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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 4002-4005
Copyright © 1998 by The Endocrine Society

Original Studies

Trp64Arg Variant of the ß3-Adrenoceptor and Insulin Resistance in Obese Postmenopausal Women1

Ernesto GarcÍa-Rubi2, Raymond D. Starling2, André Tchernof, Dwight E. Matthews, Jeremy D. Walston, Alan R. Shuldiner, Kristi Silver, Eric T. Poehlman and Jorge Calles-Escandón

Department of Medicine, University of Vermont College of Medicine (E.G.R., R.D.S., A.T., D.E.M., E.T.P., J.C.E.), Burlington, Vermont 05405; Division of Geriatric Medicine and Gerontology, Johns Hopkins University (J.D.W.), Baltimore, Maryland 21224; and the Division of Diabetes, Obesity, and Nutrition, Department of Medicine, University of Maryland (K.S., A.R.S.), and the Geriatric Research Education and Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Eric T. Poehlman, Ph.D., Department of Medicine, University of Vermont, Burlington, Vermont 05405. E-mail: epoehlma{at}zoo.uvm.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
There is controversy regarding the role of the Trp64Arg variant of the ß3-adrenergic receptor (ß3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 ± 6 yr old) heterozygous for the ß3AR variant and in 14 women (57 ± 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in ß3AR heterozygotes (241 ± 135 mg/min) vs. normal homozygotes (379 ± 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 ± 27 mg/min) and normal homozygotes (164 ± 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 ± 57 mg/min) and normal homozygotes (56 ± 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 ± 111 mg/min) than for normal homozygotes (441 ± 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the ß3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEVERAL association studies suggest that the Trp64Arg variant of the ß3-adrenergic receptor (ß3AR) gene may be related to the development of obesity, insulin resistance, noninsulin-dependent diabetes mellitus (1, 2, 3), and phenotypes of the insulin resistance syndrome (4, 5, 6, 7, 8, 9). Other studies showed no associations with these metabolic disorders (10, 11, 12, 13). Discrepant results among investigations are not unexpected when studying a single susceptibility gene in a polygenic disorder. Reconciling divergent results among investigations is difficult due to different study designs, various methods to measure insulin sensitivity, a modest effect of the Trp64Arg variant, ethnic differences, and the failure to control for factors that confound gene effects on insulin sensitivity (14). It also has been suggested that the effect of the Trp64Arg variant in its heterozygous form may be gender and age dependent (6, 9, 15). To this end, we tested the hypothesis that obese postmenopausal women with the Trp64Arg variant of the ß3-AR gene display greater insulin resistance than carriers of the normal gene. We assessed insulin sensitivity using hyperinsulinemic/euglycemic clamp methodology. We also matched groups for body composition, regional fat distribution, physical activity level, and menopause status, because of their potential confounding influence on insulin sensitivity (16, 17, 18, 19, 20, 21, 22).


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

Postmenopausal obese Caucasian women in the greater Burlington, VT area were recruited by local advertisements. Subjects initially needed to have stopped menstruating for more than 1 yr, have a body mass index of 28 kg/m2 or more, be physically inactive, be a nonsmoker, and not be receiving hormonal replacement therapy.

Diabetic volunteers controlled only with diet were included. Eligible subjects were invited to a genotype screening with the potential to complete clinical and metabolic testing. This study was approved by the committee on human research and medical sciences of the University of Vermont and was conducted at the General Clinical Research Center (GCRC) of the University of Vermont.

Genetic screening

All eligible subjects were genotyped for the Trp64Arg variant of the ß3AR gene using PCR-restriction fragment length polymorphism (PCR-RLFP), as previously described (2).

Clinical and metabolic testing

After genotypes were identified, those subjects willing to participate in the study received a complete medical history, physical examination, fasting blood chemistries, urinalysis, and resting electrocardiogram. During an out-patient screening visit to the GCRC, a 2-h 75-g oral glucose tolerance test was performed (after 3 days of >250 g carbohydrate consumption) according to the guidelines of the National Diabetes Data Group (23). Volunteers were excluded if they had clinical evidence of atherosclerosis, diabetes mellitus, poorly controlled hypertension (diastolic blood pressure >90 mm Hg), orthopedic limitations or a history of pathologic fractures, weight loss or gain greater than 5 kg within the previous 6 months, thyroid or pituitary disease, or were currently smoking. Eligible volunteers were weight stabilized for 1 month before metabolic testing (within 2 kg), and dietary intake was standardized (55% carbohydrate, 30% fat, and 15% protein) 3 days before testing by food supplied from the metabolic kitchen of the GCRC. Maximal aerobic power was measured with a graded exercise test, as previously described (24). Leisure time activity was evaluated using the Minnesota Leisure Time Physical Activity Questionnaire (25). Body composition was determined with dual energy x-ray absorptiometry using a Lunar DPX-L densitometer (Lunar Corp., Madison, WI). Intraabdominal and sc fat for the abdomen was quantified by computed tomography using a GE High Speed Advantage scanner (General Electric Medical Systems, Milwaukee, WI). A single 5-mm scan was obtained at the abdominal region (L4–L5), according to the procedures of Sjostrom et al. (26).

