OBJECTIVE—To examine whether decreased serum levels of adiponectin are an independent risk factor for the progression to type 2 diabetes in a Japanese population.

RESEARCH DESIGN AND METHODS—The serum levels of adiponectin and tumor necrosis factor-α (TNF-α) at baseline (from 1995 to 1997) were evaluated in 1,792 individuals (1,023 women and 769 men, aged 58.5 ± 12.5 years) from a cohort population (n = 3,706) of the Funagata study. Glucose tolerance was evaluated at baseline and also at 5-year follow-up examinations (n = 978, follow-up rate, 54.6%) according to the 1985 World Health Organization criteria. The correlation of clinical traits with serum levels of adiponectin was examined. The association of the traits with the progression to type 2 diabetes at the 5-year follow-up was also examined.

RESULTS—Among the traits examined, the correlation with aging was highest (r = 0.312, P < 0.001). Eighteen subjects with normal glucose tolerance (NGT) developed diabetes, and 709 remained NGT at the 5-year follow-up examinations. The subjects who became diabetic had decreased serum levels of adiponectin (7.29 ± 2.35 vs. 9.13 ± 2.35 10 × log μg/ml, P = 0.009). Multiple logistic regression analysis with age, sex, waist-to-hip ratio, and 2-h plasma glucose as the variables revealed that serum adiponectin level (odds ratio [per 0.1 log μg/ml] 0.766, P = 0.029) was an independent risk factor for the progression to type 2 diabetes. The subjects whose serum levels of adiponectin were in the lowest tertile were 9.320 times (95% CI 1.046–83.1) more likely to develop diabetes than those in the highest tertile (P = 0.046).

CONCLUSIONS—Decreased serum adiponectin level is an independent risk factor for progression to type 2 diabetes.

Adipose tissue, in addition to its function as the major storage depot for lipids, plays active roles in normal metabolic homeostasis and in the development of several diseases, such as type 2 diabetes, dyslipidemia, and atherosclerosis (1,2). These roles are mediated by factors known as adipocytokines, which are secreted from adipose tissue (3). Among those factors, tumor necrosis factor-α (TNF-α), leptin, and plasminogen-activator inhibitor type 1 (PAI-1) are well annotated, and the association of the dysregulated production of these factors with the pathophysiology of obesity-related insulin resistance and thrombosis is well established (3–6).

Adiponectin/ACRP30 is another adipocytokine, first identified in 1995 (7). The association of decreased plasma adiponectin levels with the presence of coronary artery disease (8) indicated the pathophysiological roles of adiponectin in the development of coronary artery disease. On the other hand, adiponectin’s roles in stimulating β-oxidation in muscle and decreasing insulin resistance in the liver (9) indicated its possible involvement in the development of type 2 diabetes. Indeed, its involvement was shown in many animal studies. Administration of adiponectin improved diabetes in mice (10,11), and adiponectin-knockout mice exhibited diet-induced insulin resistance (12). The involvement of adiponectin has also been examined in clinical settings. After 1999, when the measurement of circulating (plasma and/or serum) levels of adiponectin using an enzyme-linked immunosorbent assay (ELISA) became available (13), several epidemiological studies revealed that the circulating levels of adiponectin were lower in obese and diabetic than in lean and nondiabetic humans, respectively (8,13). Later, another human study showed that decreased circulating levels of adiponectin were more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance (14). A recent study (15) that focused on the plasma levels of adiponectin during the progression to type 2 diabetes in rhesus monkeys genetically predisposed to insulin resistance showed that circulating levels of adiponectin decreased in parallel with the progression of insulin resistance. Altogether, it seems to be clear at this point that the prediabetic development of insulin resistance correlates with a decrease in the circulating levels of adiponectin, although it has not been well established whether the decreased levels are a cause or an effect of the dysregulated metabolic state.

In this report, we first examined the correlation of serum levels of adiponectin with traits related to type 2 diabetes, obesity, dyslipidemia, and hypertension in a large population-based Japanese sample. Then we examined whether decreased serum levels of adiponectin can be considered an independent risk factor for the progression to type 2 diabetes. We also measured the serum levels of TNF-α to examine the correlation between serum levels of adiponectin and TNF-α, since these adipocytokines have been reported to suppress each other’s production locally in adipose tissue and each other’s function remotely in muscle (12).

The Funagata study is a population-based study designed to clarify the risk factors, related conditions, and consequences of type 2 diabetes from an epidemiological point of view (16). In Funagata, an agricultural area ∼400 km north of Tokyo, the population >35 years of age was 4,183 in 1995. Only residents >35 years of age participated in the study. Individuals (n = 377) with cerebrovascular diseases or other disabilities were unable to participate in the study and excluded. One-hundred residents, who had been identified by public health nurses and through contacts in outpatient clinics and were receiving medication for type 2 diabetes, were also excluded. Therefore, the number of residents registered for the study was 3,706. From 1995 to 1997, 2,013 residents attended the study. Among them, 1,792 were enrolled for this study (participation rate 48.4%).

