High Serum Adiponectin Level Is a Risk Factor for Anemia in Japanese Men: A Prospective Observational Study of 1,029 Japanese Subjects
Adiponectin Level Is a Risk Factor for Anemia in
Japanese Men: A Prospective Observational Study
High Serum Adiponectin Level Is a Risk Factor for Anemia in Japanese Men: A Prospective Observational Study of 1,029 Japanese Subjects
Kei Kohno 0 1 2
Hiroto Narimatsu 0 2
Yosuke Shiono 0 1 2
Ikuko Suzuki 0 1 2
Yuichi Kato 0 1 2
Ri Sho 0 2
Katsumi Otani 0 2
Kenichi Ishizawa 0 2
Hidetoshi Yamashita 0 2 3
Isao Kubota 0 2
Yoshiyuki Ueno 0 2
Takeo Kato 0 1 2
Akira Fukao 0 2
Takamasa Kayama 0 2
0 Current address: Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya City, Aichi , Japan
1 Department of Neurology, Hematology, Metabolism , Endocrinology and Diabetology , Yamagata University School of Medicine , Yamagata City, Yamagata , Japan , 2 Cancer Prevention and Control Division, Kanagawa Cancer Center Research Institute , Yokohama City, Kanagawa , Japan , 3 Department of Public Health, Yamagata University Graduate School of Medicine , Yamagata City, Yamagata , Japan , 4 Department of Hematology and Cell Therapy, Yamagata University School of Medicine , Yamagata City, Yamagata , Japan
2 Editor: Andreas Zirlik , Universitatsklinikum Freiburg , GERMANY
3 Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine , Yamagata City, Yamagata , Japan , 6 First Department of Internal Medicine, Yamagata University School of Medicine , Yamagata City, Yamagata , Japan , 7 Second Department of Internal Medicine, Yamagata University School of Medicine , Yamagata City, Yamagata , Japan , 8 Department of Neurosurgery, Yamagata University School of Medicine , Yamagata City, Yamagata , Japan
Erythroid abnormalities including anemia and polycythemia are often observed in the general clinical setting. Because recent studies reported that adiponectin negatively affects hematopoiesis, we performed a prospective observational study to assess the relationship between anemia and adiponectin, as well as other parameters, in 1029 Japanese subjects (477 men and 552 women) 40 years of age and older. Body measurements, blood tests, and nutrition intake studies were performed at baseline, and 5 to 7 years later (follow-up). Hemoglobin (Hb) and hematocrit (Hct) levels in men with high serum adiponectin levels were lower at follow-up than at baseline. Multiple regression analysis showed that age, body mass index, adiponectin, and glutamic-pyruvic transaminase were significantly associated with erythroid-related variables (red blood cells, Hb, and Hct) in both men and women (P <0.05). In a logistic regression analysis, adiponectin, fasting blood glucose, and β-natriuretic peptide were significant risk factors for anemia in men, and blood urea nitrogen and amylase were significant risk factors in women. Physical features and nutrient intake were not risk factors for anemia. Our study demonstrates, both clinically and epidemiologically, that a high serum adiponectin level decreases the amounts of erythroid-related variables and is a
Funding: This work was supported by a
Grant-inAid from the Global Center of Excellence program
of the Japan Society for the Promotion of Science
risk factor for anemia in Japanese men.
