OBJECTIVE—We sought to determine whether levels of inflammatory markers and different cytokines are abnormal in nondiabetic offspring of type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS—Cytokine levels were measured in 19 healthy control subjects and 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance [NGT] and 20 with impaired glucose tolerance [IGT]). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography.

RESULTS—Levels of C-reactive protein and inflammatory cytokines were elevated in nondiabetic offspring of type 2 diabetic subjects. Interleukin (IL)-1β was increased in the NGT group and decreased in the IGT group. In contrast, levels of IL-1 receptor antagonist (IL-1Ra) were increased in both groups. IL-1β and -Ra levels correlated inversely (P < 0.05) with rates of whole-body glucose uptake and IL-1β positively with visceral fat mass (P < 0.05) in normoglycemic offspring.

CONCLUSIONS—Nondiabetic offspring of type 2 diabetic subjects have changes in the levels of inflammatory cytokines. The level of IL-1Ra seems to be the most sensitive marker of cytokine response in the pre-diabetic state.

Impaired glucose tolerance (IGT) precedes type 2 diabetes and is attributable to either insulin resistance or decreased insulin secretion, or both. Proinflammatory cytokines deleteriously influence insulin sensitivity and β-cell function (1). Tumor necrosis factor (TNF)-α blocks insulin action by inducing serine phosphorylation of insulin receptor substrate 1 (2). Furthermore, long-term cytokinemia impairs insulin secretion in the β-cells (3). Thus, accumulating evidence supports the hypothesis that type 2 diabetes is a disease of the innate immune system (3,4).

C-reactive protein (CRP) and proinflammatory cytokine levels are elevated in both IGT and overt type 2 diabetes, and they predict the conversion to type 2 diabetes (3–8). However, Krakoff et al. (9) failed to show that CRP and interleukin (IL)-6 levels predict diabetes in Pima Indians. Although TNF-α causes insulin resistance at the cellular level, circulating TNF-α levels are neither associated with type 2 diabetes nor with the future risk of diabetes (4,10). The elevation of both IL-6 and -1β increases the risk of type 2 diabetes more strongly than elevated levels of IL-6 alone (4).

Inflammation in autoimmune diseases is characterized by a balance between pro- and anti-inflammatory cytokines. The members of the IL-1 cytokine superfamily, IL-1α and -1β, are strong inducers of inflammation (11–13). IL-1 receptor antagonist (IL-1Ra) acts in an antagonistic manner and serves as a natural compensatory mechanism for the IL-1–induced disease process (11,14). In healthy individuals, IL-1Ra is detectable in plasma, in contrast to usually undetectable levels of IL-1β (12). White adipose tissue is an important source of IL-1Ra (15). IL-1Ra levels are increased in human obesity (16) and may contribute to the development of insulin resistance (17).

In various disease states, the levels of IL-1β are increased. IL-1β has been shown to mediate impaired β-cell function and apoptosis in both type 1 and type 2 diabetes (18–20). The apoptotic pathway has been suggested to link both forms of diabetes. However, recent studies have shown that high glucose in vitro and in the diabetic milieu does not induce IL-1β production or nuclear factor-κB activation in human islets, which argues against the notion that the IL-1β–nuclear factor-κB–Fas pathway is a common mediator of β-cell death in type 2 diabetes (21,22).

IL-18, a member of the IL-1 cytokine superfamily, is an important regulator of innate and acquired immune response. Elevated levels of IL-18 have been observed in type 2 diabetic subjects (23,24). Low levels of IL-10, a cytokine with strong anti-inflammatory properties, have been associated with the metabolic syndrome and type 2 diabetes (25).

The offspring of patients with type 2 diabetes are at increased risk of developing diabetes, but only three previous studies have measured the levels of one proinflammatory cytokine, TNF-α, in offspring of type 2 diabetic patients (26–28). Therefore, we investigated whether levels of CRP and different cytokines are already abnormal in nondiabetic offspring of type 2 diabetic subjects.

The subjects were healthy nondiabetic offspring of patients with type 2 diabetes. Type 2 diabetic probands were randomly selected among patients living in the region of the Kuopio University Hospital. Spouses of the probands had to have normal glucose tolerance (NGT), as determined by an oral glucose tolerance test. One to three offspring from each family were included in this study. The exclusion criteria for the offspring were as follows: 1) diabetes or any other disease that could potentially disturb carbohydrate metabolism, 2) diabetes in both parents, 3) pregnancy, 4) any ongoing infection, and 5) age <25 or >50 years. A total of 129 offspring (61 men and 68 women) from 78 families (43 families with one child, 29 families with two children, and 6 families with three children) were studied. The control group included 19 healthy volunteers (8 men and 11 women) with NGT and without a family history of diabetes. The inclusion criteria were identical to the selection of offspring described above. The study protocol was approved by the ethics committee of the University of Kuopio and the Kuopio University Hospital.

