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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0101
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4249-4254
Copyright © 2005 by The Endocrine Society

The Effect of the Ala12 Allele of the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene on Skeletal Muscle Glucose Uptake Depends on Obesity: A Positron Emission Tomography Study

Markku Vänttinen1, Pirjo Nuutila1, Jussi Pihlajamäki, Kirsti Hällsten, Kirsi A. Virtanen, Riikka Lautamäki, Pauliina Peltoniemi, Jukka Kemppainen, Teemu Takala, Antti P. M. Viljanen, Juhani Knuuti and Markku Laakso

Department of Medicine (M.V., J.P., M.L.), University of Kuopio, 70211 Kuopio, Finland; and Positron Emission Tomography Center (P.N., K.H., K.A.V., R.L., P.P., J.K., A.P.M.V., J.K.), and Department of Medicine (P.N., T.T.), University of Turku, 20521 Turku, Finland

Address all correspondence and requests for reprints to: Dr. Markku Laakso, Department of Medicine, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland. E-mail: markku.laakso{at}uku.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-{gamma}2 gene is associated with insulin sensitivity. Obesity is a major risk factor for insulin resistance, but the association of the Pro12Ala polymorphism with body weight has been controversial. Furthermore, obesity may modulate the effect of this polymorphism on insulin sensitivity.

Objective: The aim of our study was to investigate the effects of the Pro12Ala polymorphism on skeletal muscle and adipose tissue glucose uptake (GU) in nonobese and obese subjects.

Design: The design was a cross-sectional study.

Study Subjects: The rates of GU were investigated in 124 (72 nonobese and 52 obese; body mass index cutoff point, 27 kg/m2) healthy subjects with the euglycemic hyperinsulinemic clamp. Skeletal muscle and adipose tissue GU and skeletal muscle perfusion were measured using fluorine-18-labeled fluorodeoxyglucose, [15O]H2O, and positron emission tomography.

Results: The rates of skeletal muscle GU were higher in nonobese subjects carrying the Ala12 allele than in subjects carrying the Pro12Pro genotype (P = 0.004), whereas no differences were found in skeletal muscle perfusion between the groups. In contrast, in obese subjects the rates of skeletal muscle GU did not differ between carriers of the Ala12 allele and carriers of the Pro12Pro genotype. No difference in adipose tissue GU was found in either nonobese or obese subjects according to Pro12Ala polymorphism.

Conclusions: We conclude that the Pro12Ala polymorphism modulates skeletal muscle GU differently in nonobese and obese subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PEROXISOME PROLIFERATOR-activated receptor-{gamma} (PPAR{gamma}) has been shown to regulate adipocyte differentiation and glucose and lipid metabolism (1). Four isoforms (PPAR{gamma}1 to PPAR{gamma}4) of the PPAR{gamma} gene have been identified (2, 3).

PPAR{gamma}2 expression is confined almost exclusively to adipose tissue (1). The substitution of proline for alanine in codon 12 of exon B of PPAR{gamma}2 results in the Pro12Ala polymorphism. The prevalence of the rare Ala12 allele varies among ethnic groups, being most prevalent (~12%) in Caucasians (1, 4, 5). The Ala12 allele has been associated with improved insulin sensitivity (6) and a low prevalence of type 2 diabetes (4). Obesity is a major contributor to insulin resistance, and a number of studies have investigated the relationship between the Pro12Ala polymorphism and body weight. However, these studies have yielded inconsistent results (6, 7, 8, 9, 10, 11, 12, 13). This might be due to a different action of the Pro12Ala polymorphism in normal weight and obese subjects (9, 14) or different responses to diet and exercise (13, 15, 16).