This study was approved by the Ethical Committee of Yamagata University School of Medicine, and informed consent to participate was obtained from the participants. The following traits were analyzed: height, body weight, results of a 75-g oral glucose tolerance test, HbA1c, waist circumference, hip circumference, waist-to-hip ratio (WHR), BMI, percent body fat, homeostasis model assessment of insulin resistance (HOMA-IR), systolic blood pressure, diastolic blood pressure, total serum cholesterol, serum triglyceride, and serum HDL cholesterol. Percent body fat was assessed on the principles of bioelectrical impedance (17). The participant’s physical conditions were assessed with questionnaires. None replied that they were pregnant, lactating, on estrogen hormone replacement treatment, or on calorie restriction. The sera of the participants were kept at −20° C for future use. The mean age ± SD and the sex ratio (female/male) of the study group were 58.5 ± 12.5 years and 1,023/769, respectively. Glucose tolerance was diagnosed according to the 1985 World Health Organization criteria (18). The numbers of subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes were 1,458, 246, and 88, respectively. Five years later (from 2000 to 2002), the glucose tolerance of the subjects was reexamined. At the 5-year follow-up examination, 978 subjects attended (follow-up rate 54.6%). In 2002, the levels of adiponectin (13) and TNF-α (Medgenix Diagnostics SA, Fleurus, Belgium) of the sera retained (namely, the serum levels at baseline) were measured by ELISA, as previously reported, in a commercial laboratory (Biomedical Laboratory, Tokyo, Japan).

Statistical analysis

Data are given as means ± SD. The statistical significance of the differences in the trait values between any two groups was assessed by ANOVA. Scheffe’s test was used for post hoc analysis. The differences in the serum levels of adiponectin and TNF-α between the groups were also evaluated after the adjustment for clinical traits by ANCOVA. The statistical significance of the difference of the sex ratio was analyzed by χ2 tests. Simple and stepwise linear regression analyses with the traits as covariates were performed to examine the correlation of the traits with the serum levels of adiponectin and TNF-α. Multiple logistic regression analyses determined the independent association of age, sex, WHR, 2-h plasma glucose, and serum levels of adiponectin and TNF-α with the progression to type 2 diabetes by the 5-year follow-up examinations. The subjects were divided into tertiles and quartiles based on serum levels of adiponectin. This information was used for multiple logistic regression analysis. For the analyses, the serum levels of adiponectin and TNF-α were log transformed (log10) to approximate a normal distribution. A value of P < 0.05 was accepted as statistically significant.

Factors correlated with the serum levels of adiponectin and TNF-α

Baseline characteristics are shown in Table 1. As expected, the individuals in the type 2 diabetic and IGT groups were more obese, more insulin-resistant, and more dyslipidemic. Those who were known to be receiving medication for diabetes at the baseline were excluded from the current study. Therefore, subjects of the diabetic group were expected to be in an early stage of type 2 diabetes. Indeed, their HbA1c levels were significantly, though not greatly, higher than those of the NGT group. The serum levels of adiponectin were significantly lower in the type 2 diabetic group than in the NGT group, while serum levels of TNF-α were significantly higher in the diabetic and IGT groups than in the NGT group. These significant differences were observed even after adjustment for age, BMI, systolic blood pressure, 2-h plasma glucose, and HOMA-IR (adiponectin: type 2 diabetes versus NGT, P < 0.001, IGT versus NGT, P = 0.008; TNF-α: type 2 diabetes versus NGT and IGT versus NGT, P < 0.001). These results seemed to indicate a negative correlation between the serum levels of adiponectin and TNF-α. However, simple regression analysis revealed only a weak correlation between them (r = −0.074, P = 0.002). The serum levels of adiponectin and TNF-α in women were significantly higher and lower, respectively, than in men (adiponectin: 9.72 ± 2.12 vs. 7.91 ± 2.43 10 × log μg/ml, P < 0.001; TNF-α: 11.3 ± 1.40 vs. 11.6 ± 1.29 10 × log pg/ml, P < 0.001).

As shown in Table 2, simple regression analyses revealed that the serum levels of adiponectin were positively correlated with age, systolic blood pressure, and serum levels of HDL cholesterol and negatively correlated with WHR, BMI, percent body fat, 2-h plasma glucose, HOMA-IR, and serum levels of triglyceride in the NGT group. Stepwise multiple regression analysis further confirmed the correlation of most of the traits independently from each other (r2 = 0.404). However, in the type 2 diabetic group, age and WHR were the only traits that were correlated with the serum levels of adiponectin independently from the other traits (r2 = 0.472). These results indicate that the traits related to diabetes, obesity, insulin resistance, and dyslipidemia contribute substantially to the serum levels of adiponectin in subjects with NGT but not in subjects with diabetes. A correlation of the serum levels of TNF-α with most of the traits mentioned above was also observed in the NGT group by simple regression analysis (Table 2). However, only four traits (age, BMI, diastolic blood pressure, and serum levels of HDL cholesterol) were shown by stepwise multiple regression analysis to be independently correlated, and the r2 of the test was low (0.063). Furthermore, in the type 2 diabetic group, only WHR was shown to be independently correlated (r2 = 0.070). These results indicated that the traits related to diabetes, obesity, insulin resistance, hypertension, and dyslipidemia contributed little to the serum levels of TNF-α.

