© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Plasma Concentrations of a Novel, Adipose-Specific Protein, Adiponectin, in Type 2 Diabetic Patients
From the Department of Internal Medicine and Molecular Science (K. Hotta, T.F., Y.A., M.T., M. Matsuda, Y. Okamoto, H.I., H.K., N.O., K.M., M.N., S.K., N.S., T. Nakamura, S.Y., T.H., Y.M.), Graduate School of Medicine, Osaka University, Osaka, Japan; the Toyonaka City Hospital (T. Nakajima), Osaka, Japan; the Health Administration Department (K. Hasegawa), ITOCHU Corporation, Osaka, Japan; and the Cellular Technology Institute (M. Muraguchi, Y. Ohmoto), Otsuka Pharmaceutical Co, Ltd., Tokushima, Japan.
Correspondence to Kikuko Hotta, MD, PhD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail khotta{at}imed2.med.osaka-u.ac.jp
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Abstract |
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Abstract—Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)–matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6±0.4 versus 7.9±0.5 µg/mL in men, 7.6±0.7 versus 11.7±1.0 µg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0±0.4 versus 6.6±0.4 µg/mL, P<0.001 in men; 6.3±0.8 versus 7.6±0.7 µg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.
Key Words: adiponectin • diabetes mellitus • coronary artery disease • adipose tissue
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Introduction |
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Atherosclerotic cardiovascular complications are the major causes of morbidity and mortality in type 2 diabetic patients.1 The precise mechanism underlying the development of atherosclerotic vascular disease has not been fully elucidated. Abnormalities in lipid metabolism and hemostatic factors and the presence of insulin resistance are thought to contribute to atherosclerotic vascular damage in diabetes. Plasma plasminogen activator inhibitor type 1 (PAI-1) concentrations are elevated in type 2 diabetic patients, and increased plasma PAI-1 reduces fibrinolytic activity, which may play a role in the development of vascular complications.2 3 Recent experimental and clinical studies have revealed that adipose tissue, especially intra-abdominal visceral adipose tissue, is an important source of plasma PAI-1.4 5 Traditionally, adipose tissue has been considered to be an organ that passively stores excess energy as fat. Substantial research has explored the notion that adipose tissue secretes a variety of biologically active molecules, including cytokines, growth factors, and complement factors, into the circulation.6 7 8 9 Tumor necrosis factor (TNF)-
decreases tyrosine kinase activity of
the insulin receptor and is overproduced in adipose tissues in
insulin-resistant rodents and humans, suggesting that it is a
possible mediator of insulin resistance in obesity and
diabetes.6 10 11 Leptin is produced specifically by
adipose tissue and transmits a satiety signal to the central nervous
system.7 The molecule also affects glucose
metabolism and insulin sensitivity.12 13 These
data suggest that the multiple molecules produced by adipose tissue
contribute to the development of insulin resistance and atherosclerotic
complications in diabetes mellitus.
Adiponectin is a novel, adipose-specific protein belonging to the
collectin family.14 15 The protein is present
abundantly in the circulation, accounting for 
0.01% of total plasma
protein.16 When the endothelium of the
carotid arteries is injured by a balloon catheter in rats, adiponectin
accumulates in the vascular walls.17 Recently, we observed
that adiponectin suppressed the attachment of monocytes to
endothelial cells,18 which is an early
event in atherosclerotic vascular change. Adiponectin may have a role
in protection against vascular damage. Although the expression of
adiponectin mRNA is restricted in adipose tissue, its plasma
concentrations are decreased in obesity.16 The
significance of adiponectin in diabetes mellitus has not been
investigated. Plasma adiponectin may be dysregulated in disorders
susceptible to atherosclerotic vascular diseases, such as diabetes
mellitus. In this report, we investigated the plasma adiponectin
concentrations in type 2 diabetic humans, especially with respect to
atherosclerotic coronary vascular complications.
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Methods |
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ELISA of Plasma Adiponectin and Leptin
All blood samples were drawn after an overnight fast unless otherwise indicated. Plasma samples were kept at -80°C for subsequent assay. The concentration of plasma adiponectin was determined by ELISA as described previously.16 The plasma leptin levels were also determined by ELISA. Briefly, recombinant human leptin cloned into pET3a (Novagen Inc) was expressed in Escherichia coli BL21 (DE3) (Novagen Inc). Monoclonal and polyclonal anti-leptin antibodies were produced against the recombinant leptin. Ten microliters of plasma was applied to a 96-well microtiter plate coated with mouse anti-leptin monoclonal antibody. The wells were washed and further incubated with rabbit anti-leptin polyclonal antibody, followed by incubation with horseradish peroxidase–labeled anti-rabbit IgG. Each well was reacted with o-phenylenediamine dihydrochloride (Sigma), and the absorbance at 492 nm was measured. Recombinant human leptin protein as described above was used as the standard.