and by the Institute for Regional Innovation at
Erythroid abnormalities such as anemia and polycythemia are often encountered in the
general clinical setting. Anemia is influenced by aging, as well as iron, the hematopoietic factor
erythropoietin (EPO), vitamin B12, folic acid, and other vitamins [
]. Some elderly people,
however, have anemia that is unrelated to nutrient deficiency, renal insufficiency, or chronic
Recent studies implicate the cytokine adiponectin in hematopoiesis [4±14]. Adiponectin,
which is secreted by adipocytes, enhances insulin sensitivity and has anti-inflammatory and
anti-atherosclerosis effects. Its production increases with age and decreases with mast cell
enlargement, and loss of adiponectin is a causative factor for diabetes and atherosclerosis [15±
18]. Adiponectin negatively regulates the growth of hematopoietic stem cells and
myelomonocytes [6±8]; according to some reports, it also regulates bone mass and bone marrow
mesenchymal stem cell migration [12±14]. Therefore, it presumably influences erythropoiesis
indirectly rather than having a direct effect on erythrocytes. In a small-scale cohort study, high
serum adiponectin levels were observed in postmenopausal women with mild anemia [
addition, our previous large-scale cohort study of middle-aged and elderly individuals was the
first to show that adiponectin, when highly expressed in serum, decrease red blood cell (RBC)
counts in men as well as in women [
]. Recently, Lewerin et al. reported that high adiponectin
levels were associated with low blood hemoglobin (Hb) levels in elderly men in a large cohort
Previous basic biological and clinical epidemiological studies including ours [4±14] suggest
that adiponectin is an important factor in hematopoiesis and a potential factor in unexplained
anemia. However, because of the cross-sectional design of the clinical epidemiological studies
[9±11], it was not clear whether a high adiponectin level was a prognostic factor for anemia
and therefore useful in clinical practice. Determination of the relationship between anemia
and adiponectin requires a prospective observational study, which has been long awaited.
The Takahata study is a large-scale, population-based study that examines lifestyle habits,
collects hematological data and data related to lipid metabolism and diabetes, and conducts
investigations involving adiponectin [
]. Using the prospective observational data of the
Takahata study, we assessed the prognostic value of various factors, most notably adiponectin,
in anemia in middle-aged and elderly Japanese people. The factors evaluated were chosen
because of their association with anemia and, in addition to adiponectin, include physical
features, nutrient uptake parameters, and laboratory test parameters. Our overall goal was to the
prognostic impact of adiponectin on the onset of anemia.
Subjects and Methods
The Takahata cohort study focuses on Japanese people 40 years of age and older. A baseline
study of 3519 people (1579 men and 1940 women) was conducted from 2004 to 2006, and a
follow-up study of 1029 people (477 men and 552 women) was conducted in 2011. Written
informed consent was obtained from all subjects. The Takahata cohort study was approved by
the ethics committee of the Yamagata University Faculty of Medicine.
Laboratory test parameters
The methods used in the baseline study were previously described [
]. The baseline study
included body measurements, Brinkman indices, blood tests, assessment of renal and hepatic
function, and measurement of lipid, fasting blood glucose (FBG), β-natriuretic peptide (BNP),
2 / 14
pancreatic amylase, lipase, cholinesterase (ChE), and serum adiponectin levels. The Japan
Diabetes Society index was used to standardize hemoglobin A1c (HbA1c) values and is thought to
result in values 0.4% lower than those standardized in accordance with the National
Glycohemoglobin Standardization Program. Daily intake of individual nutrients was calculated using
the Brief Self-Administered Diet History Questionnaire [
The follow-up study included body measurements and the same laboratory tests as in the
baseline study with the following exceptions: pancreatic amylase, lipase, and BNP levels and
Brinkman indices were not determined, and ChE levels were measured via a different
The 1029 patients in the Takahata cohort study were divided into four groups according to the
Hb level at baseline as follows: men with anemia (Hb <13.0 g/dL, n = 33); women with anemia
(Hb <12.0 g/dL, n = 66); men without anemia (Hb 13.0 g/dL, n = 444); and women without
anemia (Hb 12.0 g/dL, n = 486). In addition, each non-anemia group was subdivided into
three subgroups according to serum adiponectin levels at baseline using the k-means
clustering method as follows: low (<6.4 μg/mL for men, n = 192 and <9.2 μg/mL for women,
n = 219); intermediate (6.4±11.1 μg/mL for men, n = 197 and 9.2±16.0 μg/mL for women,
n = 178); and high (>11.1 μg/mL for men, n = 55 and >16.0 μg/mL for women, n = 89).