The mechanisms by which the Pro12Ala polymorphism influences glucose homeostasis have not been established. Altered transcriptional activity in adipocytes could regulate the effect of insulin on lipolysis, and thus the release of free fatty acids (FFAs) (10). Secondary to low FFA levels, skeletal muscle could use more glucose upon insulin stimulation (17). During hyperinsulinemia, most of the glucose is used by skeletal muscle; therefore, the Ala12 allele may be associated with better skeletal muscle insulin sensitivity. However, the effect of the Pro12Ala polymorphism on skeletal muscle and adipose tissue glucose uptake (GU) has not been previously studied. Moreover, the effect of the Ala12 allele on the rate of GU in skeletal muscle could depend on the degree of obesity. Positron emission tomography (PET), oxygen-15-labeled water ([15O]H2O), and fluorine-18 labeled fluorodeoxyglucose ([18F]FDG) allow noninvasive quantification of blood flow and GU directly in human skeletal muscle and adipose tissue (18, 19, 20). In this study we investigated the relationship between the Pro12Ala polymorphism and skeletal muscle and adipose tissue insulin-stimulated GU and perfusion in nonobese and obese subjects using these techniques (20, 21, 22).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 124 volunteers (109 men and 15 women), who had previously participated in PET studies at Turku PET Center (Turku, Finland), were recruited for this study (18, 19, 22, 23, 24). They all were healthy, as judged by their medical history, physical examination, and laboratory tests, and were not taking any medication. The characteristics of study subjects are shown in Table 1Go. Subjects were divided into two groups (nonobese and obese) using a cutoff point of 27 kg/m2 for body mass index (BMI). Obese subjects were somewhat older than nonobese subjects and had higher systolic and diastolic blood pressures as well as higher triglyceride levels compared with nonobese subjects. They also tended to have higher total cholesterol and low density lipoprotein cholesterol levels and lower high density lipoprotein cholesterol levels. Fasting plasma glucose and serum insulin levels were higher in obese subjects than in nonobese subjects. Written inform consent was obtained after the nature, purpose, and potential risks of the study were explained to the subjects. The commission on ethics of the Municipal Hospital District of Southwest Finland approved the study protocol.


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  		TABLE 1. Baseline characteristics of study subjects

 
Study design

Studies were performed after an overnight fast. The consumption of alcohol and caffeine was prohibited 24 h before the study, and subjects were instructed to avoid strenuous physical activity 1 d before the study. The subjects were lying in a supine position throughout the PET scanning. Two catheters were inserted: one was inserted in an antecubital vein for the infusion of glucose and insulin and the injection of [15O]H2O and [18F]FDG, and one was inserted in either the radial artery or the antecubital vein of the opposite upper extremity that was warmed with a heating pillow to arterialize venous blood. At 0 min, an iv infusion of insulin (1 mU/kg·min) was started for 140 ± 20 min. At 50 ± 5 min, [15O]H2O was injected iv, and a dynamic scan of both femoral regions for 6–15 min was performed in 65 subjects as previously described (18). To determine the input function, arterial blood samples were drawn for the measurement of plasma radioactivity. [18F]FDG was injected at 90 ± 20 min, and a dynamic scan of the femoral region was performed for 20–30 min as previously described (19, 23, 24). Forty-two subjects performed intermittent isometric exercise with one leg during the scan (19, 24), but only the measurements of the noncontracting, i.e. control leg, were used in this report. The whole body insulin sensitivity was assessed using the hyperinsulinemic, euglycemic clamp technique (25). The levels of insulin and FFA were determined every 30 or 60 min, respectively. Blood samples for DNA analyses were drawn, and DNA analyses were performed at University of Kuopio.

Production of PET tracers

[18F]FDG was synthesized with a computer-controlled apparatus according to a modified method of Hamacher et al. (26). [15O]H2O was produced using a dialysis technique in a continuously working water module or a membrane technique using sterile exchangeable tubing in the device (27, 28).

Image acquisition and processing

An eight-ring ECAT 931/08 tomograph (Siemens/CTI, Inc., Knoxville, TN) was employed. Photon attenuation was corrected by transmission scans on the femoral region with a removable ring source containing 68Ge. All data obtained were corrected for dead time, decay, and measured photon attenuation and were reconstructed into a 128 x 128 matrix. The Bayesian iterative reconstruction algorithm, using median root prior with iterations and a Bayesian coefficient of 0.3, was used for image processing when possible (29). Regions of interest were drawn in the anteromedial muscular compartments of the femoral region in four planes in both legs as previously described (24). Large blood vessels were avoided when outlining the regions. Localization of the great vessels and muscle compartments were verified by comparison of the flow images with the transmission (attenuation) image. Regions of interests in sc adipose tissue were drawn as previously described (30).

Measurements of skeletal muscle and adipose tissue GU

Femoral muscle and adipose tissue GU were calculated using the three-compartment model of [18F]FDG kinetics (31), and plasma and tissue time-activity curves were graphically analyzed to quantitate the fractional phosphorylation rate (Ki) for the tracer (32). The GU rates are obtained by multiplying Ki by the plasma glucose concentration divided by a lumped constant, which accounts for the differences in transportation and phosphorylation of [18F]FDG and glucose. A lumped constant value of 1.2 for skeletal muscle and 1.14 for adipose tissue were used, as previously described (20, 33).

Measurement of femoral muscle blood flow and oxygen consumption

The calculation of blood flow with [15O]H2O-PET is based on Kety’s principle of inert gas exchange between blood and tissues (34). The autoradiographic method was employed to calculate the blood flow pixel by pixel using arterial input curve corrected for dispersion and delay (35).