Determination of Plasma Adiponectin Levels in Nondiabetic and
Diabetic Subjects
Blood specimens were obtained before and 2 hours after ingestion
of a 75-g glucose load for assay of plasma glucose concentrations.
Diabetes was diagnosed according to World Health Organization (1985)
criteria. Plasma glucose was measured by a glucose oxidase method. A
total of 183 diabetic patients including 127 men and 56 women were
studied. The diabetic patients who suffered from myocardial infarction
or who showed ischemic electrocardiographic changes on exercise
testing with or without cardiac symptoms underwent coronary
angiography. Among them, 64 (45 men and 19 women) were angiographically
diagnosed as having CAD. The criteria of CAD was the reduction in
luminal diameter of a major coronary artery branch by >75%.
Forty-four patients (21 men and 23 women) had
retinopathy, which was diagnosed by an ophthalmologist.
Sixty patients (42 men and 18 women) had nephropathy, with
a urinary albumin concentration of >20 mg/g
creatinine. Urinary albumin concentrations were
determined by radioimmunoassay and adjusted to urinary
creatinine concentrations. Eighty-two age- and body mass
index (BMI)–matched subjects with normal glucose tolerance, including
54 men and 28 women, were selected from healthy volunteers who
underwent a medical examination and served as controls (Table 1
). Subjects with impaired glucose
tolerance were excluded from the study. All women studied herein were
postmenopausal. Informed consent was obtained from all subjects.
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Serum cholesterol and triglyceride concentrations were determined by enzymatic methods. HDL cholesterol was also measured by an enzymatic method after heparin and calcium precipitation. The value of hemoglobin A1c was determined by high-performance liquid chromatography.
Change in Plasma Adiponectin Concentrations Before and After
Weight Reduction
To study the effect of weight reduction on plasma adiponectin
levels, 13 nondiabetic, obese subjects (6 men and 7 women; BMI,
36.8±1.2 kg/m2; age, 45±5 years) and 9
diabetic, obese subjects (6 men and 3 women; BMI, 34.8±2.6
kg/m2; age, 50±3 years) were hospitalized and
placed on a calorie-restricted diet to reduce their body weight. The
weight reduction therapy was performed according to the calorie
restriction program in our clinic. In brief, starting at 2000 kcal/d,
total calorie intake was decreased sequentially ( -400 kcal/d for 2
weeks) to 800 kcal/d (carbohydrate 50%, fat 25%, and protein 25%),
and this calorie level was maintained. Their BMI decreased
significantly within 2 months (nondiabetic, 33.2±1.0
kg/m2, P<0.001; diabetic, 30.4±2.0
kg/m2, P<0.01). Mean BMI changes of
10±1% in nondiabetic subjects and of 12±2% in diabetic subjects
were achieved. The plasma was obtained before and at the end of the
weight reduction period.
Daily Profile of Plasma Adiponectin Concentrations
The circadian variation in plasma adiponectin concentrations was
investigated in 7 nondiabetic subjects (3 men and 4 women) and 6
diabetic subjects (4 men and 2 women). Their BMI was 31.1±2.4
kg/m2 (range, 24.5 to 39.3
kg/m2) in nondiabetic subjects (age, 54±5 years)
and 33.0±3.5 kg/m2 (range, 22.4 to 44.8
kg/m2) in diabetic subjects (age, 54±8 years).
Each subject was hospitalized and received breakfast at 7
AM, lunch at noon, and dinner at 6 PM. Plasma
was obtained from each subject at 6:30, 9:30, and 11:30 AM
and at 2:30, 5:30, 8:30, and 9:30 PM. The plasma levels of
glucose, insulin, adiponectin, and leptin were determined.
Statistics
Data are expressed as mean±SEM. Intergroup differences in the
parameters were analyzed by t test.
Significant group differences and daily changes in the plasma
adiponectin and leptin levels were compared by one-way ANOVA and tested
further by the Fisher multiple comparison method. Linear relationships
between key variables were tested by Pearson’s correlation
coefficient. Multiple linear regression analysis was performed
to evaluate the independent relationship of the studied
variables.