Changes in RBC counts, Hb levels, and hematocrit (Hct) levels (erythroid-related variables)
were compared between each group and each subgroup. We performed all analyses on the
basis of sex, owing to physiological sex-related differences [
]; RBC counts, Hb levels, and
Hct levels are significantly higher in men than in women, whereas adiponectin levels are
To identify the baseline variables that affect the erythroid-related variables at follow up, a
multiple regression analysis of all subjects was conducted. The dependent variables at
followup were RBC counts, Hb levels, and Hct levels, and the independent variables at baseline were
physical features, nutrient intake, and levels of the laboratory test parameters as follows: serum
levels of adiponectin, iron, ferritin, high-sensitivity C-reactive protein (hsCRP), creatinine,
glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), ChE,
amylase, lipid parameters, FBG, HbA1c, and BNP.
We also performed a logistic regression analysis in the non-anemic groups to determine
whether a high adiponectin was a risk factor for anemia. In the logistic regression analysis, the
odds ratios (ORs) of anemia at follow-up were calculated. Multivariate logistic regression
models were constructed for adiponectin and the factors found to be significant in univariate
logistic regression analyses. All analyses were adjusted for age and body mass index (BMI).
Statistical analyses were performed using R version 2.14.1 software (R Foundation for
Statistical Computing, Vienna, Austria) and the EZR software package [
]. All values are
presented as mean plus/minus standard deviation. The t-test was used to compare mean
values between two groups. In the multiple regression analysis, the stepwise backward
elimination method based on the P-value was used. In all analyses, P <0.05 was considered
4 / 14
* Signi®cant difference (P <0.05) between the baseline and follow-up values.
※ChE levels were measured via different methods in the baseline and follow-up studies.
SD, standard deviation; BMI, body mass index; BP, blood pressure; RBC, red blood cell; Hb, hemoglobin; Hct, hematocrit; Fe, serum iron; hsCRP,
highsensitivity C-reactive protein; TP, total protein; ALB, albumin; BUN, blood urea nitrogen; Cr, creatinine; GOT, glutamic-oxaloacetic transaminase; GPT,
glutamic-pyruvic transaminase; ChE, cholinesterase; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; TG, triglycerides; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; BNP, β-natriuretic peptide.
significant increases in age and ferritin, hsCRP, FBG, HbA1c, and adiponectin levels, and
significant decreases in total protein, albumin, amylase, and low-density lipoprotein cholesterol
(LDL-C) levels, in both men and women at follow-up compared with baseline. Also significant
were decreases in BMI, diastolic blood pressure, and Hb, serum uric acid, and GPT levels in
men at follow-up and increases in systolic blood pressure, RBC counts, and Hct and GOT
levels in women at follow-up. No patients had polycythemia (Hb >18.5 g/dL in men, Hb >16.5
g/dL in women).
Levels of the erythroid-related variables as a function of time
Fig 1 shows the Hb and Hct levels and RBC counts (the erythroid-related variables) at baseline
and follow-up. In anemic men and women, the RBC counts and levels of Hb and Hct were
higher at follow-up than at baseline. Conversely, in non-anemic men, Hb and Hct levels were
lower at follow-up than at baseline, whereas only Hb levels were unchanged in non-anemic
Fig 2 shows the values of the erythroid-related variables stratified according to adiponectin
levels. In the non-anemia groups, Hb and Hct levels and RBC counts were lower in the high
adiponectin subgroup than in the intermediate and low subgroups at baseline. In men with
high adiponectin levels, Hb and Hct levels were lower at follow-up than at baseline, whereas
RBC counts were unchanged. In women with high adiponectin levels, Hb levels were lower at
follow-up, whereas RBC counts and Hct levels were higher.
5 / 14
Fig 1. Differences in erythroid parameters stratified according to hemoglobin (Hb) levels at baseline. In men without anemia,
Hb [Fig 1.B] and hematocrit (Hct) [Fig 1.C] levels were lower at follow-up than at baseline, whereas red blood cells (RBC) counts [Fig
1.A] were unchanged. In women without anemia, RBC counts [Fig 1.D] and Hct levels [Fig 1.F] were higher at follow-up than at
baseline, whereas Hb levels [Fig 1.E] were unchanged. In both men and women with anemia, all three parameters were higher at
6 / 14
Fig 2. Differences in the levels of the erythroid-related parameters stratified according to adiponectin levels at
baseline. The non-anemia groups were subdivided into three subgroups (low, intermediate, and high) according to
serum adiponectin levels at baseline. In men in the high adiponectin subgroup, hemoglobin (Hb) [Fig 2.B] and
hematocrit (Hct) [Fig 2.C] levels were lower at follow-up than at baseline, whereas red blood cell (RBC) counts [Fig 2.A]
were unchanged. In women in the high adiponectin subgroup, Hb levels [Fig 2.E] were lower, and RBC counts [Fig 2.D]
and Hct [Fig 2.F] were higher at follow-up than at baseline.