Risk factors for the progression to type 2 diabetes

We reevaluated the glucose tolerance of 978 subjects 5 years later at the follow-up examinations. The subjects were divided based on the changes in their glucose tolerance. The divisions are as follows (change, n): NGT to NGT 709, NGT to IGT 110, NGT to diabetes 18, IGT to NGT 27, IGT to IGT 47, IGT to diabetes 36, diabetes to NGT 5, diabetes to IGT 5, and diabetes to diabetes 21. To examine the risk factors for the progression to diabetes, these subjects were also grouped as follows: subjects whose glucose tolerances were IGT at baseline and who had not progressed to diabetes by the 5-year follow-up examinations (IGT to nondiabetic: IGT to NGT and IGT to IGT), subjects who were not diabetic at baseline and who either remained nondiabetic or became diabetic by the 5-year follow-up examinations (remained nondiabetic [NGT to NGT, NGT to IGT, IGT to NGT, and IGT to IGT] or progressed to type 2 diabetes [NGT to diabetes and IGT to diabetes], respectively). The baseline characteristics of NGT to NGT, NGT to IGT, NGT to diabetes, IGT to nondiabetes, and IGT to diabetes are shown in Table 3. The ratios of male sex, glycemic levels, and WHR were significantly higher in the NGT to diabetes group than in the NGT to NGT group. HOMA-IR and the traits related to dyslipidemia were not significantly different among the groups. The serum levels of adiponectin were significantly lower in the NGT to diabetes group than in the NGT to NGT group, while levels of TNF-α were not significantly different among the groups. The traits that varied significantly among the groups were expected to be the risk factors for the progression to type 2 diabetes from NGT by the 5-year follow-up examinations. In addition, the serum levels of adiponectin were not different between the IGT to diabetes and IGT to nondiabetes groups, indicating that the levels may not be considered a risk factor for the progression to diabetes from IGT.

Multiple logistic regression analysis was then used to examine whether these risk factors were independent of each other and to determine the extent of the contribution (odds ratio [OR]) of the factors to the progression to type 2 diabetes from NGT. Sex, age, WHR, 2-h plasma glucose, and the serum levels of adiponectin and TNF-α were used as the covariates in this analysis. WHR and 2-h plasma glucose were chosen as the representatives of the traits related to obesity and glycemic levels, respectively. As shown in Fig. 1, this analysis revealed that an increase in 2-h plasma glucose, a decrease in serum levels of adiponectin, and male sex were independent risk factors for the progression to diabetes, whereas age, WHR, and serum levels of TNF-α were not. WHR was not shown to be an independent risk factor in this analysis. However, simple logistic regression analysis showed that WHR was a significant risk factor with an OR of 1.106 (95% CI 1.032–1.185, P = 0.004). Serum levels of TNF-α were not shown to be a risk factor, even in simple logistic regression analysis (1.166, 0.815–1.670, P = 0.400).

The association of the serum levels of adiponectin with the progression to diabetes from NGT was analyzed in another way. The subjects were divided into tertiles based on serum levels of adiponectin. As shown in the lower part of Fig. 1, the subjects in the lowest tertile developed diabetes by the 5-year follow-up examinations 9.320 times more than those in the highest tertile (P = 0.046). Because the number of subjects in the NGT to diabetes group was not high, these analyses could lead to an overestimation. Thus, we performed the same analyses with the “progressed to type 2 diabetes” and “remained nondiabetic” groups, although performing these analyses could in turn lead to an underestimation. These analyses, however, also showed that the decrease in serum levels of adiponectin was an independent risk factor (OR 0.825, 95% CI 0.704–0.956, P = 0.011), and that the subjects in the lowest quartile (≤5.32 μg/ml) developed diabetes by the 5-year follow-up examinations 3.469 (1.106–10.884) times more than those in the highest quartile (≥11.72 μg/ml) (P = 0.033). Together, these results clearly indicate that decreased serum levels of adiponectin are a significant independent risk factor for the progression to type 2 diabetes by the 5-year follow-up examinations.

The correlation of circulating levels of adiponectin with clinical traits has been examined extensively (8,14,19–21). We found decreased serum levels of adiponectin in the type 2 diabetes and IGT groups and in men. A negative correlation of serum levels of adiponectin with serum levels of triglyceride, fasting and postprandial plasma glucose levels, and traits related to obesity and insulin resistance, as well as a positive correlation of its serum levels with serum levels of HDL cholesterol, were also found. All of these results were in good agreement with previous reports (8,14,19–21). The finding of a positive correlation of serum levels of adiponectin with age (r = 0.312, P < 0.001) was novel. Only one previous report examined the correlation between serum levels of adiponectin and age, and no correlation was found between them (22). However, in the study cited, the study population (45.1 ± 10.3 years, range 30–65) was much younger and less diverse than the one in our study (58.5 ± 12.5, 35–93). Furthermore, the number of subjects (967) was relatively small compared with our study (1,792). Very recently, Combs et al. (23) reported that adiponectin levels in mice increased abruptly by the third week of postnatal life but were relatively stable thereafter. TNF-α has been reported to suppress the production of adiponectin locally in adipose tissue (12), and the serum levels of TNF-α increased significantly with age (r = 0.160, P < 0.001). Therefore, a concomitant decrease in the serum levels of adiponectin was initially expected. However, as shown here, there was no concomitant decrease. Furthermore, the correlation coefficient between serum levels of adiponectin and TNF-α was very low (−0.074, P = 0.002). Therefore, serum levels of adiponectin might be induced by some factors strong enough to overcome its suppression by TNF-α.