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Results |
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Plasma Adiponectin Levels in Nondiabetic and Diabetic Subjects With and Without CAD
Plasma levels of the adipose-specific proteins adiponectin and leptin were measured in 183 patients with type 2 diabetes and in 82 age- and BMI-matched healthy subjects with normal glucose tolerance. There was no significant difference in the plasma levels of leptin between diabetic and nondiabetic groups. In contrast, plasma levels of adiponectin were significantly lower in the diabetic than in the nondiabetic subjects in both men and women (5.7±0.3 versus 7.9±0.5 µg/mL in men, P<0.001; 7.2±0.5 versus 11.7±1.0 µg/mL in women, P<0.001). The diabetic subjects were subdivided into 2 groups, those with and without CAD. Plasma adiponectin concentrations in diabetic women without CAD were significantly lower than those in nondiabetic women (7.6±0.7 versus 11.7±1.0 µg/mL, P<0.001). Diabetic women with CAD exhibited even lower plasma adiponectin concentrations (Table 1
and Figure 1). In men, diabetic subjects without CAD
also showed lower plasma adiponectin levels compared with nondiabetic
subjects (6.6±0.4 versus 7.9±0.5 µg/mL, P=0.07),
although this difference was not statistically significant. Plasma
adiponectin levels in diabetic men with CAD were even lower and
statistically significant when compared with diabetic men without CAD
(4.0±0.4 versus 6.6±0.4 µg/mL, P<0.001). No significant
difference was found in plasma leptin concentrations between diabetic
subjects with and without CAD. The plasma adiponectin levels did not
differ between patients with and without retinopathy
(6.1±0.9 versus 5.5±0.5 µg/mL in men, 7.6±0.9 µg/mL versus
6.9±0.8 µg/mL in women) nor in those with and without
nephropathy (5.2±0.6 versus 5.8±0.7 µg/mL in men,
6.1±0.9 µg/mL versus 7.4±0.9 µg/mL in women). There was no
correlation between plasma adiponectin levels and urinary
albumin concentrations (men, r=0.11; women,
r=0.14).
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Next we analyzed the correlation between plasma levels of
adiponectin and other parameters. Plasma levels of
adiponectin were negatively correlated with BMI (r=-0.29,
P<0.001) as previously reported.16 No
significant correlation was found between the plasma levels of
adiponectin and age (r=0.05). The plasma concentration of
adiponectin was negatively correlated with plasma glucose level
(r=-0.26, P<0.001), the value of hemoglobin A1c
(r=-0.23, P<0.001), and plasma insulin level
(r=-0.18, P<0.01). Among the lipid
parameters, the serum triglyceride level was
negatively correlated (r=-0.32, P<0.001) and
the HDL cholesterol level positively correlated
(r=0.35, P<0.001) with the plasma adiponectin
level. Total cholesterol level was not correlated with
plasma adiponectin level (r=0.12). A multiple linear
regression analysis revealed that the presence of diabetes and
CAD was significantly associated with the decreased plasma level of
adiponectin, independent of BMI in women. In men, the presence of CAD
but not of diabetes was significantly associated with the decreased
plasma adiponectin concentration. Plasma insulin and HDL
cholesterol levels were not independent
parameters associated with the decreased plasma adiponectin
concentration. Serum triglyceride concentration remained an
independent parameter to the plasma adiponectin level
(Table 2).
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Regulation of Plasma Adiponectin Levels in Diabetic
Patients
Fasting plasma levels of adiponectin were decreased in diabetic
subjects. Regulation of plasma levels of adiponectin may be disturbed
in the diabetic state. It is well known that plasma leptin levels are
regulated by adiposity, and they are reduced by weight
reduction.19 20 We investigated the effect of weight
reduction on plasma adiponectin concentrations in both nondiabetic and
diabetic subjects. An 10% reduction of BMI (nondiabetics,
-10±1%; diabetics, -12±2%) was achieved in 13 nondiabetic and 9
diabetic subjects. Plasma leptin levels were decreased in both
nondiabetic (-58±4%, P<0.001) and diabetic (-46±9%,
P<0.01) subjects. On the other hand, plasma adiponectin
significantly increased after body weight reduction in nondiabetic
subjects (42±13%, P<0.01). An equivalent increase was
observed in diabetic subjects (65±22%, P<0.05; Figure 2). Therefore, the plasma adiponectin
level is negatively regulated by adiposity. Regulation by adiposity was
conserved in the diabetic subjects.
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Plasma leptin levels are known to show circadian variation: they are
low in the morning and high in the evening.21 The daily
profile of plasma adiponectin was investigated. Plasma glucose and
insulin levels were elevated after every meal. Plasma leptin level
showed a single peak at 6 PM. Plasma adiponectin showed no
daily change in both the nondiabetic and diabetic subjects (Figure 3).
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Discussion |
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Adiponectin is a collagen-like protein produced specifically by adipose tissue and is abundantly present in the circulation. When the vascular endothelium is injured, adiponectin accumulates in the subintimal space of the arterial wall through its interaction with collagens in the vascular intima.17 Adiponectin attenuates TNF-
–induced
expression of adhesion molecules in endothelial
cells,18 which is an initial step of
atherosclerosis.22 23 The significance of
adiponectin in human disease has not been fully elucidated. In a
previous study, we showed that obese subjects and subjects with CAD
exhibited decreased plasma concentrations of
adiponectin.16 18 In the present study, we
investigated the plasma adiponectin concentrations in subjects with
type 2 diabetes mellitus.
