) 0.27 (0.110.42)*
Values are expressed as number (n) or median (range). The difference between 2 paired variables was analyzed by Wilcoxon signed
rank test.
*P0.05 vs before treatment.
Adiponectin concentrations in patients with essential hyperten-
sion before and after 2-week treatment with temocapril (4 mg/d)
or candesartan (8 mg/d). Both temocapril and candesartan sig-
nicantly increased adiponectin concentrations. White and black
circles represent men and women, respectively. The difference
between 2 paired variables was analyzed by Wilcoxon signed
rank test. *P0.05.
78 Hypertension July 2003
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
this is the first report on the effect of RAS blockade on
circulating adiponectin concentrations.
Both temocapril and candesartan, which were used in the
present study, have been reported to improve insulin sensi-
tivity.
18,19
Several possible mechanisms of improvement in
insulin sensitivity by RAS blockade have been suggested.
22
Angiotensin II has been shown to increase serine phosphor-
ylation of the insulin receptor, insulin receptor substrate 1,
and phosphatidylinositol-3-kinase (PI3K), which result in an
impairment of insulin signaling.
23
A possible mechanism of
improvement in insulin sensitivity is that RAS blockade
causes inhibition of the impairment of insulin signaling by
angiotensin II, resulting in activation of the glucose trans-
porter and its translocation from an intracellular membrane
compartment to a plasma membrane fraction. Other mecha-
nisms may include the following: vasodilation, which in-
creases the blood flow in skeletal muscle;
24
an increase in the
ratio of insulin-sensitive type 1 fiber in muscle fiber compo-
sition;
25
and a decrease in TNF- in skeletal muscle.
26
An
increase in adiponectin levels caused by RAS blockade may
also be a novel mechanism for RAS blockademediated
enhancement of whole-body insulin sensitivity.
However, the precise mechanisms by which RAS blockade
leads to an increase in circulating adiponectin levels are
unclear. It has been suggested that adiponectin levels can be
increased after weight reduction.
8,27
RAS blockade, however,
did not affect BMI in the present study. We speculate that the
mechanisms of an increase in adiponectin concentrations may
include the following processes.
First, the increase in serum adiponectin levels could be the
result of enhanced insulin sensitivity. It has been reported that
insulin infusion during a glucose clamp study leads to a
decrease in adiponectin concentrations,
28
suggesting that
chronic hyperinsulinemia associated with an insulin-resistant
state leads to a decrease in adiponectin concentrations. This
raises the idea that the effect of RAS blockade on adiponectin
levels is, at least partly, mediated by the decrease in insulin
levels, which is secondary to the effect of RAS blockade on
enhancing insulin sensitivity. Although administration of
thiazolidinediones, peroxisome proliferator-activated recep-
tor (PPAR) agonists, has been shown to increase adiponec-
tin concentrations,
1113
treatment with metformin, a non
PPAR-associated antihyperglycemic agent, or fenofibrate, a
PPAR agonist that has recently been shown to improve
insulin sensitivity,
29
has been reported to have no effect on
adiponectin concentrations in mice.
13
This indicates that the
change in adiponectin concentrations is not simply a conse-
quence of an improved metabolic phenotype and that the
change in adiponectin levels is indeed (directly or indirectly)
RAS blockademediated.
Second, based on results of recent in vitro studies showing
that angiotensin II markedly inhibits adipogenic differentia-
tion of human adipocytes via the angiotensin type I receptor
and that expression of angiotensin IIforming enzymes in
adipose tissue is inversely correlated with insulin sensitivity,
Sharma et al
30
have hypothesized that RAS blockade pro-
motes the recruitment and differentiation of preadipocytes
and that increased formation of small insulin-sensitive adipo-
cytes counteracts the ectopic deposition of lipids in muscle
and liver, thereby improving insulin sensitivity. With regard
to thiazolidinediones, it has been shown in a previous study
that 15-day treatment with troglitazone did not change the
total weight of white adipose tissues but increased the number
of small adipocytes and decreased the number of large
adipocytes.
31
Adiponectin secretion may be directly affected
by adipocyte differentiation. RAS blockade is likely to
promote an increase in adipogenesis that may result in a
greater net capacity for adiponectin production. However,
because the hypothesis by Sharma et al has not been proved
yet in vivo, further investigations of adipogenesis during a
relatively short period of RAS blockade seem to be needed.
Moreover, the increase in adiponectin levels caused by
RAS blockade may be regulated at a level of post-
transcription, including translation and/or secretion, because
the magnitude of increase in adiponectin levels caused by
RAS blockade for 2 weeks in the present study was low
compared with the previously reported 130% increase in
circulating adiponectin concentrations in normal glucose-
tolerant subjects after 14-day treatment with rosiglitazone, a
PPAR agonist.