Subjects were admitted to the metabolic ward of the Department of Medicine of the Kuopio University Hospital on three different occasions, 1–2 months apart. The order of the tests was the same for each subject. On day 1, a standardized interview was conducted to collect information on medical history, smoking, alcohol consumption, and physical activity. Weight and height were measured to the nearest 0.5 cm and 0.1 kg, respectively. Other clinical parameters were measured as previously described in detail (29). Fasting blood samples were drawn after a 12-h fast followed by an oral glucose tolerance test (75 g glucose). Glucose tolerance status was evaluated according to World Health Organization criteria (30).

On day 2, an intravenous glucose tolerance test was performed to evaluate first-phase insulin secretion capacity after an overnight fast. Immediately after an intravenous glucose tolerance test, the euglycemic-hyperinsulinemic clamp was started to determine the degree of insulin sensitivity, as previously described (29). After a priming dose of insulin, plasma insulin was maintained at 5.0 mmol/l by a continuous insulin infusion (insulin infusion rate of 40 mU/min per m2 body surface area) and blood glucose kept constant for the next 120 min by infusing 20% glucose at varying rates according to blood glucose measurements performed at 5-min intervals. The amount of glucose infused was used to calculate the rates of whole-body glucose uptake (WBGU). Body composition was determined by bioelectrical impedance (RJL Systems, Detroit, MI) in the supine position after a 12-h fast.

On day 3, abdominal fat distribution was evaluated by computed tomography (Siemens Volume Zoom; Siemens, Erlangen, Germany) at the level of fourth lumbal vertebra according to the method of Sjöström et al. (31). Subcutaneous and intraabdominal fat areas were calculated as previously described (32).

Plasma glucose was measured by the glucose oxidase method (Glucose & Lactate Analyzer 2300 Stat Plus; Yellow Springs Instrument, Yellow Springs, OH) and plasma insulin and C-peptide by radioimmunoassay (Phadeseph Insulin RIA 100; Pharmacia Diagnostics, Uppsala, Sweden, and 125J RIA kit; Incstar, Stillwater, MN, respectively). Cholesterol and triglyceride levels from whole serum and lipoprotein fractions were assayed by automated enzymatic methods (Roche Diagnostics, Mannheim, Germany).

For the determination of cytokines, blood was collected into EDTA tubes on ice and immediately centrifuged and the plasma stored at −70°C (maximum storage time 3 years). Plasma concentrations of TNF-α, IL-1β, IL-1Ra, IL-6, IL-10, and IL-18 were measured using assay kits from R&D Systems (Minneapolis, MN). IL-8 was measured using a kit from Biosource International (Camarillo, CA). CRP was measured using an Immulite analyzer and a DPC High Sensitivity CRP assay (Diagnostic Products, Los Angeles, CA).

Genotyping was performed by direct sequencing (ABI prism genetic analyzator) (IL-1Ra gene: G114C), restriction length polymorphism (IL-6 gene: C-174G; IL-10 gene: A-592C; TNF-receptor 2 gene: M196R), or by TaqMan assays (CRP gene: G942C, G1059C; IL-1β gene: T511C, C3954T; IL-10 gene: A1082G; TNF-α gene: G-308A). Details of the genotyping procedures can be obtained from the authors by request.

Statistical analysis

All calculations were performed with SPSS 11.0 for Windows. The results for continuous variables are shown as means ± SD, if not stated otherwise. The differences between the three groups were assessed by ANOVA for continuous variables and the χ2 test for noncontinuous variables. Variables with skewed distribution (triglycerides and BMI), insulin, CRP, TNF-α, IL-6, IL-1Ra, IL-8, and IL-10 were logarithmically transformed for statistical analyses. The incremental insulin areas under the curve were calculated by the trapezoidal method. Linear mixed-model analysis was applied to test the differences between the groups to adjust for confounding factors. Pedigree membership was included in the model as a random factor and sex as a fixed factor. A P value <0.05 was considered statistically significant.