The subjects with type 2 diabetes mellitus showed significantly
decreased plasma adiponectin concentrations. Although plasma
adiponectin levels are negatively correlated with BMI, diabetic
subjects had lower values of plasma adiponectin than did nondiabetic
subjects, independent of BMI. Insulin regulates the secretion of
various proteins from adipose tissue. Elevated plasma insulin in the
diabetic subjects in this study may have been responsible for the
decreased plasma adiponectin concentrations. The plasma level of
leptin, another molecule specifically secreted from adipocytes, was
positively correlated with fasting plasma insulin.7 19 On
the other hand, the plasma adiponectin concentration was negatively
correlated with the fasting plasma insulin level. The daily profile of
plasma adiponectin levels revealed that it was not affected by food
intake, in contrast with increased plasma insulin levels, suggesting
that insulin does not have an acute effect on the plasma adiponectin
level. Chronic insulin resistance in type 2 diabetes may be related to
decreased plasma adiponectin. Overproduction of TNF- by
adipose tissue has been suggested in the development of insulin
resistance.6 10 11 Adiponectin interferes with TNF-
signaling in endothelial cells.18
Decreased plasma adiponectin may play a causative role in the
development of insulin resistance. The effect of adiponectin on TNF-
signaling and insulin sensitivity in muscles should be
investigated.
Another remarkable finding in this study was that plasma adiponectin levels were decreased prominently in diabetic subjects with CAD. In contrast, plasma levels of leptin did not differ between the diabetic subjects with and without CAD. Experimental research has indicated that adiponectin has potential antiatherogenic properties.17 18 Thus, the decreased plasma adiponectin in diabetic subjects may play a role in the development of atherosclerotic vascular damage. Another possibility is that accumulation of adiponectin in atherosclerotic vascular walls may accelerate its half-life in plasma, resulting in the reduction of the plasma concentration of adiponectin in subjects with CAD. The causal relationship between atherosclerotic vascular disease and decreased plasma levels of adiponectin cannot be derived from our cross-sectional study. Further experimental cell research and prospective clinical studies will be necessary to clarify these points.
In the current study, the plasma adiponectin level was independently correlated with the serum triglyceride level by multiple regression analysis. Hypertriglyceridemia is 1 of the major clinical features of the insulin resistance syndrome and is often accompanied by elevated plasma PAI-1 levels. Hypertriglyceridemia may take part in the development of atherosclerosis in concert with the dysregulation of adipocyte-derived proteins, such as elevated PAI-1 and hypoadiponectinemia.
The reason for the sex difference in adiponectin concentration in the diabetic subjects without CAD has not been made clear. Clinically normal women have higher adiponectin levels than do men, as previously reported.16 Sex hormones, including estrogen, progesterone, and androgen, may affect the plasma adiponectin level. However, all of the women in this study were postmenopausal. Thus, the sexual dimorphism in adiponectin level cannot be accounted for solely by the effect of estrogen and/or progesterone. Diabetic patients with CAD are often asymptomatic. The diabetic women in this study may include patients with latent atherosclerotic vascular diseases. Another possibility is that women with hypoadiponectinemia are susceptible to the development of insulin resistance and type 2 diabetes. It is necessary to investigate the effect of adiponectin on insulin signaling and glucose metabolism.
Different from leptin, the new adipocyte-derived protein adiponectin could be an indicator of macroangiopathy associated with diabetes. A lower adiponectin level may increase the risk of atherosclerosis. Reduction of BMI resulted in elevation of the plasma adiponectin. Consequently, attempts to reduce body weight to normalize the plasma adiponectin levels could be effective in preventing the development of atherosclerosis. However, this requires confirmation by means of prospective studies.
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Acknowledgments |
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This work was supported by the Japan Society for the Promotion of Science and Education (JSP-RFTF 97L00801) and grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (09307019, 10557100, 10557101, and 10671035). The authors express their appreciation to Kayoko Yamamoto and Akiko Takamoto for expert technical assistance.
Received December 14, 1999; accepted March 16, 2000.
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A. J. G. Hanley, D. Bowden, L. E. Wagenknecht, A. Balasubramanyam, C. Langfeld, M. F. Saad, J. I. Rotter, X. Guo, Y.-D. I. Chen, M. Bryer-Ash, et al. Associations of Adiponectin with Body Fat Distribution and Insulin Sensitivity in Nondiabetic Hispanics and African-Americans J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2665 - 2671. [Abstract] [Full Text] [PDF]
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J. Jurimae and T. Jurimae Plasma adiponectin concentration in healthy pre- and postmenopausal women: relationship with body composition, bone mineral, and metabolic variables Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E42 - E47. [Abstract] [Full Text] [PDF]
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