Insulin sensitivity

A hyperinsulinemic/euglycemic glucose clamp was performed according to the method of DeFronzo et al. (27). All subjects were tested after a 12-h overnight fast at the GCRC and 3 days of standardized meals. An iv catheter was placed in an antecubital vein at 0600 h for infusion of insulin, 20% dextrose, and [6,6-2H2]glucose tracer. A second catheter was placed retrograde to the flow in the contralateral hand for blood sampling. The hand was kept at 60 C in a "hot box" to obtain arterialized blood samples. The 120-min clamp began at 0900 h, and hyperinsulinemia was induced with a constant infusion of insulin at a rate of 240 pmol/m2·min to attain postprandial insulin levels and suppress hepatic glucose output. Euglycemia was maintained throughout the clamp by infusing 20% dextrose. Plasma glucose concentrations were measured every 5 min during the insulin infusion to correct the dextrose infusion for glucose utilization. To measure endogenous glucose production (EGP), a continuous infusion of a primed 60:1 ratio [6,6-2H2]glucose tracer (infusion rate, 4.16 mg/min) was started 2 h before (0700 h; -120 min) initiation of the insulin infusion (0900 h; time zero) and was continued until the end of the clamp (1100 h; 120 min). Blood samples for determination of the dideutero mole percent excess were taken at -40, -30, -10, and 0 min (i.e. baseline enrichment) and at 90, 100, 110, and 120 min. Samples for insulin were obtained at -30, -10, 0, 30, 60, 70, 90, 105, and 120 min of the study. Exogenous glucose infusion during the clamp (milligrams per min) was calculated from the last 30 min of the 120-min clamp. Total glucose disposal was calculated as the exogenous glucose infusion rate plus EGP during the clamp study. Rates of glucose appearance (Ra) were calculated from [6,6-2H2]glucose using Steele’s equations in the basal state and during the last 30 min of the initial isotope infusion and clamp study. EGP was calculated as the Ra in the basal state and as the Ra exogenous glucose infusion during glucose infusion of the clamp.

Biochemical analysis

Plasma glucose concentrations were measured by the glucose oxidase method with an automated glucose analyzer (YSI Instruments, Yellow Springs, OH). Serum insulin concentrations were determined with a double antibody RIA (Diagnostic Products Corp., Los Angeles, CA). Gas chromatographic/mass spectrometric analysis of [6,6-2H2]glucose enrichment was performed on a Hewlett-Packard 5971 gas chromatograph-mass spectrometer (Palo Alto, CA) with a DB-1 (J&W Scientific, Folsom, CA) capillary column (20 x 0.25 mm; film thickness, 0.25 µm) and helium as the carrier gas.

Data analysis

Data are expressed as the mean ± SD. Independent t tests were used to examine potential differences between groups. All euglycemic/hyperinsulinemic clamp data were not adjusted for fat-free mass or body mass because groups were matched for these phenotypes. Significance was accepted at the P < 0.05 level.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Three-hundred and eighty women were screened, of whom 38 were heterozygotes for the ß3AR variant (allelic frequency, 0.10). Of this initial cohort, 27 women (13 heterozygotes and 14 normal homozygotes) completed clinical and metabolic testing. The physical characteristics of the participants are shown in Table 1Go. By design, there were no differences between groups for age, height, body mass, body mass index, percent body fat, fat-free mass, leisure time activity, or maximal aerobic capacity.


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  		Table 1. Descriptive characteristics of the volunteers

 
Insulin sensitivity

Concentrations of insulin achieved during the clamp were similar (P = 0.54) in heterozygotes (617 ± 121 ng/mL) and normal homozygotes (608 ± 100 ng/mL). Table 2Go shows euglycemic/hyperinsulinemic variables. The rate of exogenous glucose infusion necessary to maintain euglycemia during the last 30 min of the clamp was significantly lower for the heterozygotes than that for the normal homozygotes. Total glucose disposal (exogenous glucose infusion plus residual EGP) was lower (P = 0.049) in heterozygotes than in normal homozygotes. Basal EGP was not different between heterozygotes and normal homozygotes. No differences were found between the groups for EGP during hyperinsulinemia.


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  		Table 2. Euglycemic/hyperinsulinemic clamp data

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study demonstrates that obese postmenopausal women who are heterozygous for the ß3AR variant have greater insulin resistance than women homozygous for the normal gene. These findings are independent of body composition, regional fat distribution, physical activity level, and menopausal status. Although the ß3AR variant alone is not necessary or sufficient to cause insulin resistance, we suggest that the presence of the variant in its heterozygous form increases susceptibility to insulin resistance in older postmenopausal women.