Table 1 reports anthropometric and metabolic characteristics of the study subjects. The groups were comparable with respect to sex, but subjects with IGT were older (P < 0.05), had higher BMI (P < 0.05), and had higher levels of systolic (P < 0.05) and diastolic (P < 0.05) blood pressure than the control subjects. There were no significant differences between the groups in waist-to-hip ratio and fat percent. LDL cholesterol was higher in the NGT group (P < 0.05) than in the control group, whereas total cholesterol, HDL cholesterol, and triglycerides did not differ among groups. Plasma glucose and insulin levels at 120 min were significantly elevated in the IGT group (P < 0.001 vs. control group).

Figure 1 presents the results of metabolic studies. A significant decrease was found in the rates of WBGU in the IGT group, and a similar, but not statistically significant, trend was observed in the NGT group compared with the control group. No compensatory increase in first-phase insulin secretion was observed in the IGT group. The areas of both visceral and subcutaneous fat were significantly higher in the IGT group compared with the control group. The differences persisted after adjustment for age, sex, BMI, and familiarity. The ratio of subcutaneous to visceral fat did not differ among groups (data not shown).

Levels of fasting cytokines are shown in Fig. 2. CRP level was significantly higher in the IGT group than in the control group. Levels of TNF-α did not differ significantly among the three groups, but after adjustment for age, sex, BMI, and familiality, a statistically significant difference was observed among the three groups. There were no significant differences in fasting levels of IL-6, IL-8, IL-10, or IL-18 (data not shown) among the three groups. Compared with the control group, levels of IL-1β were significantly higher in the NGT group, whereas there was a significant decrease in IL-1β levels in the IGT group. Levels of IL-1Ra increased linearly in the NGT and IGT groups compared with the control group.

The correlations of fasting cytokines with metabolic parameters are shown in Table 2. In the NGT group, IL-6 (P < 0.05), CRP (P < 0.01), IL-1β (P < 0.05), and IL-1Ra levels (P < 0.05) correlated inversely with WBGU. Inverse correlations were also significant among IL-6, IL-1Ra, and WBGU in the IGT group (P < 0.05 and P < 0.01, respectively). Significant correlations between IL-6 level and the amount of visceral and subcutaneous fat were found in both NGT and IGT groups (visceral fat: P < 0.01 and P < 0.05, respectively; subcutaneous fat: P < 0.01 in both groups). CRP (P < 0.05) and IL-1Ra (P < 0.05) correlated significantly with first-phase insulin secretion in the NGT group. The correlation was even stronger between IL-1Ra and first-phase insulin secretion in the IGT group (P < 0.01), whereas correlation with CRP was not statistically significant in the IGT group. In the NGT group, IL-6 (P < 0.05), IL-1β (P < 0.01), and IL-1Ra levels (P < 0.05) correlated significantly with CRP. In the IGT group, CRP correlated significantly with IL-6 (P < 0.05) and IL-1Ra (P < 0.05) but not with IL-1β levels.

Common polymorphisms that have been previously associated with insulin resistance, insulin resistance–related quantitative traits, or risk of diabetes in the CRP (G942C and G1059C), TNF-α (G-308A), TNF-receptor 2 (M-196R), IL-1β (T511C and C3954T), IL-1Ra (G114C), IL-6 (C-174G), or IL-10 (A-592C) genes were not associated with corresponding cytokine levels (data not shown).

The offspring of type 2 diabetic subjects are at increased risk of diabetes. Our study showed that CRP and proinflammatory cytokine levels are elevated in nondiabetic offspring compared with the control group, supporting the concept that low-grade inflammation is one of the earliest findings in the pathogenesis of type 2 diabetes. The novel finding of our study was that the level of IL-1Ra is the most sensitive marker of cytokine response in the pre-diabetic state.

Low-grade inflammation is linked to the onset of type 2 diabetes (33). To our knowledge, there are only three previously published studies that have investigated the role of inflammatory cytokines in nondiabetic offspring of patients with type 2 diabetes. However, these studies have measured only levels of TNF-α but not those of other proinflammatory cytokines. Kellerer et al. (27) showed that circulating TNF-α level did not contribute to obesity-induced insulin resistance. Maltezos et al. (28) observed significantly elevated concentrations of TNF-α in healthy nondiabetic offspring of type 2 diabetic subjects. Costa et al. (26) showed that the TNF-α pathway could predispose to the development of type 2 diabetes in the first-degree relatives of type 2 diabetic patients. In our study, we did not find increased levels of TNF-α or IL-6 in the offspring of type 2 diabetic individuals. However, we found that glucose-intolerant offspring of type 2 diabetic patients had elevated CRP levels, which is in line with previous studies (3–8,25).

