OBJECTIVE—We investigated whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes as well as the potential of leptin, adiponectin, and resistin as biomarkers for lifestyle-induced improvements in glucose metabolism and insulin resistance.

RESEARCH DESIGN AND METHODS—In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 men and women with impaired glucose tolerance (IGT) were randomized to either a combined diet-and-exercise intervention or a control program. At baseline and after 1 year, an oral glucose tolerance test, an exercise test, and anthropometric measurements were performed. After 1 year, complete data of 103 subjects (50 intervention and 53 control subjects) were obtained.

RESULTS—Lifestyle intervention reduced plasma leptin concentrations (−14.2%) in IGT subjects but did not alter plasma adiponectin (−0.3%) or resistin (−6.5%) concentrations despite marked improvements in glucose tolerance and insulin resistance.

CONCLUSIONS—Changes in leptin concentration were related to improvements in insulin sensitivity independent of changes in body composition.

Adipokines produced by adipose tissue, such as adiponectin, resistin, and leptin, may link obesity to insulin resistance, impaired glucose metabolism, and type 2 diabetes (1). Cross-sectional evidence for an association between insulin resistance and inflammation profile is ample (2). Nevertheless, the reported effects of lifestyle intervention on adipokines are limited and inconclusive (3,4). The first aim of the present study was to investigate whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes. Second, we investigated the potential of leptin, adiponectin, and resistin as biomarkers for lifestyle-induced improvements in glucose metabolism and insulin resistance. We addressed these aims in the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM).

Study design, inclusion and exclusion criteria, and the diet and exercise program of SLIM, an ongoing, randomized, controlled trial, have previously been described in detail (5,6). Each year, anthropometry, body fat percentage (7), physical fitness (Vo2max), and plasma metabolites during fasting and 2 h after a 75-g oral glucose load are determined. The study protocol was approved by the local medical ethical committee of the Maastricht University. All subjects gave written informed consent.

Fasting plasma adiponectin (full length and globular, coefficient of variation [CV] 6.2%), resistin (homodimeric, CV 4.0%), and leptin (CV 5.8%) were simultaneously analyzed with enzyme-linked immunosorbent assays (Biovendor, Heidelberg, Germany). Of the 147 subjects enrolled, 131 completed the first year. For regression analysis, 28 subjects were excluded because of missing values for dietary intake (n = 3), Vo2max (n = 23), or both (n = 2). No differences were observed between the included and excluded subjects.

Repeated-measures ANOVA were used for differences between groups over time. A two-tailed P value <0.05 was considered statistically significant. Data are presented as means ± SEM or, if not normally distributed (insulin, leptin, and adiponectin), as median (25th–75th percentile).

Lifestyle intervention was effective to improve glucose tolerance and insulin sensitivity, as shown by an improved 2-h glucose concentration (control group 0.36 ± 0.3 mmol/l and intervention group −0.78 ± 0.2 mmol/l; P < 0.001) and a reduced 2-h insulin response (1-year change 9.9 mU/l [−22.8 to 33.1] for the control group and −15.8 mU/l [−33.2 to 10.0] for the intervention group; P < 0.01). Adherence to the intervention was demonstrated by reduced body weight (−3%; P = 0.003) and BMI (−3%; P < 0.001) and increased physical fitness (Vo2max + 5.6%; P < 0.001) after 1 year, as previously described (8). Leptin concentrations were reduced by −14.2% in the intervention group (baseline 16.7 ng/ml [6.4–27.2] and 1-year change −2.37 ng/ml [−5.5 to −0.3]) compared with the 0.5% increase in control subjects (baseline 11.6 ng/ml [5.9–24.8] and 1-year change 0.06 ng/ml [−2.2 to 1.5]; P < 0.01). No effects were observed on adiponectin for the intervention group (baseline 12.6 μg/ml [8.6–19.6] and 1-year change −0.06 μg/ml [−1.4 to 1.1]; −0.3%) or control group (baseline 14.1 μg/ml [9.3–19.3] and 1-year change −0.03 μg/ml [−1.0 to 1.2]; −0.2%). Also, in subjects with the highest body weight loss (>5%, n = 18), adiponectin concentrations did not change (Δadiponectin −0.1 μg/ml [−0.7 to 3.8]; P = 0.43). Observations were similar for resistin in intervention (baseline 3.69 ± 0.21 μg/ml and 1-year change −0.24 ± 0.11 μg/ml; −6.5%) and control (baseline 3.67 ± 0.21 μg/ml and 1-year change −0.06 ± −0.07 μg/ml; −1.6%) subjects.