To our knowledge, this is the first study to measure insulin sensitivity using the hyperinsulinemic/euglycemic clamp technique in older postmenopausal women heterozygous for the Trp64Arg variant. Kurabayashi et al. (9) and Sakane et al. (28) found associations of the Trp64Arg variant with obesity and phenotypic characteristics of the insulin resistance syndrome in women heterozygous or homozygous for the variant. These investigators, however, did not directly measure insulin sensitivity, but relied on proxy measures of insulin resistance, such as fasting insulin concentrations or the insulinemic response during an oral glucose tolerance test. Similarly, in a Finnish population, heterozygous carriers of the Trp64Arg variant were more likely than normal homozygotes to have an earlier onset of noninsulin-dependent diabetes mellitus and elevated 2-h glucose and 2-h insulin levels during an oral glucose tolerance test than individuals homozygous for the normal ß3AR gene (2).

Divergent results are found in the literature regarding the importance of the Trp64Arg variant and its phenotypic expression of insulin resistance (10, 11, 12, 13). This variability may partially relate to differences in ethnic background, accuracy of measures of insulin sensitivity, experimental designs (i.e. association vs. linkage analyses), and a modest effect of the variant on trait expression (14, 15). It is also possible that clinical manifestations of the variant in its heterozygous form may depend on gender and age (6, 9, 15). Support for this idea is found in association studies by Kurabayashi et al. (9) and Widen et al. (2), which showed that women heterozygous for the ß3AR variant, but not men, have clinical manifestations of obesity and the insulin resistance syndrome. Moreover, it has been shown that older (2), but not younger (4, 29), individuals exhibit traits of insulin resistance. The hypothesis that the Trp64Arg variant is age and gender dependent is, however, speculative, and awaits further testing.

The power of our study to detect an effect of the Trp64Arg variant on insulin sensitivity was enhanced by our experimental design and dietary control. Groups were closely matched for age, intraabdominal fat, body composition, physical activity, and menopausal status. Failure to control for these factors and their influence on insulin sensitivity (16, 17, 18, 19, 20, 21, 22) may overwhelm any modest effect of the Trp64Arg variant on this phenotype. All individuals were also weight stabilized (within 1–2 kg) 1 month before metabolic testing to limit the effects of perturbations in energy balance on insulin sensitivity. Moreover, volunteers received standardized diets 3 days before testing to limit the influence of fluctuations in macronutrient composition on insulin sensitivity.

The mechanism through which the Trp64Arg variant alters insulin sensitivity cannot be elucidated from our studies. It has been postulated that those individuals with the ß3AR Trp64Arg variant may have increased delivery of portal free fatty acids due to their higher visceral fat (30). Indirect support for this hypothesis is found in genetic rodent models of insulin resistance, in which administration of specific ß3 agonists partially improves insulin sensitivity in these rodents by decreasing the concentration of free fatty acids in the portal vein (31). Support for this hypothesis in the present study is not compelling given that no differences in intraabdominal fat were noted between groups. An alternative mechanism to explain the effect of the Trp64Arg variant on insulin sensitivity is a decrease in the responsiveness of the receptor in the blood vessels of subjects harboring the variant, as approximately 30% of insulin-induced glucose disposal by the skeletal muscle is determined by changes in regional blood flow (32, 33). Further investigations are needed to elucidate the exact mechanisms of insulin resistance in ß3AR variants. In summary, our results suggest that obese postmenopausal women who are heterozygous for the ß3AR gene variant have greater insulin resistance than normal homozygotes.


   Acknowledgments
 
We thank the nursing staff of the General Clinical Research Center at the University of Vermont for their help, and Mary Kaskoun, R.D., for her assistance with the computed tomography scans. We gratefully acknowledge the work of Amy Turner, R.D., and Denise DeFalco-McGeein, R.N.C., N.P., in the clinical management of the volunteers.


   Footnotes
 
1 This work was supported by Grant R01-DK-52752 (to E.T.P.), a Minority Supplement (DK-52752–01S1) and Minority Clinical Associate Physician grant (RR-109–32S1 and R01-DK-52752–01S1; both to E.G.-R.), General Clinical Research Center Grant RR-00109 from the NIH, a National Research Service Award (F32-AG-05791; to R.D.S.), a Research Fellowship from the Canadian Diabetes Association (to A.T.), a Clinical Associate Physician Award (3-MO1-RR-2719–1153; to R.D.S.), a Brookdale National Fellowship (to J.D.W.), and the Paul Beeson Physician Faculty Award from the American Federation of Aging Research (to A.D.S.). Back

2 These authors contributed equally to this work. Back

Received June 4, 1998.

Revised July 20, 1998.

Accepted July 23, 1998.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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