Measurement of whole body GU

The rates of whole body GU were measured independently of the PET measurements with the hyperinsulinemic, euglycemic clamp technique (25). Euglycemia (plasma glucose, ~5 mmol/liter) was maintained using a variable rate of 20% glucose infusion based on arterial plasma glucose measurements taken every 10 min (36). The rates of whole body GU (M-value; micromoles per kilogram per minute) was calculated between 60–120 min of hyperinsulinemia (25).

Biochemical analyses

Plasma glucose was determined in duplicate by the glucose oxidase method (36). Serum insulin concentration, determined every 30 min during the clamp, was measured by immunoassay (37), and serum FFA concentration was measured by a fluorometric method (38). Serum total cholesterol, high density lipoprotein cholesterol, and triglycerides were assessed using standard enzymatic methods (Roche, Mannheim, Germany) with a fully automated analyzer (Hitachi 704, Hitachi Corp., Tokyo, Japan). Serum low density lipoprotein cholesterol was calculated using the Friedewald formula (39).

Genotyping of the Pro12Ala polymorphism of the PPAR{gamma}2 gene

DNA samples were available from all subjects. Genotyping was performed using TaqMan Allelic Discrimination Assays (Applied Biosystems, Foster City, CA). The TaqMan genotyping reaction was amplified on a GeneAmp PCR system 2700 (50 C for 2 min, 95 C for 10 min, followed by 40 cycles of 95 C for 15 sec and 60 C for 1 min), and fluorescence was detected on an ABI PRISM 7000 sequence detector (Applied Biosystems).

Statistical methods

All calculations were performed with the SPSS/Win statistical program (version 10.0 for Windows, SPSS, Inc., Chicago, IL). All data are represented as the mean ± SD. Insulin, FFA, and triglyceride concentrations were log transformed before statistical analysis to achieve a normal distribution. Interaction between the effects of the Pro12Ala polymorphism and obesity on the rates of whole body and skeletal muscle GU were investigated using linear regression analysis. Adjustment for confounding factors (gender and age) was performed, when appropriate, with the analysis of covariance when comparing the genotype groups. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical and laboratory characteristics

Among all study subjects, the frequency of the Ala12 allele was 0.17, and the genotype distribution followed the Hardy-Weinberg equilibrium. No difference was observed in allele frequencies between nonobese and obese groups (0.17 vs. 0.16; P = 0.947). In nonobese and obese subjects, no significant differences in body weight, BMI, fasting serum insulin, plasma glucose, or serum FFA concentrations were found according to the Pro12Ala polymorphism.

Metabolic characteristics during the study

During hyperinsulinemia, carriers of the Ala12 allele and carriers of the Pro12Pro genotype had similar plasma glucose concentrations in the nonobese and obese groups (Table 2Go). There were no differences in insulin and FFA concentrations during the clamp between the genotypes in either the nonobese or obese group.


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  		TABLE 2. Clinical and laboratory characteristics according to the Pro12Ala polymorphism of the PPAR{gamma}2 gene in nonobese and obese subjects

 
Skeletal muscle and whole body GU

We found a significant interaction between the effects of the Pro12Ala polymorphism and obesity on the rates of skeletal muscle GU (P = 0.009). Therefore, all results are presented separately for nonobese and obese subjects. In the nonobese group, the Ala12 allele was associated with higher rates of skeletal muscle GU (62.8 ± 26.3 µmol/kg·min in subjects with the Ala12 allele vs. 46.4 ± 20.8 µmol/kg·min in subjects with the Pro12Pro genotype; P = 0.004, adjusted for gender and age; P = 0.003, adjusted for gender, age, and BMI; Fig. 1BGo). Similarly, the rates of whole body GU tended to be higher in carriers of the Ala12 allele than in carriers of the Pro12Pro genotype (40.9 ± 14.6 vs. 34.4 ± 12.5 µmol/kg·min; P = 0.055, adjusted for gender and age; P = 0.019, adjusted for gender, age, and BMI; Fig. 1AGo). In contrast, in obese subjects, the rates of whole body GU (18.7 ± 9.6 vs. 18.2 ± 9.6 µmol/kg·min; P = 0.872) and skeletal muscle GU (24.4 ± 13.3 vs. 30.33 ± 21.3 µmol/kg·min; P = 0.283) did not differ between subjects with the Ala12 allele and carriers of the Pro12Pro genotype (Fig. 1Go).



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  		FIG. 1. The effect of the Pro12Ala polymorphism of PPAR{gamma}2 on the rates of whole body (A), skeletal muscle (B), and sc adipose tissue (C) GU in nonobese and obese subjects (by analysis of covariance, adjusted for gender and age). {square}, Subjects with the Pro12Pro genotype; {cjs2113}, carriers of the Ala12 allele. Error bars indicate ±SD.