13
It has also been reported that angiotensin II
does not influence the gene expression of adiponectin in
3T3-L1 adipocytes.
32
The fact that insulin-stimulated adi-
ponectin exocytosis in 3T3-L1 adipocytes is mediated in a
PI3K-dependent fashion
33
may be relevant to a post-
translational mechanism, because angiotensin II has been
shown to inhibit insulin-mediated PI3K activity.
23
Lastly, since it has been shown that TNF- suppresses
expression and secretion of adiponectin in 3T3-L1 adipo-
cytes
11
and that RAS blockade decreases TNF- levels in
skeletal muscle and mononuclear cells but not yet confirmed
in adipose tissue,
26,34
the increase in adiponectin secretion
could be caused by a decrease in TNF- levels or actions in
adipocytes.
The influence of candesartan on serum adiponectin con-
centrations seems to be greater than that of temocapril in the
present study. However, the mean change in the M value
caused by candesartan was higher, but not significantly, than
that caused by temocapril. Because change in the M value
was correlated with change in adiponectin concentrations, the
difference between changes in adiponectin levels caused by
candesartan and temocapril may be related to the change in
the M value.
There have been 2 recent reports on the concentrations
of adiponectin in patients with essential hypertension.
16,17
Adamczak et al
16
reported that plasma adiponectin concen-
trations were decreased in patients with essential hyperten-
sion. In contrast, Mallamaci et al
17
showed that adiponectin
levels were higher in hypertensive patients than in normoten-
sive subjects and were inversely related to creatinine clear-
ance in hypertensive patients and that creatinine clearance
was the only independent predictor of adiponectin concentra-
tions. It is possible that latent renal dysfunction had compli-
cated essential hypertension in the latter study. Thus, results
of recent studies on adiponectin in essential hypertension
have been inconsistent. Our results showed that adiponectin
concentrations were reduced in insulin-resistant essential
hypertensives but not normotensives or noninsulin-resistant
Furuhashi et al Adiponectin and Renin-Angiotensin System Blockade 79
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
hypertensives, suggesting that hypoadiponectinemia in essen-
tial hypertensives is associated with insulin resistance.
Adiponectin concentrations were not related to mean blood
pressure in the present study. Contrary to this result, signif-
icant negative correlations were found between plasma adi-
ponectin concentration and mean, systolic, and diastolic
blood pressures in 33 essential hypertensives and 33 normo-
tensives.
16
Other studies, however, demonstrated that adi-
ponectin levels were not related to blood pressure in 180
overweight/obese Asian subjects
35
or in 36 hypertensive
patients.
17
Moreover, another study showed that serum adi-
ponectin levels were negatively correlated with systolic blood
pressure and diastolic blood pressure in a large number of
Japanese subjects (705 men and 262 women), but these
correlations were not significant after adjustment for age,
gender, and BMI.
36
In animal studies, effects of recombinant
adiponectin on body weight, glucose, and lipid metabolism
have been clearly demonstrated.
9,37,38
However, its effect on
blood pressure regulation has not been reported. The delin-
eation of the relation between adiponectin and blood pressure
requires more study.
One limitation of this study is the small number of subjects
enrolled. We demonstrated that serum adiponectin concentra-
tions were gender-related, being higher in women than in men
as previously reported.
8,36
Although there was no intergroup
difference in gender in the present study, it is important to
confirm our findings by studies with more patients. Further-
more, studies with larger populations of subjects in whom
various kinds of RAS blocking agents are used seem to be
needed.
In conclusion, our results suggest that hypoadiponectine-
mia and disturbance of lipid metabolism are associated with
insulin resistance in patients with essential hypertension and
that RAS blockade increases serum adiponectin concentra-
tions with improvement in insulin sensitivity.
Perspectives
It has been suggested that adiponectin modulates endothelial
function and has an inhibitory effect on vascular smooth
muscle cell proliferation.
39,40
Moreover, adiponectin has been
shown to be accumulated in an injured artery from the plasma
and to suppress macrophage-to-foam cell transformation in
vitro and in vivo.
10,41,42
On the basis of these observations, it
is possible that reduction in adiponectin concentrations may
account, at least in part, for the higher incidence of athero-
sclerotic diseases in essential hypertension and that RAS
blockade may prevent, at least in part, atherosclerosis via
increased adiponectin concentrations.