In our study, the level of IL-1β was increased in the NGT group, whereas it was decreased in the IGT group. To determine the biological activity of IL-1β, we calculated the ratio of IL-1Ra to IL-1β. Eizirik et al. (34) have shown that a 10- to 100-fold excess of IL-1Ra over IL-1β suffices to block the effects of IL-1β on pancreatic islets. We found >100-fold excess of the ratio of IL-1Ra to IL-1β, indicating a decreased biological activity of IL-1β in the NGT group (999) and, more markedly, in the IGT group (2,538). The excess of IL-1Ra should block the biological activity of IL-1β by human islets. In line with recently published studies, we suggest that it is unlikely that IL-1β would mediate β-cell failure during progression to type 2 diabetes.

Decreased concentrations of IL-1Ra have been reported in type 2 diabetes (14), whereas IL-1Ra overproduction has been observed in men with the insulin resistance syndrome (35). The level of IL-Ra has been shown to be markedly and reversibly elevated in human obesity and predicted by lean body mass and insulin levels (16). In our study, IL-1Ra levels were elevated in normoglycemic offspring and even more so in offspring with IGT compared with those in the control group. IL-1Ra had an inverse correlation with WBGU in the NGT and IGT groups. IGT offspring had a significantly higher amount of visceral and subcutaneous fat than control subjects, which, together with increased IL-1Ra levels, supports the finding that adipose tissue is an important source of IL-1Ra (15). It is possible that the elevation of IL-1Ra and the negative correlation between IL-1Ra and WBGU reflects insulin resistance in the NGT and IGT groups. Although IL-1Ra is considered a protective cytokine, increased levels of IL-1Ra might rather expose than protect the offspring at high risk of diabetes from insulin resistance.

Promoter polymorphisms of the TNF-α and IL-6 genes have been shown to predict the conversion from IGT to type 2 diabetes (36), and variants in the TNF-α gene regulate insulin sensitivity (26). Therefore, we analyzed the effects of common polymorphisms of CRP and cytokine genes (TNF-α, TNF-receptor 2, IL-β, IL-1Ra, IL-6, and IL-10) on fasting levels of CRP and cytokines, but no associations were found.

Our study has some limitations. First, the control group and the IGT group are small, limiting the statistical power of our study. Second, subjects in the control group were significantly younger and thinner than those in the IGT group, which could explain some of the differences between the groups, although adjustment for age and BMI was done in statistical analyses of the data.

In summary, our results add new insights to the understanding of inflammatory mechanisms in the pathogenesis of type 2 diabetes. Our study is the first to show that the offspring of type 2 diabetic patients have changes in levels of CRP, IL-1β, and IL-1Ra. It remains to be proven whether this cytokine imbalance is one of the fundamental defects in the pre-diabetic state and in type 2 diabetes.

Figure 1—
Figure 1—. Rates of WBGU (A), first-phase insulin secretion (B), visceral fat (C), and subcutaneous fat (D) in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. P value after the adjustment for age, sex, BMI, and family relationship (mixed linear model). Data are means ± SE. *P < 0.05, **P < 0.01 for IGT vs. control group.
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Rates of WBGU (A), first-phase insulin secretion (B), visceral fat (C), and subcutaneous fat (D) in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. P value after the adjustment for age, sex, BMI, and family relationship (mixed linear model). Data are means ± SE. *P < 0.05, **P < 0.01 for IGT vs. control group.

Figure 1—
Figure 1—. Rates of WBGU (A), first-phase insulin secretion (B), visceral fat (C), and subcutaneous fat (D) in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. P value after the adjustment for age, sex, BMI, and family relationship (mixed linear model). Data are means ± SE. *P < 0.05, **P < 0.01 for IGT vs. control group.
View largeDownload slide

Rates of WBGU (A), first-phase insulin secretion (B), visceral fat (C), and subcutaneous fat (D) in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. P value after the adjustment for age, sex, BMI, and family relationship (mixed linear model). Data are means ± SE. *P < 0.05, **P < 0.01 for IGT vs. control group.

Close modal
Figure 2—
Figure 2—. Fasting cytokines in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. The individual data for IL-1β and IL-1Ra is shown in scattergrams (□ in all respective groups). P value after the adjustment for sex, BMI, and familiality (mixed linear model). Means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 for NGT or IGT vs. control group.
View largeDownload slide

Fasting cytokines in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. The individual data for IL-1β and IL-1Ra is shown in scattergrams (□ in all respective groups). P value after the adjustment for sex, BMI, and familiality (mixed linear model). Means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 for NGT or IGT vs. control group.