The modulation of insulin sensitivity or insulin resistance by adiponectin has been examined extensively (14,19–21). Decreased serum levels of adiponectin are correlated with an increase in insulin resistance. Furthermore, a report (15) that focused on the serum levels of adiponectin during the progression to diabetes in rhesus monkeys revealed that the serum levels decreased in parallel with the progression of insulin resistance and thus preceded diabetes development. Therefore, the decreased serum levels of adiponectin were expected to be a risk factor for the progression to type 2 diabetes. Indeed, multiple logistic regression analysis showed that decreased serum levels of adiponectin were a risk factor for the progression to type 2 diabetes that was independent of age, sex, WHR, and 2-h plasma glucose. As shown in Table 3, the ratio of male sex in the NGT to diabetes group was much higher than in the NGT to NGT group, and serum levels of adiponectin were significantly lower in men than in women. Therefore, the decrease in the serum levels of adiponectin in the NGT to diabetes group could be attributed to the larger number of men in the group. However, as shown in Fig. 1, serum levels of adiponectin were shown to be a risk factor for the progression to diabetes even after adjustment for sex. Among the traits examined that were associated with progression to diabetes, WHR is of interest. An increase in WHR seemed to be a risk factor for diabetes progression. However, when serum levels of adiponectin were included as a covariate for the analysis, WHR was not a risk factor (Fig. 1). These findings indicated that the changes in WHR and serum levels of adiponectin were correlated and the change in serum levels of adiponectin contributed more to the progression to diabetes than WHR. Therefore, serum levels of adiponectin seem to be a more reliable trait to estimate the risk for diabetes progression than WHR.

Lindsay et al. (24) recently reported that decreased plasma levels of adiponectin were a risk factor for the development of type 2 diabetes (mean follow-up to diagnosis, 4–6 years) independent of age, fasting plasma glucose, 2-h plasma glucose, fasting insulin, and waist circumference. Their study was a nested case-control study (n = 70 each) in the Pima Indian population. The Pima Indians are prone to obesity and have the highest known prevalence of type 2 diabetes of any population. Our study was a population-based study of Japanese subjects, and the number of subjects was much larger. The incidence of type 2 diabetes in our study population in the follow-up period (5 years) was 5.7%, which was similar to that observed in other populations. Therefore, our study seemed to draw more universal findings. We noted the number of nondiabetic subjects at baseline but who developed diabetes at the 5-year follow-up examinations and determined the risk factors for the progression to type 2 diabetes. Our study was novel in this respect. In conclusion, a decrease in serum levels of adiponectin was a risk factor for the progression to type 2 diabetes in a Japanese population.

Figure 1—
Figure 1—. Risk factors for the progression to type 2 diabetes by the 5-year follow-up examination. The results of the multiple logistic regression analyses are shown, including all variables. ORs are shown above the vertical bars. Horizontal bars are 95% CIs.
View largeDownload slide

Risk factors for the progression to type 2 diabetes by the 5-year follow-up examination. The results of the multiple logistic regression analyses are shown, including all variables. ORs are shown above the vertical bars. Horizontal bars are 95% CIs.

Figure 1—
Figure 1—. Risk factors for the progression to type 2 diabetes by the 5-year follow-up examination. The results of the multiple logistic regression analyses are shown, including all variables. ORs are shown above the vertical bars. Horizontal bars are 95% CIs.
View largeDownload slide

Risk factors for the progression to type 2 diabetes by the 5-year follow-up examination. The results of the multiple logistic regression analyses are shown, including all variables. ORs are shown above the vertical bars. Horizontal bars are 95% CIs.