7 / 14
Multiple regression analysis of the erythroid-related variables
Tables 2 and 3 show the results of a multiple regression analysis of the erythroid-related
variables at follow-up for each independent variable. The physical variables significantly associated
with the erythroid-related variables were age and BMI in both sexes. The laboratory variables
significantly associated with the erythroid-related variables excepting RBC counts in women
were adiponectin and GPT levels. Creatinine levels in men and LDL-C levels in women were
also significantly associated with the erythroid-related variables. Nutrient intake was not a
significant factor in men, whereas some nutrient intake-related variables were significant in
women. However, the R2 value was low (Table 3), and the P-values for Hb (P = 0.068) and Hct
(P = 0.099) were not significant. In summary, the baseline factors that affected the
erythroidrelated variables at follow-up were age and BMI in both sexes, and the effects of laboratory and
nutrient intake factors were sex-dependent.
Risk factors for anemia
We assessed the potential risk factors for anemia in non-anemic men (n = 444) and women
(n = 486) at baseline. At follow-up, 33 (7.4%) men and 33 (6.7%) women were anemic. The
Model 1 was adjusted for age and physical features; model 2 was adjusted for age and nutrient intake; model 3 was adjusted for age and levels of the
laboratory test parameters at baseline.
r, regression coef®cient; P, P-value. RBC, red blood cell; Hb, hemoglobin; Hct, hematocrit; BMI, body mass index; BP, blood pressure; Cr, creatinine; GOT,
glutamic-oxaloacetic transaminase; GPT, glutamic-pyruvic transaminase; BNP, β-natriuretic peptide; ChE, cholinesterase; HbA1c, hemoglobin A1c; FBG,
fasting blood glucose.
Model 1 was adjusted for age and physical features; model 2 was adjusted for age and nutrient intake; model 3 was adjusted for age and levels of the
laboratory test parameters at baseline.
r, regression coef®cient; P, P-value. RBC, red blood cell; Hb, hemoglobin; Hct, hematocrit; BMI, body mass index; BP, blood pressure; ChE, cholinesterase;
LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; GPT, glutamic-pyruvic transaminase; TP, total protein; HDL-C, high-density lipoprotein
cholesterol; Fe, serum iron.
mean Hb levels at follow-up were 11.5 g/dL (range, 9±12.9 g/dL) for men and 11.3 g/dL
(range, 8.2±11.9 g/dL) for women. The degree of anemia was mild to moderate.
In a logistic regression analysis where the independent variables were physical features, age
(OR, 1.075; P = 0.001) was the only significant risk factor for anemia in men. In the logistic
regression analysis where the independent variables were related to nutrient intake, there was
no significant risk factor for anemia (P >0.05 for all variables).
Table 4 shows the results of the logistic regression analysis where the independent variables
were laboratory test parameters. In the univariate analysis, the significant laboratory test
9 / 14
CI, con®dence level; BMI, body mass index; BUN, blood urea nitrogen; ChE, cholinesterase; HDL-C, high-density lipoprotein cholesterol; FBG, fasting
blood glucose; BNP, β-natriuretic peptide.