 
Muscle perfusion

In nonobese subjects, femoral muscle blood flow did not differ between carriers of the Ala12 allele and carriers of the Pro12Pro genotype (3.0 ± 2.1 vs. 2.8 ± 1.7 ml/kg·min; P = 0.786). Similarly, no differences were found in the rates of the femoral muscle blood flow in obese subjects between the two genotypes (2.1 ± 0.8 vs. 3.2 ± 2.6 ml/kg·min; Ala12 allele vs. Pro12Pro genotype, P = 0.121).

Adipose tissue GU

In nonobese subjects, the rates of sc adipose tissue GU did not differ between subjects with the Ala12 allele and the Pro12Pro genotype (19.5 ± 11.9 vs. 17.3 ± 8.0 µmol/kg·min, respectively; P = 0.520; Fig. 1CGo). In the obese group, the rates of sc adipose tissue GU did not differ between the genotypes (10.7 ± 6.1 vs. 10.3 ± 5.0 µmol/kg·min; Ala12 allele vs. Pro12Pro genotype, P = 0.946; Fig. 1CGo).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
No previous studies have been published on the effects of the Pro12Ala polymorphism of PPAR{gamma}2 on the rates of skeletal muscle and sc adipose tissue GU. The novel finding of our study was that in nonobese subjects the rates of skeletal muscle GU were higher in subjects carrying the Ala12 allele than in subjects carrying the Pro12Pro genotype. In contrast, in obese subjects, no differences were found in the rates of whole body GU, skeletal muscle GU, and sc adipose tissue GU between subjects with the Ala12 allele and the Pro12Pro genotype. The higher skeletal muscle GU in nonobese carriers of the Ala12 allele was attributable to glucose extraction, because no difference in skeletal muscle perfusion, potentially contributing to skeletal muscle GU (18, 40, 41), was found between the genotype groups.

PET allows a noninvasive assessment of tissue-specific perfusion and GU. The use of PET combined with radioactive tracers for the quantitation of skeletal muscle metabolism offers advantages compared with other methods used for skeletal muscle studies in humans. The parameters can be measured directly in skeletal muscle or adipose tissue, thus avoiding any confounding effects caused by catheters or other tissues close to the target organs. When [18F]FDG is used for the measurement of GU, the differences between glucose and its analog are corrected using so-called lumped constants, previously reported from our laboratory for skeletal muscle (33) and sc adipose tissue (20). [15O]H2O is a freely diffusible tracer and is validated for perfusion measurements (18, 35).

In our study, the Ala12 allele was associated with better insulin sensitivity only in nonobese subjects. Our results could explain the controversial findings of earlier studies, because the effect of the Pro12Ala polymorphism on insulin sensitivity has not been investigated separately in nonobese and obese subjects. Gene-environmental interaction may play an important role in this respect. Carriers of the Ala12 allele who are consuming a high fat diet are protected from obesity (15), and they benefit more from the combined effect of diet and exercise intervention than carriers of the Pro12Pro genotype (13, 42). However, insulin-sensitive subjects carrying the Ala12 allele are prone to weight gain (43, 44) and changes in body weight over time (45), which could contribute to insulin resistance and thus mask the insulin-sensitizing effect of the Ala12 allele (44). Finally, gene-gene interactions could modify the effect of the Pro12Ala polymorphism on insulin sensitivity.

PPAR{gamma} is primarily expressed in adipose tissue, but our findings show that the Pro12Ala polymorphism affects insulin sensitivity in skeletal muscle. The mechanisms for our findings remain unclear. However, because FFAs are natural ligands of PPAR{gamma}, the Pro12Ala polymorphism might regulate circulating FFA levels and lipolysis in adipose tissue (46). Upon insulin stimulation, the suppression of FFA levels could increase insulin sensitivity in skeletal muscle. Furthermore, PPAR{gamma} regulates the transcription of several genes, including adipose tissue-derived adipokines, such as TNF{alpha}, adiponectin, and leptin, which could influence insulin sensitivity in skeletal muscle, but not in adipose tissue (47).

In conclusion, our results support the view that the effect of the Pro12Ala polymorphism on GU in skeletal muscle depends on obesity. We demonstrated that this polymorphism has an effect on skeletal muscle GU only in normal weight subjects. This strong gene-environment interaction could explain the discrepant findings of earlier studies.


   Footnotes
 
First Published Online April 26, 2005

1 M. V. and P. N. contributed equally to this work. Back

Abbreviations: BMI, Body mass index; [18F]FDG, fluorine-18-labeled fluorodeoxyglucose; FFA, free fatty acid; GU, glucose uptake; PET, positron emission tomography; PPAR{gamma}2, peroxisome proliferator-activated receptor-{gamma}2.

Received January 18, 2005.

Accepted April 19, 2005.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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