Close modal
Table 1—

Baseline characteristics of the study groups

TraitDiabetes
IGT
NGT
Mean ± SDPMean ± SDPMean ± SD
Sex (F/M) 45/43 0.249 141/105 0.979 837/621 
Age (years) 64.9 ± 11.1 <0.001* 64.2 ± 10.5 <0.001* 57.1 ± 12.4 
Height (cm) 151.9 ± 7.6 0.002* 152.3 ± 8.0 <0.001* 155.7 ± 8.8 
Body weight (kg) 59.0 ± 10.2 0.330 57.7 ± 10.3 0.837 57.1 ± 9.8 
Waist circumference (cm) 83.6 ± 9.0 <0.001* 82.1 ± 9.2 <0.001* 77.9 ± 8.83 
Hip circumference (cm) 94.3 ± 6.7 0.014* 93.0 ± 6.4 0.070* 91.9 ± 5.8 
WHR 0.887 ± 0.064 <0.001* 0.882 ± 0.067 <0.001* 0.847 ± 0.071 
BMI (kg/m2) 25.5 ± 3.9 <0.001* 24.8 ± 3.5 <0.001* 23.5 ± 3.2 
Percent body fat 29.6 ± 8.2 <0.001* 28.2 ± 8.1 <0.001* 26.1 ± 6.8 
Fasting plasma glucose (mg/dl) 126.6 ± 24.8 <0.001* 100.2 ± 11.1 <0.001* 92.0 ± 9.2 
2-h plasma glucose (mg/dl) 256.3 ± 58.7 <0.001* 159.8 ± 16.6 <0.001* 99.3 ± 21.7 
HbA1c (%) 6.70 ± 1.10 <0.001* 5.73 ± 0.47 <0.001* 5.33 ± 0.36 
Fasting serum insulin (μU/ml) 6.31 ± 5.46 <0.001* 5.36 ± 3.61 <0.001* 4.25 ± 2.99 
HOMA-IR 1.98 ± 1.76 <0.001* 1.35 ± 0.91 <0.001* 0.98 ± 0.75 
Systolic blood pressure (mmHg) 136.9 ± 20.5 <0.001* 133.4 ± 16.9 <0.001* 124.2 ± 17.2 
Diastolic blood pressure (mmHg) 77.0 ± 11.9 0.006* 76.1 ± 9.2 0.003* 73.3 ± 9.9 
Total cholesterol (mg/dl) 209.4 ± 29.1 0.339 215.2 ± 34.0 <0.001* 203.8 ± 36.4 
Triglyceride (mg/dl) 169.5 ± 211.4 <0.001* 120.9 ± 65.6 0.469 112.6 ± 88.8 
HDL cholesterol (mg/dl) 52.3 ± 15.2 0.013* 55.1 ± 14.4 0.103 57.3 ± 14.3 
Adiponectin (10 × log μg/ml) 8.01 ± 2.55 <0.001* 8.60 ± 2.43 0.064 9.06 ± 2.41 
TNF-α (10 × log pg/ml) 11.8 ± 1.27 0.006* 11.8 ± 1.37 <0.001* 11.4 ± 1.35 
TraitDiabetes
IGT
NGT
Mean ± SDPMean ± SDPMean ± SD
Sex (F/M) 45/43 0.249 141/105 0.979 837/621 
Age (years) 64.9 ± 11.1 <0.001* 64.2 ± 10.5 <0.001* 57.1 ± 12.4 
Height (cm) 151.9 ± 7.6 0.002* 152.3 ± 8.0 <0.001* 155.7 ± 8.8 
Body weight (kg) 59.0 ± 10.2 0.330 57.7 ± 10.3 0.837 57.1 ± 9.8 
Waist circumference (cm) 83.6 ± 9.0 <0.001* 82.1 ± 9.2 <0.001* 77.9 ± 8.83 
Hip circumference (cm) 94.3 ± 6.7 0.014* 93.0 ± 6.4 0.070* 91.9 ± 5.8 
WHR 0.887 ± 0.064 <0.001* 0.882 ± 0.067 <0.001* 0.847 ± 0.071 
BMI (kg/m2) 25.5 ± 3.9 <0.001* 24.8 ± 3.5 <0.001* 23.5 ± 3.2 
Percent body fat 29.6 ± 8.2 <0.001* 28.2 ± 8.1 <0.001* 26.1 ± 6.8 
Fasting plasma glucose (mg/dl) 126.6 ± 24.8 <0.001* 100.2 ± 11.1 <0.001* 92.0 ± 9.2 
2-h plasma glucose (mg/dl) 256.3 ± 58.7 <0.001* 159.8 ± 16.6 <0.001* 99.3 ± 21.7 
HbA1c (%) 6.70 ± 1.10 <0.001* 5.73 ± 0.47 <0.001* 5.33 ± 0.36 
Fasting serum insulin (μU/ml) 6.31 ± 5.46 <0.001* 5.36 ± 3.61 <0.001* 4.25 ± 2.99 
HOMA-IR 1.98 ± 1.76 <0.001* 1.35 ± 0.91 <0.001* 0.98 ± 0.75 
Systolic blood pressure (mmHg) 136.9 ± 20.5 <0.001* 133.4 ± 16.9 <0.001* 124.2 ± 17.2 
Diastolic blood pressure (mmHg) 77.0 ± 11.9 0.006* 76.1 ± 9.2 0.003* 73.3 ± 9.9 
Total cholesterol (mg/dl) 209.4 ± 29.1 0.339 215.2 ± 34.0 <0.001* 203.8 ± 36.4 
Triglyceride (mg/dl) 169.5 ± 211.4 <0.001* 120.9 ± 65.6 0.469 112.6 ± 88.8 
HDL cholesterol (mg/dl) 52.3 ± 15.2 0.013* 55.1 ± 14.4 0.103 57.3 ± 14.3 
Adiponectin (10 × log μg/ml) 8.01 ± 2.55 <0.001* 8.60 ± 2.43 0.064 9.06 ± 2.41 
TNF-α (10 × log pg/ml) 11.8 ± 1.27 0.006* 11.8 ± 1.37 <0.001* 11.4 ± 1.35 

P values compared subjects with diabetes or IGT with subjects with NGT.

*

P < 0.05.