parameters for men were adiponectin, blood urea nitrogen (BUN), ChE, high-density
lipoprotein cholesterol, FBG, and BNP. In the multivariate analysis, the significant factors for men
were adiponectin (OR, 1.116; P = 0.033), FBG (OR, 1.018; P = 0.029), and BNP (OR, 1.010;
P = 0.045). Mean age and serum adiponectin, FBG and BNP levels at baseline were
significantly higher in men with anemia (n = 33) than in men without anemia (n = 411) at follow-up
(age, 66.7 vs. 61.2 years, P <0.01; adiponectin, 9.9 vs. 7.1 μg/mL, P <0.01; FBG, 103.4 vs. 96.3
mg/dL, P = 0.02; BNP, 18.4 vs. 16.5 pg/mL, P <0.01). In women, BUN (OR, 0.862; P = 0.007)
and amylase (OR, 1.013; P = 0.009) were significant risk factors in both the univariate and
multivariate analyses. Mean BUN levels were significantly lower and serum amylase levels were
significantly higher in women with anemia (n = 33) than in women without anemia (n = 453)
(BUN, 14.0 vs. 15.7 mg/dL, P = 0.02; amylase, 122.0 vs. 107.3 U/L, P = 0.01). There were no
significant differences in adiponectin levels in anemic versus non-anemic women (12.2 vs.
10.9 μg/mL, P = 0.19). High serum adiponectin levels were a risk factor for anemia in men but
not in women.
Our prospective observational study demonstrates that high adiponectin levels decrease the
levels of three erythroid-related variables (Hb levels, Hct levels, and RBC counts). In Japanese
men, a high adiponectin level was a risk factor for anemia. In Japanese women, a high
adiponectin level reduced the levels of the erythroid-related variables but was not a risk factor for
anemia. Basic biological studies suggest that adiponectin negatively regulates the growth of
hematopoietic cells [
], and our study clinically and epidemiologically shows that
adiponectin negatively affects erythropoiesis.
10 / 14
The present study indicates that Japanese men with high adiponectin levels will develop
anemia. It also provides relevant information for optimal management of anemia. A previous
study reported that plasma adiponectin levels correlated negatively with body fat percentage in
older men [
], and our study showed that serum adiponectin levels correlated negatively with
BMI (S1 Fig). Reduction of high adiponectin levels in men requires intervention to prevent the
development of anemia. However, low adiponectin levels can increase the risk of cardiac
disease and diabetes [
]; thus, careful clinical management is needed. Although adiponectin
production increases with age, the normal values for each age have not been determined. A
future goal is to establish appropriate serum adiponectin levels for each age.
None of subjects in this study had severe anemia (Hb <8 mg/dL in men, Hb <7 mg/dL in
women); instead they had mild to moderate anemia. Several studies have associated high
adiponectin levels with mild anemia [9±11]. If anemia is severe, factors in addition to adiponectin
(e.g., hemorrhage and hematologic malignancies) should be considered.
In our previous cross-sectional study [
], we suggested that management of anemia
according to sex is necessary, and this study confirms this premise. In this study, the risk
factors for anemia varied according to sex. The risk factors for men were high FBG and BNP
levels. Anemia is a well-known complication of diabetes [24±26]. Shola and Olugbenda found
that a hyperglycemic environment caused anemia in diabetic rats [
], perhaps by eliciting an
intravascular hemolytic event. BNP is a cardiac hormone secreted from the ventricles, and
plasma BNP is a biomarker of ventricular dysfunction. Several studies have shown that patients
with anemia have high BNP levels, thereby suggesting that elevated BNP levels are potential
indicators of anemia and are associated with low Hb levels in the absence of heart failure [28±
30]. The risk factors for anemia in women in our study were low BUN levels and high serum
amylase levels. It has been anecdotally reported that BUN levels correlate with protein intake
] and that thin people have high serum amylase levels . In agreement, we found that
BUN levels were significantly associated with protein intake and that serum amylase levels
were significantly associated with BMI in women (S2 Fig). Collectively, the above findings
suggest that sex-based management of parameters such as cardiac function, carbohydrate
metabolism, and nutritional status could prevent the onset of anemia.
The present study provides new information about the relationship between anemia and
risk factors. However, it has several limitations. First, intervention was not controlled, and the
possibility that intervention may have affected the results in some patients cannot be ruled out.
Some but not all participants received health education at baseline. Although some patients
had increased levels of all three erythroid-related variables at follow-up, they were not anemic.
This may be due to routine medical examinations, a high health consciousness, and a healthy
lifestyle owing to health education in these patients.
Second, our cohort did not include people less than 40 years of age. Because the number of
premenopausal women in our cohort was small, we did not consider menstrual status.