Recent clinical trials, such as the Captopril Primary Pre-
vention Project (CAPPP),
43
the Heart Outcomes Prevention
Evaluation (HOPE),
44
and the Losartan Intervention For
Endpoint reduction in hypertension study (LIFE),
45
suggest
that RAS blockade may substantially lower the risk for type
2 diabetes. One of the mechanisms underlying this effect may
be an increase in adiponectin concentrations by RAS block-
ade. The demonstration that RAS blockade increases adi-
ponectin concentrations with improvement in insulin sensi-
tivity might provide a scientific rationale for the use of
angiotensin-converting enzyme inhibitors or angiotensin II
receptor blockers for the prevention of diabetes in high-risk
hypertensive patients.
References
1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel
serum protein similar to C1q, produced exclusively in adipocytes. J Biol
Chem. 1995;270:2674626749.
2. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara
K. cDNA cloning and expression of a novel adipose specific collagen-like
factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys
Res Commun. 1996;221:286289.
3. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene
dysregulated in obesity. J Biol Chem. 1996;271:1069710703.
4. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and
characterization of GBP28, a novel gelatin-binding protein purified from
human plasma. J Biochem (Tokyo). 1996;120:803812.
5. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta
K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M,
Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y,
Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific
protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;
257:7983.
6. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta
K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T,
Matsuzawa Y. Novel modulator for endothelial adhesion molecules:
adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:
24732476.
7. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE,
Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close
association with insulin resistance and hyperinsulinemia. J Clin Endo-
crinol Metab. 2001;86:19301935.
8. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y,
Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai
N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T,
Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a
novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
Arterioscler Thromb Vasc Biol. 2000;20:15951599.
9. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y,
Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y,
Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M,
Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki
T. The fat-derived hormone adiponectin reverses insulin resistance asso-
ciated with both lipoatrophy and obesity. Nat Med. 2001;7:941946.
10. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi
K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi
T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein
E-deficient mice. Circulation. 2002;106:27672770.
11. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K,
Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K,
Nakamura T, Shimomura I, Matsuzawa Y. PPAR ligands increase
expression and plasma concentrations of adiponectin, an adipose-derived
protein. Diabetes. 2001;50:20942099.
12. Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang
JP, Chen CL, Tai TY, Chuang LM. Synthetic peroxisome proliferator-
activated receptor- agonist, rosiglitazone, increases plasma levels of
adiponectin in type 2 diabetic patients. Diabetes Care. 2002;25:376380.
13. Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB,
Tanen M, Berg AH, ORahilly S, Savage DB, Chatterjee K, Weiss S,
Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller
DE. Induction of adipocyte complement-related protein of 30 kilodaltons
by PPAR agonists: a potential mechanism of insulin sensitization. Endo-
crinology. 2002;143:9981007.
14. Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential
hypertension. J Hypertens. 1995;13:14571462.
15. Iimura O. Insulin resistance and hypertension in Japanese. Hypertens Res.
1996;19(suppl 1):S1S8.
16. Adamczak M, Wiecedil;cek A, Funahashi T, Chudek J, Kokot F, Matsuzawa
Y. Decreased plasma adiponectin concentration in patients with essential
hypertension. Am J Hypertens. 2003;16:7275.
17. Mallamaci F, Zoccali C, Cuzzola F, Tripepi G, Cutrupi S, Parlongo S,
Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin
in essential hypertension. J Nephrol. 2002;15:507511.
18. Miyazaki Y, Murakami H, Hirata A, Fukuoka M, Masuda A, Ura N,
Shimamoto K. Effects of the angiotensin converting enzyme inhibitor
80 Hypertension July 2003
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from
temocapril on insulin sensitivity and its effects on renal sodium handling
and the pressor system in essential hypertensive patients. Am J Hypertens.
1998;11:962970.
19. Iimura O, Shimamoto K, Matsuda K, Masuda A, Takizawa H, Higashiura
K, Miyazaki Y, Hirata A, Ura N, Nakagawa M. Effects of angiotensin
receptor antagonist and angiotensin converting enzyme inhibitor on
insulin sensitivity in fructose-fed hypertensive rats and essential hyper-
tensives. Am J Hypertens. 1995;8:353357.
20. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method
for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:
E214E223.
21. Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin
concentrations in women with dyslipidemia. J Clin Endocrinol Metab.
2002;87:27642769.
22. Katovich MJ, Pachori A. Effects of inhibition of the renin-angiotensin
system on the cardiovascular actions of insulin. Diabetes Obes Metab.
2000;2:314.
23. Folli F, Saad MJ, Velloso L, Hansen H, Carandente O, Feener EP, Kahn
CR. Crosstalk between insulin and angiotensin II signalling systems. Exp
Clin Endocrinol Diabetes. 1999;107:133139.
