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czkowski,
Agnieszka Adamska,
Agnieszka Nikolajuk,
Monika Karczewska-Kupczewska,
El
bieta Otziomek and
Maria Górska
Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland
Address all correspondence and requests for reprints to: Irina Kowalska, M.D., Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, M.C. Sklodowskiej 24a, 15-276, Bialystok, Poland. E-mail: irinak{at}poczta.onet.pl.
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Abstract |
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Objective: The aim of the present study was to estimate the relationships between serum RBP4 concentration with insulin sensitivity and oxidative and nonoxidative glucose metabolism in lean and obese women.
Design and Participants: The study group consisted of 67 women with normal glucose tolerance, 27 lean and 40 overweight or obese. Insulin sensitivity was estimated with the euglycemic hyperinsulinemic clamp. Glucose and lipid oxidation was measured with indirect calorimetry in the basal state and during the last 30 min of the clamp. Nonoxidative glucose metabolism was calculated in insulin-stimulated conditions by subtracting glucose oxidation from total glucose metabolism.
Results: There was no difference in serum RBP4 concentration between lean and obese women. Serum RBP4 was inversely related to insulin sensitivity and nonoxidative glucose metabolism in the entire group (r = –0.36, P =0.003 in both cases) and within the subgroups of lean (r = –0.41, P =0.034 and r = –0.41, P =0.031) and obese women (r = –0.41, P =0.009 and r = –0.40, P =0.01, respectively). These relationships were independent of potential confounding factors. RBP4 levels were not associated with oxidative metabolism of glucose or lipid.
Conclusions: Our data indicate that serum RBP4 is related to decreased insulin sensitivity, mostly through its association with nonoxidative glucose metabolism.
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Introduction |
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In skeletal muscle glucose might be either oxidized or stored as a glycogen. The process of the glycogen synthesis is the most important determinant of whole-body nonoxidative glucose metabolism (6). It is not known whether RBP4 is related to oxidative or nonoxidative glucose metabolism or to both of these processes. Therefore, in the present study, we examined the relationships between serum RBP4 and oxidative and nonoxidative glucose metabolism, measured by indirect calorimetry in basal state and hyperinsulinemic conditions, in the group of 67 women with normal glucose tolerance.
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Subjects and Methods |
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The study group consisted of 67 women, 27 lean [body mass index (BMI) < 25 kg/m2] and 40 overweight or obese (BMI > 25 kg/m2) aged 18–45 yr. Women with obesity were from the outpatient clinic of the Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, Bialystok, Poland, and the collaborating primary care practice. Subjects in both groups were also partly from the medical staff and students.
All women had fasting plasma glucose less than 100 mg/dl, and all had normal glucose tolerance in the oral glucose tolerance test according to World Health Organization criteria. Exclusion criteria were also morbid obesity (BMI > 40 kg/m2), cardiovascular disease, hypertension, polycystic ovary syndrome, acute infections, or other serious medical problems. All women were nonsmokers and not taking any antiinflammatory drugs (within previous 3 months) or drugs known to affect carbohydrate and lipid metabolism. Before entering the study, physical examination and appropriate laboratory tests were performed. All analyses were made after an overnight fast. The study protocol was approved by the Ethics Committee of Medical University of Bialystok. All subjects gave their informed written consent before entering the study.
Anthropometry
BMI was calculated as body weight in kilograms divided by height in meters squared. The waist circumference was measured as the smallest circumference between the rib cage and the iliac crest, with the subject in standing position. The percentage of body fat was calculated by the bioelectric impedance analysis using the Tanita TBF-511 body fat analyzer (Tanita Corp., Tokyo, Japan), the method validated in previous studies (7).
Insulin sensitivity
Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp technique according to DeFronzo et al. (8), as previously described (9). The rate of whole-body glucose uptake (M value) was calculated as the mean glucose infusion rate from 80 to 120 min, corrected for glucose space, and normalized per kilogram of fat-free mass (ffm).
Indirect calorimetry
The whole-body glucose and lipid oxidation was measured with indirect calorimetry, using the ventilated hood technique (Oxycon Pro; Viasys GmbH, Erich Jaeger, Hochberg, Germany). The measurements were taken while the subjects were lying in the supine position at baseline (in the fasting state) and during the last 30 min of the clamp. The average gas exchange recorded over the two 30-min periods was used to calculate the rates of glucose and lipid oxidation (10). Total glucose metabolism was calculated from the clamp study. The nonoxidative glucose metabolism was calculated in insulin-stimulated conditions by subtracting glucose oxidation from total glucose metabolism.
Other laboratory analyses
Fasting blood samples were taken from the antecubital vein before the clamp. Blood glucose was measured immediately by the enzymatic method using glucose analyzer (YSI 2300 STAT Plus; Yellow Springs Instruments, Yellow Springs, OH), which immediately calculated plasma glucose, using the previously entered hematocrit value. Serum lipids were analyzed as previously described (9).
Before determining serum RBP4 and insulin concentration, the samples were kept frozen at –70 C. Serum insulin was measured with the monoclonal immunoradiometric assay (Medgenix Diagnostics, Fleunes, Belgium) with the sensitivity of 1 µIU/ml and intraassay and interassay coefficients of variation less than 2.2 and 6.5%, respectively.