However, our previous study showed that menstrual status strongly influenced the development of
anemia, whereas lifestyle and eating habits had little effect in women [
]. Thus, whether
adiponectin contributes to anemia in younger adults, including premenopausal women, was not
addressed. A prospective observational study in young people is warranted.
Third, we did not examine other factors related to anemia, most notably EPO. A recent
cross-sectional study suggests that adiponectin affects Hb levels along with EPO, estradiol, and
thyroid hormone [
]. In our study, we measured serum iron, ferritin, creatinine, and hsCRP
levels but not EPO, estradiol, or thyroid hormone levels. hsCRP levels were within the normal
range in all subjects, and only three mem (n = 444, 0.6%) had creatinine levels >1.2 mg/dL
(range, 1.3±1.4 mg/dL). These findings suggest that these factors are unrelated to renal or
inflammatory anemia. Sixteen men (n = 202, 7.9%) and 11 women (n = 222, 4.9%) had
11 / 14
decreased serum ferritin levels (<20 ng/mL in men, <10 ng/mL in women). The three men
and one woman with low ferritin levels became anemic. The Cochran-Armitage test (a trend
analysis) showed no significant correlation between low ferritin levels and anemia (data not
shown). Future studies that include EPO and other hormones are necessary.
In conclusion, this clinical cohort study shows that high adiponectin levels significantly
correlate with anemia in Japanese men. It provides important evidence for determining the basic
mechanism whereby adiponectin prevent anemia.
S1 Fig. Correlation of adiponectin levels and body mass index (BMI) in men. Serum
adiponectin levels correlated negatively with BMI in men.
S2 Fig. Correlation of blood urea nitrogen (BUN) levels and protein intake, amylase levels
and body mass index (BMI) in women. BUN levels directly correlated protein intake (A) and
serum amylase levels inversely correlated with BMI (B) in women.
We would like to thank Editage (www.editage.jp) for English language editing.
Conceptualization: KK HN.
Data curation: KK HN.
Formal analysis: KK HN.
Methodology: KK HN.
Investigation: KK HN YS IS YK RS KO KI HY IK YU T. Kato AF T. Kayama.
Resources: KK HN YS IS YK RS KO KI HY IK YU T. Kato AF T. Kayama.
Writing ± original draft: KK HN.
Writing ± review & editing: KK HN YS IS YK RS KO KI HY IK YU T. Kato AF T. Kayama.
12 / 14
13 / 14
1. Carmel R . Anemia and aging: an overview of clinical, diagnostic and biological issues . Blood Reviews . 2001 ; 15 : 9± 18 . doi: 10 .1054/blre. 2001 .0146 PMID: 11333135
2. Milman N. Anemia-still a major health problem in many parts of the world ! Ann Hematol. 2011 ; 90 : 369 ± 377 . doi: 10 .1007/s00277-010 -1144-5 PMID: 21221586
3. Guralnik JM , Eisenstaedt RS , Ferrucci L , Klein HG , Woodman RC . Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia . Blood . 2004 ; 104 : 2263 ± 2268 . doi: 10 .1182/blood-2004 -05-1812 PMID: 15238427
4. Iversen PO , Wiig H . Tumor necrosis factor α and adiponectin in bone marrow interstitial fluid from patients with acute myeloid leukemia inhibit normal hematopoiesis . Clin Cancer Res . 2005 ; 11 : 6793 ± 6799 . doi: 10 .1158/ 1078 - 0432 .CCR- 05 -1033 PMID: 16203766
5. Avcu F , Ural AU , Yilmaz MI , Bingol N , Nevruz O , Caglar K. Association of plasma adioponectin concentrations with chronic lymphocytic leukemia and myeloproliferative diseases . Int J Hematol . 2006 ; 83 : 254 ± 258 . doi: 10 .1532/IJH97.NA0411 PMID: 16720558