Figure 2—
Figure 2—. Fasting cytokines in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. The individual data for IL-1β and IL-1Ra is shown in scattergrams (□ in all respective groups). P value after the adjustment for sex, BMI, and familiality (mixed linear model). Means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 for NGT or IGT vs. control group.
View largeDownload slide

Fasting cytokines in offspring of type 2 diabetic patients. □, control group; ▒, NGT group; ▪, IGT group. The individual data for IL-1β and IL-1Ra is shown in scattergrams (□ in all respective groups). P value after the adjustment for sex, BMI, and familiality (mixed linear model). Means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 for NGT or IGT vs. control group.

Close modal
Table 1—

Characteristics of the study population

ControlOffspring of patients with type 2 diabetes
P
NGTIGT
n 19 109 20  
Sex (M/F) 8/11 53/56 8/12 0.715 
Age (years) 34.5 ± 4.5 35.0 ± 6.1 38.6 ± 6.6* 0.042 
Waist-to-hip ratio 0.84 ± 0.1 0.87 ± 0.8 0.88 ± 0.1 0.161 
BMI (kg/m2) 24.6 ± 2.6 25.8 ± 4.3 28.0 ± 6.2* 0.075 
Fat percent 29 ± 9 29 ± 8 32 ± 9 0.275 
Systolic blood pressure (mmHg) 124 ± 10 126 ± 11 133 ± 18* 0.020 
Diastolic blood pressure (mmHg) 82 ± 10 83 ± 9 90 ± 14* 0.004 
Fasting glucose (mmol/l) 5.1 ± 0.6 5.2 ± 0.4 5.2 ± 0.5 0.746 
120-min glucose (mmol/l) 5.6 ± 1.1 5.8 ± 1.0 8.7 ± 0.8† <0.001 
Fasting insulin (pmol/l) 47.9 ± 23.0 44.6 ± 19.1 57.9 ± 34.4 0.087 
120-min insulin (pmol/l) 194.0 ± 107.2 219.2 ± 159.4 400.1 ± 261.7† <0.001 
Total cholesterol (mmol/l) 4.73 ± 0.96 4.89 ± 0.91 4.94 ± 0.64 0.731 
LDL cholesterol (mmol/l) 2.80 ± 0.7 3.19 ± 0.81* 3.16 ± 0.60 0.116 
HDL cholesterol (mmol/l) 1.37 ± 0.33 1.27 ± 0.28 1.26 ± 0.32 0.343 
Total triglycerides (mmol/l) 1.24 ± 0.84 1.12 ± 0.62 1.25 ± 0.53 0.461 
ControlOffspring of patients with type 2 diabetes
P
NGTIGT
n 19 109 20  
Sex (M/F) 8/11 53/56 8/12 0.715 
Age (years) 34.5 ± 4.5 35.0 ± 6.1 38.6 ± 6.6* 0.042 
Waist-to-hip ratio 0.84 ± 0.1 0.87 ± 0.8 0.88 ± 0.1 0.161 
BMI (kg/m2) 24.6 ± 2.6 25.8 ± 4.3 28.0 ± 6.2* 0.075 
Fat percent 29 ± 9 29 ± 8 32 ± 9 0.275 
Systolic blood pressure (mmHg) 124 ± 10 126 ± 11 133 ± 18* 0.020 
Diastolic blood pressure (mmHg) 82 ± 10 83 ± 9 90 ± 14* 0.004 
Fasting glucose (mmol/l) 5.1 ± 0.6 5.2 ± 0.4 5.2 ± 0.5 0.746 
120-min glucose (mmol/l) 5.6 ± 1.1 5.8 ± 1.0 8.7 ± 0.8† <0.001 
Fasting insulin (pmol/l) 47.9 ± 23.0 44.6 ± 19.1 57.9 ± 34.4 0.087 
120-min insulin (pmol/l) 194.0 ± 107.2 219.2 ± 159.4 400.1 ± 261.7† <0.001 
Total cholesterol (mmol/l) 4.73 ± 0.96 4.89 ± 0.91 4.94 ± 0.64 0.731 
LDL cholesterol (mmol/l) 2.80 ± 0.7 3.19 ± 0.81* 3.16 ± 0.60 0.116 
HDL cholesterol (mmol/l) 1.37 ± 0.33 1.27 ± 0.28 1.26 ± 0.32 0.343 
Total triglycerides (mmol/l) 1.24 ± 0.84 1.12 ± 0.62 1.25 ± 0.53 0.461 

Data are means ± SD. NGT/IGT vs. control subjects:

*

P < 0.05;

†

P < 0.001.