24. Kodama J, Katayama S, Tanaka K, Itabashi A, Kawazu S, Ishii J. Effect
of captopril on glucose concentration. Possible role of augmented post-
prandial forearm blood flow. Diabetes Care. 1990;13:11091111.
25. Higashiura K, Ura N, Takada T, Li Y, Torii T, Togashi N, Takada M,
Takizawa H, Shimamoto K. The effects of an angiotensin-converting
enzyme inhibitor and an angiotensin II receptor antagonist on insulin
resistance in fructose-fed rats. Am J Hypertens. 2000;13:290297.
26. Togashi N, Ura N, Higashiura K, Murakami H, Shimamoto K. The
contribution of skeletal muscle tumor necrosis factor- to insulin
resistance and hypertension in fructose-fed rats. J Hypertens. 2000;18:
16051610.
27. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL,
Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma levels
of an adipose-derived anti-inflammatory protein, adiponectin. J Clin
Endocrinol Metab. 2001;86:38153819.
28. Mohlig M, Wegewitz U, Osterhoff M, Isken F, Ristow M, Pfeiffer AF,
Spranger J. Insulin decreases human adiponectin plasma levels. Horm
Metab Res. 2002;34:655658.
29. Furuhashi M, Ura N, Murakami H, Hyakukoku M, Yamaguchi K,
Higashiura K, Shimamoto K. Fenofibrate improves insulin sensitivity in
connection with intramuscular lipid content, muscle fatty acid-binding
protein, and -oxidation in skeletal muscle. J Endocrinol. 2002;174:
321329.
30. Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin
blockade prevents type 2 diabetes by formation of fat cells. Hypertension.
2002;40:609611.
31. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono
K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T.
Troglitazone increases the number of small adipocytes without the change
of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998;
101:13541361.
32. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal
regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem
Biophys Res Commun. 2002;290:10841089.
33. Bogan JS, Lodish HF. Two compartments for insulin-stimulated exo-
cytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and
GLUT4. J Cell Biol. 1999;146:609620.
34. Schindler R, Dinarello CA, Koch KM. Angiotensin-converting-enzyme
inhibitors suppress synthesis of tumour necrosis factor and interleukin 1
by human peripheral blood mononuclear cells. Cytokine. 1995;7:
526533.
35. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL,
Chen CL, Tai TY, Chuang LM. Plasma adiponectin levels in overweight
and obese Asians. Obes Res. 2002;10:11041110.
36. Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K,
Okazaki Y, Ishii T, Nishikai K, Saruta T. Correlation of the adipocyte-
derived protein adiponectin with insulin resistance index and serum
high-density lipoprotein-cholesterol, independent of body mass index, in
the Japanese population. Clin Sci (Lond). 2002;103:137142.
37. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-
secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;
7:947953.
38. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT,
Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte
complementrelated protein increases fatty acid oxidation in muscle and
causes weight loss in mice. Proc Natl Acad Sci USA. 2001;98:20052010.
39. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta
K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T,
Yamashita S, Funahashi T, Matsuzawa Y. Adiponectin, an adipocyte-
derived plasma protein, inhibits endothelial NF-B signaling through a
cAMP-dependent pathway. Circulation. 2000;102:12961301.
40. Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada
M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I,
Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte-
derived plasma protein adiponectin acts as a platelet-derived growth
factor-BB-binding protein and regulates growth factor-induced common
postreceptor signal in vascular smooth muscle cell. Circulation. 2002;
105:28932898.
41. Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M,
Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J,
Funahashi T, Matsuzawa Y. An adipocyte-derived plasma protein, adi-
ponectin, adheres to injured vascular walls. Horm Metab Res. 2000;32:
4750.
42. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y,
Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi
M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-
derived plasma protein, adiponectin, suppresses lipid accumulation and
class A scavenger receptor expression in human monocyte-derived mac-
rophages. Circulation. 2001;103:10571063.
43. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A,
Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester
PO, Bjorck JE. Effect of angiotensin-converting-enzyme inhibition
compared with conventional therapy on cardiovascular morbidity and
mortality in hypertension: the Captopril Prevention Project (CAPPP)
randomised trial. Lancet. 1999;353:611616.
44. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH,
Zinman B. Ramipril and the development of diabetes. JAMA. 2001;286:
18821885.
45. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U,
Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm
LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular mor-
bidity and mortality in the Losartan Intervention For Endpoint reduction
in hypertension study (LIFE): a randomised trial against atenolol. Lancet.
2002;359:9951003.
Furuhashi et al Adiponectin and Renin-Angiotensin System Blockade 81
by guest on June 15, 2014 http://hyper.ahajournals.org/ Downloaded from