Serum RBP4 concentration was measured with the ELISA kit (DRG Instruments GmBH, Marburg, Germany) with the sensitivity of 0.09 µg/ml and with intraassay and interassay coefficients of variation less than 5 and 10%, respectively.
Statistical analysis
The statistics were performed with STATISTICA 7.0. (StatSoft, Krakow, Poland) The variables, which did not have normal distribution [fasting and postload insulin, triglycerides (TGs) , glucose and lipid oxidation] were log transformed before analyses. For the purpose of the data presentation these variables were again antilog transformed to absolute values in Results. The differences between groups were evaluated with the unpaired Student’s t test. The relationships between serum RBP4 and other variables were evaluated with the Pearson product-moment correlation analysis and multiple regression analysis. The level of significance was accepted at P < 0.05. Our study had a sufficient power (1 - β 
0.80, 
= 0.05) to detect relationships with medium effect size (r = 0.30).
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Results |
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). The obese group had also lower glucose oxidation and higher lipid oxidation in insulin-stimulated conditions (Table 1). Serum RBP4 concentration was not different between the groups of lean and obese women (Table 1). We also divided the obese women into subgroups on the basis of waist circumference, with cutoff point of 94.5 cm (median value of waist girth in the obese group). We observed that women with waist circumference above 94.5 cm (n = 20) had significantly higher serum RBP4 concentration in comparison with women with waist circumference less than 94.5 cm (n = 20) (113.0 ± 37.5 vs. 88.5 ± 22.9 µg/ml, P = 0.017).
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) and nonoxidative glucose metabolism (r = –0.36, P = 0.003, Fig. 1B). The relationships between serum RBP4 and insulin sensitivity and with nonoxidative glucose metabolism were also present within the subgroups of lean (r = –0.41, P = 0.034 and r = –0.41, P = 0.031) and obese women (r = –0.41, P = 0.009 and r = –0.40, P = 0.01, respectively). Additionally, in the obese group, serum RBP4 was positively related to BMI (r = 0.43, P = 0.005) and waist circumference (r = 0.41, P = 0.008) and negatively to high-density lipoprotein-cholesterol (r = –0.32, P = 0.046). Such relationships were not found in the lean subjects and the entire group. No significant associations between serum RBP4 and glucose and lipid oxidation in basal or hyperinsulinemic state were observed.
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Discussion |
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The inverse relationship between serum RBP4 and insulin sensitivity has been reported by other groups (2, 4, 5), although opposite findings have also been demonstrated (11, 12). The reasons for the discrepancies in the results are at present unknown; probably it might be partly explained by the differences in the characteristics of the study groups between the reports. As mentioned, we did not observe an increase in RBP4 in obesity. Serum RBP4 was related to insulin sensitivity within the subgroups of lean and obese women, and it negatively predicted insulin sensitivity independently of anthropometrical and biochemical parameters. These findings do not indicate that adiposity might influence an association between serum RBP4 and insulin sensitivity. However, visceral fat was not measured in our study, and the measurement of total body fat with bioelectric impedance analysis gave only approximate results.
The relationships between RBP4 and nonoxidative glucose metabolism were very similar to its relation to the whole-body glucose uptake. It is generally accepted that nonoxidative glucose metabolism reflects mostly muscle glycogen synthesis. Damsbo et al. (13) demonstrated that nonoxidative glucose metabolism, measured by the means of the hyperinsulinemic euglycemic clamp and indirect calorimetry (as in the present study), was significantly related to the glycogen synthase activity in the skeletal muscle. It was also observed that in subjects predisposed to type 2 diabetes mellitus, insulin resistance was connected with an impaired nonoxidative glucose disposal (14, 15). So far, no data are available regarding the relationships between serum RBP4 and oxidative and nonoxidative glucose metabolism. Additionally, although it was reported that RBP4 inhibited insulin signaling in the skeletal muscle at the level of insulin receptor substrate-1 and phosphatidylinositol 3-kinase (1), the effect of RBP4 on glycogen synthase activity is not known.
Serum RBP4 was not related to glucose and lipid oxidation. In the obese group, the carbohydrate oxidation was lower and lipid oxidation was higher in insulin-stimulated conditions. Therefore, our data suggest that serum RBP4 is not related to all features of decreased insulin sensitivity.
The limitation of our study is that we used only indirect measurement of the rate of glycogen synthesis. To confirm our results, further studies with the measurements of muscle glycogen synthase activity or the rate of glycogen synthesis with magnetic resonance spectroscopy would be advisable.
Our data indicate that serum RBP4 is related to decreased insulin sensitivity mostly through its association with nonoxidative glucose metabolism.
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Footnotes |
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Disclosure Information: All authors have nothing to declare.
First Published Online April 22, 2008
Abbreviations: BMI, Body mass index; ffm, fat-free mass; RBP, retinol-binding protein; TG, triglyceride.
Received January 11, 2008.
Accepted April 16, 2008.
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