View Large
Table 2—

Factors correlated with the serum levels of adiponectin and TNF-α determined by regression analysis

TraitDiabetes
IGT
NGT
Adiponectin
TNF-α
Adiponectin
TNF-α
Adiponectin
TNF-α
SimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwise
r2 of the test — 0.472 — 0.070 — 0.377 — 0.080 — 0.404 — 0.065 
Age (years) 0.629† 0.612† −0.092 NA 0.375† 0.305† 0.209† 0.231† 0.327† 0.372† 0.136† 0.136† 
WHR −0.315† −0.277† 0.265* 0.265* −0.307† −0.283† 0.184† NA −0.350† −0.305† 0.088† NA 
BMI (kg/m2) −0.221* NA 0.134 NA −0.256† NA 0.089 NA −0.259† −0.120† 0.131† 0.069* 
Percent body fat −0.077 NA −0.059 NA −0.140* NA 0.082 NA −0.090† 0.198† 0.074† NA 
2-h plasma glucose (mg/dl) −0.038 NA −0.176 NA −0.083 NA 0.054 NA −0.061* −0.046* 0.028 NA 
HOMA-IR −0.333† NA 0.064 NA −0.327† −0.137* 0.065 NA −0.274† −0.129† 0.111† NA 
Systolic blood pressure (mmHg) 0.170 NA 0.083 NA 0.058 NA 0.136* NA 0.080† NA 0.127† NA 
Diastolic blood pressure (mmHg) −0.061 NA 0.072 NA −0.114 NA 0.121 NA −0.034 NA 0.117† 0.076† 
Total cholesterol (mg/dl) −0.156 NA 0.198 NA 0.067 NA 0.051 NA 0.010 NA 0.005 NA 
Triglyceride (mg/dl) −0.365† NA 0.149 NA −0.339† NA 0.094 NA −0.333† −0.128† 0.082† NA 
HDL cholesterol (mg/dl) 0.364† NA −0.149 NA 0.423† 0.285† −0.166* −0.193† 0.371† 0.187† −0.176† −0.163† 
TraitDiabetes
IGT
NGT
Adiponectin
TNF-α
Adiponectin
TNF-α
Adiponectin
TNF-α
SimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwiseSimpleStepwise
r2 of the test — 0.472 — 0.070 — 0.377 — 0.080 — 0.404 — 0.065 
Age (years) 0.629† 0.612† −0.092 NA 0.375† 0.305† 0.209† 0.231† 0.327† 0.372† 0.136† 0.136† 
WHR −0.315† −0.277† 0.265* 0.265* −0.307† −0.283† 0.184† NA −0.350† −0.305† 0.088† NA 
BMI (kg/m2) −0.221* NA 0.134 NA −0.256† NA 0.089 NA −0.259† −0.120† 0.131† 0.069* 
Percent body fat −0.077 NA −0.059 NA −0.140* NA 0.082 NA −0.090† 0.198† 0.074† NA 
2-h plasma glucose (mg/dl) −0.038 NA −0.176 NA −0.083 NA 0.054 NA −0.061* −0.046* 0.028 NA 
HOMA-IR −0.333† NA 0.064 NA −0.327† −0.137* 0.065 NA −0.274† −0.129† 0.111† NA 
Systolic blood pressure (mmHg) 0.170 NA 0.083 NA 0.058 NA 0.136* NA 0.080† NA 0.127† NA 
Diastolic blood pressure (mmHg) −0.061 NA 0.072 NA −0.114 NA 0.121 NA −0.034 NA 0.117† 0.076† 
Total cholesterol (mg/dl) −0.156 NA 0.198 NA 0.067 NA 0.051 NA 0.010 NA 0.005 NA 
Triglyceride (mg/dl) −0.365† NA 0.149 NA −0.339† NA 0.094 NA −0.333† −0.128† 0.082† NA 
HDL cholesterol (mg/dl) 0.364† NA −0.149 NA 0.423† 0.285† −0.166* −0.193† 0.371† 0.187† −0.176† −0.163† 

Correlation coefficients (r) are shown. (r > 0.3 and < −0.3 are underlined).

Parameters indicated by NA are those not accepted as significant for stepwise multiple regression analysis.

*

P < 0.05,

†

P < 0.01.

View Large
Table 3—

Baseline characteristics of the subjects who progressed to diabetes and who remained nondiabetic at the 5-year follow-up examination