6. Yokota T , Oritani K , Takahashi I , Ishikawa J , Matsuyama A , Ouchi N , et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages . Blood . 2000 ; 96 : 1723 ± 1732 . PMID: 10961870
7. DiMascio L , Voermans C , Uqoezwa M , Duncan A , Lu D , Wu J , et al. Identification of adiponectin as a novel hemopoietic stem cell growth factor . J Immunol . 2007 ; 178 : 3511 ± 3520 . PMID: 17339446
8. Crawford LJ , Peake R , Price S , Morris TC , Irvine AE . Adiponectin is produced by lymphocytes and is a negative regulator of granulopoiesis . J Leukoc Biol . 2010 ; 88 : 807 ± 811 . doi: 10 .1189/jlb.1109723 PMID: 20643815
9. Matsubara M , Namioka K , Katayose S . Relationships between plasma adiponectin and blood cells, hepatopancreatic enzymes in women . Thromb Haemost . 2004 ; 91 : 360 ± 366 . doi: 10 .1160/TH03-04- 0256 PMID: 14961165
10. Kohno K , Narimatsu H , Shiono Y , Suzuki I , Kato Y , Fukao A , et al. Management of erythropoiesis: cross-sectional study of the relationships between erythropoiesis and nutrition, physical features, and adiponectin in 3519 Japanese people . Eur J Haematol 2014 ; 92 : 298 ± 307 . doi: 10 .1111/ejh.12250 PMID: 24329589
11. Lewerin C , Johansson H , Lerner UH , Karlsson MK , Lorentzon M , Barrett-Connor E , et al. High serum adiponectin is associated with low blood haemoglobin in elderly men: the Swedish MrOS study . J Intern Med . 2015 ; 278 : 68 ± 76 . doi: 10 .1111/joim.12340 PMID: 25491722
12. Naveiras O , Nardi V , Wenzel PL , Hauschka PV , Fahey F , Daley GQ . Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment . Nature . 2009 ; 460 : 259 ± 263 . doi: 10 .1038/ nature08099 PMID: 19516257
13. Kajimura D , Lee HW , Riley KJ , Arteaga-Solis E , Ferron M , Zhou B , et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1 . Cell Metabolism . 2013 ; 17 : 901 ± 915 . doi: 10 .1016/j.cmet. 2013 . 04 .009 PMID: 23684624
14. Yu L , Tu Q , Han Q , Zhang L , Sui L , Zheng L , et al. Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes . Stem Cells . 2015 ; 33 : 240 ± 252 . doi: 10 .1002/stem.1844 PMID: 25187480
15. Atzmon G , Pollin TI , Crandall J , Tanner K , Schechter CB , Scherer PE , et al. Adiponectin levels and genotype: a potential regulator of life span in humans . J Gerontol A Biol Sci Med Sci . 2008 ; 63 : 447 ± 453 . PMID: 18511746
16. Arita Y , Kihara S , Ouchi N , Takahashi M , Maeda K , Miyagawa J , et al. Paradoxical decrease of an adipose-specific protein, adiponectin , in obesity. Biochem Biophys Res Commun . 1999 ; 257 : 79 ± 83 . PMID: 10092513
17. Hotta K , Funahashi T , Arita Y , Takahashi M , Matsuda M , Okamoto Y , et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients . Arterioscler Thromb Vasc Biol . 2000 ; 20 : 1595 ± 1599 . PMID: 10845877
18. Karakas M , Zierer A , Herder C , Baumert J , Meisinger C , Koenig W , et al. Leptin, adiponectin, their ratio and risk of coronary heart disease: Results from the MONICA /KORA Augsburg Study 1984 ± 2002 . Atherosclerosis. 2010 ; 209 : 220 ± 225 . doi: 10 .1016/j.atherosclerosis. 2009 . 08 .020 PMID: 19732895
19. Daimon M , Sato H , Sasaki S , Toriyama S , Emi M , Muramatsu M , et al. Salt consumption-dependent association of the GNB3 gene polymorphism with type 2 DM. Biochem Biophys Res Commun . 2008 ; 374 : 576 ± 580 . doi: 10 .1016/j.bbrc. 2008 . 07 .065 PMID: 18656447