In the intervention group, leptin changes were positively associated with changes in body weight, BMI, body fat percentage, waist circumference, fasting glucose, 2-h glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol, and plasma triglycerides (all Pearson correlation coefficients >0.48; all P values <0.001). Regression analyses in the intervention group revealed that the associations with fasting insulin, HOMA-IR, and 2-h glucose were less strong after adjustment for age, sex, lifestyle factors, and body composition but remained highly significant (Table 1). After full adjustment (Table 1, model 3), a decrease in HOMA-IR of 10% corresponds with a decrease in leptin concentrations of 3.9%. Changes in adiponectin or resistin were not significantly associated with changes in parameters under investigation, although after full adjustment in the regression analysis (model 3), a 1-unit (1%) decrease in A1C was related to a 15.6% increase in adiponectin concentration.

The lifestyle intervention–induced decrease in leptin was strongly associated with a decrease in insulin resistance, and this association with insulin resistance was only partially explained by a reduction in body fat percentage. This is consistent with evidence that exercise may decrease circulating leptin concentration, independent of body composition (9). The decrease in circulating leptin may be explained by increased leptin sensitivity (10) with an effect on leptin production and clearance by feedback mechanisms. Leptin may also have peripheral effects on insulin signaling (12). Since most body weight was lost in the first 3 months and since weight loss in the last one-half year was only minor (−0.68 kg), it does not seem likely that leptin concentrations were reduced as a result of a catabolic state.

In the present study, adiponectin concentrations were not clearly altered by lifestyle changes. This was unexpected, since (extreme) weight reduction in obese individuals (∼10–57 kg) was convincingly associated with an increase in plasma adiponectin concentrations ranging from 2.1 to 9.2 μg/ml (13–16). Our findings are supported, however, by other studies using lifestyle intervention programs according to general guidelines that failed to show an effect on adiponectin in diabetic (17) and obese (18) subjects. Although the molecular form of adiponectin may be of importance, peripheral insulin resistance has not been associated with a specific form of adiponectin thus far (4,18–20). The effect of weight loss on adiponectin concentrations seems to depend on the amount of weight loss and on the way in which weight loss was achieved.

This study shows that lifestyle intervention reduces plasma leptin concentrations in subjects with IGT but does not seem to alter plasma adiponectin or resistin concentrations despite marked improvements in glucose tolerance and insulin resistance. Leptin can be a biomarker for improvements in insulin sensitivity and glucose tolerance after lifestyle intervention, independent of changes in body composition.

Table 1—

β-Coefficients of changes in adiponectin and leptin concentrations after 1 year related to changes in metabolic parameters adjusted for age, sex, changes in lifestyle factors, and body composition in intervention subjects

ΔLeptin ln (ng/ml)
ΔAdiponectin ln (μg/ml)
Model 1Model 2Model 3Model 1Model 2Model 3
ΔA1C (%) 0.13 0.12 −0.01 −0.11 −0.14 −0.17* 
ΔFasting insulin ln (mU/l) 0.60† 0.63† 0.41* 0.11 0.07 0.08 
ΔHOMA-IR (ln) 0.53† 0.56† 0.40* 0.06 0.03 0.02 
Δ2-h glucose (mmol/l) 0.09† 0.09‡ 0.07‡ 0.01 0.01 0.00 
ΔLeptin ln (ng/ml)
ΔAdiponectin ln (μg/ml)
Model 1Model 2Model 3Model 1Model 2Model 3
ΔA1C (%) 0.13 0.12 −0.01 −0.11 −0.14 −0.17* 
ΔFasting insulin ln (mU/l) 0.60† 0.63† 0.41* 0.11 0.07 0.08 
ΔHOMA-IR (ln) 0.53† 0.56† 0.40* 0.06 0.03 0.02 
Δ2-h glucose (mmol/l) 0.09† 0.09‡ 0.07‡ 0.01 0.01 0.00 

Data are unstandardized β-coefficients. Multiple regression analysis was performed to identify the contribution of changes in adipokines to changes in metabolic parameters independent of other factors, with the adipokine as the dependent variable and, as independent variables, the means of the dependent (Δleptin [ln] or Δadiponectin [ln]), the main independent variable (ΔA1C, Δfasting insulin, ΔHOMA-IR, or Δ2-h glucose), age (years), and sex in model 1, plus lifestyle factors (Δtotal fat intake in percentage of energy, ΔVo2max per kg fat-free mass in ml O2 · min−1 · kg fat-free mass−1) in model 2, plus body composition (Δwaist circumference [cm] and Δbody fat percentage estimated with skinfolds) in model 3. n = 49.

*

P < 0.05;

†

P < 0.001;

‡

P < 0.01.

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This study was supported by grants from the Dutch Diabetes Research Foundation (DFN 98.901 and DFN 2000.00.020) and the Netherlands Organization for Scientific Research (ZonMW 940-35-034, 2,200.0139).

We thank Jos Stegen, Hans Cremers, Tanja Hermans-Limpens, Ilse Nijs, and Marja Ockeloen.

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Published ahead of print at http://care.diabetesjournals.org on 21 September 2007. DOI: 10.2337/dc07-0457.

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

DIABETES CARE
2007