TraitIGT to diabetesPIGT to nondiabeticNGT to diabeticPNGT to IGTPNGT to NGT
Sex (F/M) 14/22 0.085 46/36 4/14 0.001† 53/57 0.0184* 426/283 
Age (years) 66.2 ± 9.9 0.049* 61.4 ± 9.1 60.8 ± 10.4 0.165 62.4 ± 9.5 <0.001† 56.0 ± 11.3 
Height (cm) 153.9 ± 7.8 0.788 153.4 ± 7.6 156.8 ± 6.0 0.991 153.7 ± 8.2 0.039* 156.0 ± 8.6 
Body weight (kg) 59.0 ± 9.6 0.715 59.3 ± 9.9 59.0 ± 8.9 0.785 57.2 ± 9.3 0.975 57.4 ± 9.6 
Waist circumference (cm) 84.7 ± 7.7 0.259 82.1 ± 8.4 81.3 ± 6.6 0.218 79.7 ± 8.9 0.069 77.6 ± 8.9 
Hip circumference (cm) 94.0 ± 5.5 0.624 93.2 ± 5.8 91.3 ± 4.2 0.837 92.1 ± 5.3 0.996 92.1 ± 5.9 
WHR 0.901 ± 0.061 0.228 0.880 ± 0.064 0.891 ± 0.068 0.015* 0.865 ± 0.072 0.007† 0.841 ± 0.071 
BMI (kg/m2) 24.8 ± 2.8 0.507 25.2 ± 3.4 23.9 ± 2.5 0.886 24.2 ± 3.2 0.155 23.6 ± 3.1 
Percent body fat 27.4 ± 6.6 0.319 28.4 ± 8.2 23.4 ± 7.1 0.189 26.7 ± 6.5 0.631 26.3 ± 6.7 
Fasting plasma glucose (mg/dl) 105.3 ± 9.2 <0.001* 98.4 ± 9.0 102.2 ± 13.9 <0.001† 96.4 ± 9.4 <0.001† 91.0 ± 8.0 
2-h plasma glucose (mg/dl) 164.0 ± 17.1 <0.001* 154.3 ± 12.4 114.9 ± 19.5 0.002† 111.1 ± 19.9 <0.001† 98.2 ± 20.6 
HbA1c (%) 5.95 ± 0.50 <0.001* 5.61 ± 0.37 5.63 ± 0.50 0.003† 5.50 ± 0.36 <0.001† 5.30 ± 0.34 
Fasting serum insulin (μU/ml) 4.70 ± 2.58 0.169 5.75 ± 3.92 4.30 ± 4.03 0.995 4.51 ± 2.52 0.605 4.29 ± 2.96 
HOMA-IR 1.23 ± 0.69 0.368 1.41 ± 0.93 1.09 ± 1.08 0.811 1.08 ± 0.62 0.327 0.98 ± 0.73 
Systolic blood pressure (mmHg) 136.7 ± 17.2 0.563 133.3 ± 16.8 129.0 ± 20.5 0.377 128.3 ± 14.6 0.019* 123.5 ± 16.6 
Diastolic blood pressure (mmHg) 76.6 ± 9.8 0.307 77.9 ± 9.7 74.2 ± 13.1 0.921 75.7 ± 10.2 0.099 73.3 ± 9.6 
Total cholesterol (mg/dl) 217.5 ± 33.8 0.943 216.4 ± 35.4 205.2 ± 37.9 0.980 213.4 ± 37.0 0.072 203.4 ± 36.7 
Triglyceride (mg/dl) 120.0 ± 80.8 0.886 120.8 ± 53.8 136.6 ± 117.6 0.317 114.1 ± 57.4 0.637 106.6 ± 74.3 
HDL cholesterol (mg/dl) 56.0 ± 15.3 0.933 55.1 ± 14.2 58.8 ± 16.3 0.835 56.4 ± 15.4 0.449 58.0 ± 13.9 
Adiponectin (10 × log μg/ml) 8.27 ± 2.19 0.912 8.32 ± 2.35 7.29 ± 2.35 0.009† 8.98 ± 2.32 0.672 9.13 ± 2.35 
TNF-α (10 × log pg/ml) 11.6 ± 1.4 0.448 11.8 ± 1.4 11.6 ± 1.2 0.718 11.5 ± 1.5 0.283 11.3 ± 1.3 
TraitIGT to diabetesPIGT to nondiabeticNGT to diabeticPNGT to IGTPNGT to NGT
Sex (F/M) 14/22 0.085 46/36 4/14 0.001† 53/57 0.0184* 426/283 
Age (years) 66.2 ± 9.9 0.049* 61.4 ± 9.1 60.8 ± 10.4 0.165 62.4 ± 9.5 <0.001† 56.0 ± 11.3 
Height (cm) 153.9 ± 7.8 0.788 153.4 ± 7.6 156.8 ± 6.0 0.991 153.7 ± 8.2 0.039* 156.0 ± 8.6 
Body weight (kg) 59.0 ± 9.6 0.715 59.3 ± 9.9 59.0 ± 8.9 0.785 57.2 ± 9.3 0.975 57.4 ± 9.6 
Waist circumference (cm) 84.7 ± 7.7 0.259 82.1 ± 8.4 81.3 ± 6.6 0.218 79.7 ± 8.9 0.069 77.6 ± 8.9 
Hip circumference (cm) 94.0 ± 5.5 0.624 93.2 ± 5.8 91.3 ± 4.2 0.837 92.1 ± 5.3 0.996 92.1 ± 5.9 
WHR 0.901 ± 0.061 0.228 0.880 ± 0.064 0.891 ± 0.068 0.015* 0.865 ± 0.072 0.007† 0.841 ± 0.071 
BMI (kg/m2) 24.8 ± 2.8 0.507 25.2 ± 3.4 23.9 ± 2.5 0.886 24.2 ± 3.2 0.155 23.6 ± 3.1 
Percent body fat 27.4 ± 6.6 0.319 28.4 ± 8.2 23.4 ± 7.1 0.189 26.7 ± 6.5 0.631 26.3 ± 6.7 
Fasting plasma glucose (mg/dl) 105.3 ± 9.2 <0.001* 98.4 ± 9.0 102.2 ± 13.9 <0.001† 96.4 ± 9.4 <0.001† 91.0 ± 8.0 
2-h plasma glucose (mg/dl) 164.0 ± 17.1 <0.001* 154.3 ± 12.4 114.9 ± 19.5 0.002† 111.1 ± 19.9 <0.001† 98.2 ± 20.6 
HbA1c (%) 5.95 ± 0.50 <0.001* 5.61 ± 0.37 5.63 ± 0.50 0.003† 5.50 ± 0.36 <0.001† 5.30 ± 0.34 
Fasting serum insulin (μU/ml) 4.70 ± 2.58 0.169 5.75 ± 3.92 4.30 ± 4.03 0.995 4.51 ± 2.52 0.605 4.29 ± 2.96 
HOMA-IR 1.23 ± 0.69 0.368 1.41 ± 0.93 1.09 ± 1.08 0.811 1.08 ± 0.62 0.327 0.98 ± 0.73 
Systolic blood pressure (mmHg) 136.7 ± 17.2 0.563 133.3 ± 16.8 129.0 ± 20.5 0.377 128.3 ± 14.6 0.019* 123.5 ± 16.6 
Diastolic blood pressure (mmHg) 76.6 ± 9.8 0.307 77.9 ± 9.7 74.2 ± 13.1 0.921 75.7 ± 10.2 0.099 73.3 ± 9.6 
Total cholesterol (mg/dl) 217.5 ± 33.8 0.943 216.4 ± 35.4 205.2 ± 37.9 0.980 213.4 ± 37.0 0.072 203.4 ± 36.7 
Triglyceride (mg/dl) 120.0 ± 80.8 0.886 120.8 ± 53.8 136.6 ± 117.6 0.317 114.1 ± 57.4 0.637 106.6 ± 74.3 
HDL cholesterol (mg/dl) 56.0 ± 15.3 0.933 55.1 ± 14.2 58.8 ± 16.3 0.835 56.4 ± 15.4 0.449 58.0 ± 13.9 
Adiponectin (10 × log μg/ml) 8.27 ± 2.19 0.912 8.32 ± 2.35 7.29 ± 2.35 0.009† 8.98 ± 2.32 0.672 9.13 ± 2.35 
TNF-α (10 × log pg/ml) 11.6 ± 1.4 0.448 11.8 ± 1.4 11.6 ± 1.2 0.718 11.5 ± 1.5 0.283 11.3 ± 1.3 