20. Karasawa S , Daimon M , Sasaki S , Toriyama S , Oizumi T , Susa S , et al. Association of the common fat mass and obesity associated (FTO) gene polymorphism with obesity in a Japanese population . Endocr J . 2010 ; 57 : 293 ± 301 . PMID: 20051647
21. Sasaki S , Yanagibori R , Amano K. Self-administered diet history questionnaire developed for health education: a relative validation of the test-version by comparison with 3-day diet record in women . J Epidemiol . 1998 ; 8 : 203 ± 215 . PMID: 9816812
22. Song HJ , Oh S , Quan S , Ryu OH , Jeong JY , Hong KS , et al. Gender differences in adiponectin levels and body composition in older adults: Hallym aging study . BMC Geriatr . 2014 ; 14 : 8 doi: 10.1186/ 1471 - 2318-14-8 PMID: 24460637
23. Kanda Y. Investigation of the freely available easy-to-use software ªEZRº for medical statistics . Bone Marrow Transplant . 2013 ; 48 : 452 ± 458 . doi: 10 .1038/bmt. 2012 .244 PMID: 23208313
24. Srivastava PM , Thomas MC , Calafiore P , MacIsaac RJ , Jerums G , Burrell M. Diastolic dysfunction is associated with anaemia in patients with Type II diabetes . Clin Sci . 2006 ; 110 : 109 ± 116 . doi: 10 .1042/ CS20050184 PMID: 16181149
25. Shi Z , Zhou M , Yuan B , Qi L , Dai Y , Luo Y , et al. Iron intake and body iron stores, anaemia and risk of hyperglycaemia among Chinese adults: the prospective Jiangsu Nutrition Study (JIN) . Pub Health Nutr . 2009 ; 13 : 1319 ± 1327 .
26. Kawamoto R , Tabara Y , Kohara K , Miki T , Kusunoki T , Abe M , et al. Hematological parameters are associated with metabolic syndrome in Japanese community-dwelling persons . Endocrine . 2013 ; 43 : 334 ± 341 . doi: 10 .1007/s12020-012 -9662-7 PMID: 23307027
27. Shola OB , Olugbenga FO . Hyperglycaemic environment: contribution to the anaemia associated with diabetes mellitus in rats experimentally induced with alloxan . Anemia . 2015 ; 2015 : 848921. doi: 10 . 1155/ 2015 /848921 PMID: 26697217
28. Nybo M , Benn M , Mogelvang R , Jensen JS , Schnohr P , Rehfeld JF , et al. Impact of hemoglobin on plasma pro-B-type natriuretic peptide concentrations in the general population . Clin Chem . 2007 ; 53 : 1921 ± 1927 . doi: 10 .1373/clinchem. 2007 .089391 PMID: 17872941
29. Ueno H , Nakayama M , Kojima S , Kusuhara K , Nagayoshi Y , Yamamuro M , et al. The synergistic combined effect of anemia with high plasma levels of B-type natriuretic peptide significantly predicts an enhanced risk for major adverse cardiac events . Heart Vessels . 2008 ; 23 : 243 ± 248 . doi: 10 .1007/ s00380-007 -1034-5 PMID: 18649054
30. Wu AHB , Omland T , Knudsen CW , McCord J , Nowak RM , Hollander JE , et al. Relationship of B-type natriuretic peptide and anemia in patients with and without heart failure: a substudy from the breathing not properly (BNP) multinational study . Am J Hematol . 2005 ; 80 : 174 ± 180 . doi: 10 .1002/ajh.20456 PMID: 16247751
31. Huang MC , Chen ME , Hung HC , Chen HC , Chang WT , Lee CH , et al. Inadequate energy and excess protein intakes may be associated with worsening renal function in chronic kidney disease . J Ren Nutr . 2008 ; 18 : 187 ± 194 . doi: 10 .1053/j.jrn. 2007 . 08 .003 PMID: 18267211
32. Shavit L , Lifschitz M , Galperin I. Influence of enteric nutrition on blood urea nitrogen (BUN) in very old patients with chronic kidney disease (CKD) . Arch Gerontol Geriatr . 2012 ; 54 : 288 ± 231 .
33. Muneyuki T , Nakajima K , Aoki A , Yoshida M , Fuchigami H , Munakata H , et al. Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults . Cardio Diabet . 2012 ; 11 : 80 .