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Table 2—

Spearman correlations of fasting cytokines, visceral fat, subcutaneous fat, rates of WBGU, and first-phase insulin secretion in offspring with NGT and IGT

IL-6CRPIL-1βIL-1RaTNF-αIL-8Visceral fatSubcutaneous fatWBGUFirst-phase insulin secretion
NGT           
    IL-6 1.000 0.236* 0.088 0.278† 0.196* 0.166 0.310† 0.310† −0.241* 0.024 
    CRP  1.000 0.264† 0.233* 0.188 0.121 0.189 0.254† −0.339† 0.223* 
    IL-1β   1.000 0.164 0.116 0.230* 0.290† 0.173 −0.239* 0.172 
    IL-1Ra    1.000 0.214* 0.347† 0.172 0.277† −0.205* 0.212* 
    TNF-α     1.000 0.160 0.121 0.034 −0.082 0.076 
    IL-8      1.000 0.140 0.109 −0.154 −0.137 
    Visceral fat       1.000 0.326† −0.452† 0.234* 
    Subcutaneous fat        1.000 −0.275† 0.274† 
    WBGU         1.000 −0.312† 
    First-phase insulin secretion          1.000 
IGT           
    IL-6 1.000 0.557* −0.204 0.437 −0.214 −0.381 0.524* 0.609† −0.463* 0.357 
    CRP  1.000 −0.122 0.525* −0.421 0.015 0.261 0.381 −0.334 0.179 
    IL-1β   1.000 0.389 0.325 0.289 0.161 0.155 −0.137 0.234 
    IL-1Ra    1.000 −0.293 0.081 0.549* 0.547* −0.645 0.672† 
    TNF-α     1.000 0.180 −0.112 −0.181 0.042 −0.432 
    IL-8      1.000 0.105 0.097 0.023 −0.197 
    Visceral fat       1.000 0.570* −0.668† 0.437 
    Subcutaneous fat        1.000 −0.782† 0.608† 
    WBGU         1.000 −0.640† 
    First-phase insulin secretion          1.000 
IL-6CRPIL-1βIL-1RaTNF-αIL-8Visceral fatSubcutaneous fatWBGUFirst-phase insulin secretion
NGT           
    IL-6 1.000 0.236* 0.088 0.278† 0.196* 0.166 0.310† 0.310† −0.241* 0.024 
    CRP  1.000 0.264† 0.233* 0.188 0.121 0.189 0.254† −0.339† 0.223* 
    IL-1β   1.000 0.164 0.116 0.230* 0.290† 0.173 −0.239* 0.172 
    IL-1Ra    1.000 0.214* 0.347† 0.172 0.277† −0.205* 0.212* 
    TNF-α     1.000 0.160 0.121 0.034 −0.082 0.076 
    IL-8      1.000 0.140 0.109 −0.154 −0.137 
    Visceral fat       1.000 0.326† −0.452† 0.234* 
    Subcutaneous fat        1.000 −0.275† 0.274† 
    WBGU         1.000 −0.312† 
    First-phase insulin secretion          1.000 
IGT           
    IL-6 1.000 0.557* −0.204 0.437 −0.214 −0.381 0.524* 0.609† −0.463* 0.357 
    CRP  1.000 −0.122 0.525* −0.421 0.015 0.261 0.381 −0.334 0.179 
    IL-1β   1.000 0.389 0.325 0.289 0.161 0.155 −0.137 0.234 
    IL-1Ra    1.000 −0.293 0.081 0.549* 0.547* −0.645 0.672† 
    TNF-α     1.000 0.180 −0.112 −0.181 0.042 −0.432 
    IL-8      1.000 0.105 0.097 0.023 −0.197 
    Visceral fat       1.000 0.570* −0.668† 0.437 
    Subcutaneous fat        1.000 −0.782† 0.608† 
    WBGU         1.000 −0.640† 
    First-phase insulin secretion          1.000 
*

P < 0.05;

†

P < 0.01.

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This study was partly supported by the EVO fund of Kuopio University Hospital (grant no. 5167) and the European Union (EUGENE2 [European Network on Functional Genomics of Type 2 Diabetes]: LSHM-CT-2004-512013).

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

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