Data are means ± SD. P values compared the IGT to diabetes group with the IGT to nondiabetic group, and the NGT to diabetes or the NGT to IGT groups with the NGT to NGT group.

*

P < 0.05;

†

P < 0.01.

View Large

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

1
Stehbens WE: The epidemiological relationship of hypercholesterolemia, hypertension, diabetes mellitus and obesity to coronary heart disease and atherogenesis.
J Clin Epidemiol
 
43
:
733
–741,
1990
2
Pi-Sunyer FX: Cormorbidities of overweight and obesity: current evidence and research issues.
Med Sci Sports Exerc
 
31
:
S602
–S608,
1999
3
Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y: Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.
Natur Med
 
2
:
800
–803,
1996
4
Friedman JM: Obesity in the new millenium.
Nature
 
404
:
632
–634,
2000
5
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance.
J Clin Invest
 
95
:
2409
–2415,
1995
6
Kahn BB, Flier JS: Obesity and insulin resistance.
J Clin Invest
 
106
:
473
–481,
2000
7
Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced extensively in adipocytes.
J Biol Chem
 
270
:
26746
–26749,
1995
8
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamaoto 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
 
20
:
1595
–1599,
2000
9
Berg AH, Combs TP, Scherer PE: ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism.
Trends Endocrinol Metab
 
13
:
84
–89,
2002
10
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 associated with both lipoatrophy and obesity.
Nature Med
 
7
:
941
–946,
2001
11
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
Nature Med
 
7
:
947
–953,
2001
12
Maeda N, Schimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.
Nature Med
 
8
:
731
–737,
2002
13
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa JI, 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
 
257
:
79
–83,
1999
14
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 Endocrinol Metab
 
86
:
1930
–1935,
2001
15
Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y: Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.
Diabetes
 
50
:
1126
–1133,
2001
16
Oizumi T, Daimon M, Saitoh T, Kameda W, Yamaguchi H, Ohnuma H, Igarashi M, Eguchi H, Manaka H, Tominaga M, Kato T: Genotype Arg/Arg, but not Trp/Arg, of the Trp64Arg polymorphism of the β3-adrenergic receptor is associated with type 2 diabetes and obesity in a large Japanese sample.
Diabetes Care
 
24
:
1579
–1583,
2001
17
Jebb SA, Cole TJ, Doman D, Murgatroyd PR, Prentice AM: Evaluation of the novel Tanita body-fat analyser to measure body composition by comparison with a four-compartment model.
Br J Nutr
 
83
:
115
–122,
2000
18
World Health Organization:
Diabetes Mellitus: Report of a WHO Study Group.
Geneva, World Health Org.,
1985
(Tech. Rep. Ser, no. 727)
19
Matsubara M, Maruoka S, Katayose: Decreased plasma adiponectin concentrations in women with dyslipidemia.
J Clin Endocrinol Metab
 
87
:
2764
–2769,
2002
20
Stefan N, Bunt JC, Salbe AD, Funahashi T, Matsuzawa Y, Tataranni PA: Plasma adiponectin concentrations in children: relationships with obesity and insulinemia.
J Clin Endocrinol Metab
 
87
:
4652
–4656,
2002
21
Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, Tataranni PA: Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosin phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.
Diabetes
 
51
:
1884
–1888,
2002
22
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 adoponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population.
Clin Sci
 
103
:
137
–142,
2002
23
Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS, Scherer PE: Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin.
Diabetes
 
52
:
268
–276,
2003
24
Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J: Adiponectin and development of type 2 diabetes in the Pima Indian population.
Lancet
 
360
:
57
–58,
2002
DIABETES CARE
2003