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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1695-1699
Copyright © 1999 by The Endocrine Society

Original Studies

Trp64Arg Polymorphism of the ß3-Adrenergic Receptor Gene in Pregnancy: Association with Mild Gestational Diabetes Mellitus

Andreas Festa, Walter Krugluger, Nadja Shnawa, Pierre Hopmeier, Steven M. Haffner and Guntram Schernthaner

Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center (A.F., S.H.), San Antonio, Texas 78284; and the Department of Medicine 1 (A.F., N.S., G.S.) and the Institute of Clinical Chemistry (W.K., P.H.), Rudolfstiftung Hospital, Vienna, Austria

Address all correspondence and requests for reprints to: Andreas Festa, M.D., Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7873. E-mail: festa{at}uthscsa.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A missense mutation of the ß3-adrenergic receptor gene (Trp64Arg) has been associated with obesity and increased capacity to gain weight in nonpregnant populations. Furthermore, the mutation is a potential modifying factor in the etiology of impaired glucose tolerance and type 2 diabetes. We studied the relation of the ß3-adrenergic receptor genotype to glucose tolerance during pregnancy, a state of physiological insulin resistance. In 179 pregnant women (mean age, 28.5 ± 0.4 yr), a 2-h oral glucose tolerance test was performed between gestational weeks 20 and 31. The ß3-adrenergic receptor genotype was assessed using restriction fragment length polymorphism.

The frequency of the Arg64 allele was 9.15%. In women with mild gestational diabetes (n = 70), as defined by 60 min postload glucose values, the Trp64Arg genotype was more frequent than in women with normal glucose tolerance (n = 109; 26% vs. 11%; P = 0.01). Furthermore, the Trp64Arg polymorphism was associated with increased weight gain during pregnancy (baseline to gestational weeks 20–31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test.

The results of the present study extend current knowledge about the association of the Trp64Arg ß3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The association with mild gestational diabetes suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PREGNANCY is characterized by peripheral insulin resistance, which is physiologically compensated by an increase in insulin secretion to maintain glucose homeostasis. Gestational diabetes mellitus (GDM) develops if insulin secretion fails to overcome insulin resistance (1). Fetal hyperinsulinism is considered a pathophysiological hallmark of GDM; however, mechanisms responsible for GDM-associated neonatal complications are not fully understood (2). It has been suggested that maternal substrates other than glucose, such as amino acids and serum lipids, might contribute significantly to fetal growth and consecutively to neonatal morbidity (3).

The role of obesity in pregnancy has gained particular interest recently. In a prospective study, pregravid body mass index was an independent risk factor for GDM (4). In a large epidemiological study, prepregnancy body weight was associated with adverse pregnancy outcome, namely late fetal death (5). Maternal obesity, rather than glycemia, was related to perinatal morbidity (6) and neonatal birth weight (7, 8).

A missense mutation of the ß3-adrenergic receptor gene (Trp64Arg allele) has been associated with obesity (9, 10, 11, 12) as well as an increased capacity to gain weight (13, 14). Furthermore, this mutation has been proposed as a potential modifying factor in the etiology of type 2 diabetes (9, 14, 15) and the development of features of the insulin resistance syndrome (9, 10, 15). The impact of the Trp64Arg ß3-adrenergic receptor gene polymorphism on glucose tolerance during pregnancy has not been studied.

The aim of our study was to relate the Trp64Arg polymorphism of the ß3-adrenergic receptor gene in pregnant women to body weight, weight gain, glucose tolerance status, and various metabolic variables assessed during an oral glucose tolerance test (OGTT).


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

The study subjects were consecutive pregnant women of Caucasian origin, referred to the Department of Medicine I, Rudolfstiftung Hospital (Vienna, Austria), for the assessment of glucose tolerance at 20–31 weeks gestation (mean, 25 weeks). After an initial general recruiting period (women with normal glucose tolerance as well as those with GDM), we subsequently continued recruiting women with GDM to attain a sufficiently large number of women with GDM for meaningful statistical comparison. Therefore, women with GDM are relatively overrepresented (70 of 179). A 2-h OGTT with 75 g glucose was performed in the morning after an overnight fast according to a standard protocol. Venous blood samples were drawn in the fasting state and 60 and 120 min after glucose ingestion. GDM was diagnosed, if the 1 h serum glucose value during the OGTT was 160 mg/dL (8.9 mmol/L) or more and/or the 2 h glucose value was 140 mg/dL (7.8 mmol/L) or more. These criteria were used based on the findings of Weiss et al., which demonstrated that fetal hyperinsulinism, as determined by insulin measurements in amniotic fluid, may be encountered at maternal 1 h serum glucose values during an OGTT as low as 160 mg/dL (16). Maternal height and weight (BW) were measured following a standardized protocol, and body mass index (BMI) was calculated by dividing the weight in kilograms by the height in meters squared. Weight gain during pregnancy is shown as {Delta}body weight and {Delta}BMI, indicating the change between (self-reported) prepregnancy values and values at the time of glucose tolerance testing.

Laboratory measurements

Routine blood chemistry, including serum glucose and serum lipids, was determined by an American Monitor Parallel Analyzer (Richmond, CA). Total immunoreactive insulin was determined by an automated ELISA System (E600, Boehringer Mannheim, Mannheim, Germany). C Peptide was measured using a commercial enzyme-linked immunosorbent assay (E600, Boehringer Mannheim). Hemoglobin A1c was measured using a high performance liquid chromatography technique (Bio-Rad Laboratories, Inc., Diamat, Hercules, CA). The increase in insulin during 60 min ({Delta}insulin60) and the ratio of the 60 min increase in insulin relative to the 60 min increase in glucose ({Delta}insulin60/{Delta}glucose60) during the OGTT were calculated as measures of insulin secretion. All laboratory measurements were performed at the Institute of Clinical Chemistry, Rudolfstiftung Hospital (Vienna, Austria). All samples were stored at -70 C until analysis.

PCR and genotyping of ß3-adrenergic receptor codon 64 Trp/Arg polymorphism

Genomic DNA was extracted from peripheral blood leukocytes by established methods. Exons 1 and 2 of the ß3-adrenergic receptor were amplified using primers 5'-CGCCCAATACCGCCAACAC-3' and 5'-CCACCAGGAGTCCCATCACC-3'. PCR was performed as described with denaturation at 94 C for 30 s, annealing at 58 C for 30 s, and extension at 72 C for 40 s for 35 cycles. PCR products were digested with 5 U BstNI (New England Biolabs, Beverly, MA) for 3 h at 60° C. Fragments were analyzed on 3% agarose gels.

Statistical analysis

Statistical analysis was performed using SAS statistical software (SAS Institute, Inc., Cary, NC). Analyses included analysis of variance and covariance (Tables 2Go and 3Go), {chi}2 test (Table 1Go), Pearson’s correlation analysis, multiple linear regression, and logistic regression (Table 4Go). Demographic and metabolic data stratified by ß3-adrenergic receptor genotype are shown in Table 2Go. Data are the mean ± SE. Differences between genotypes were calculated using ANOVA. Table 3Go shows the results of analysis of covariance with adjustments for age and gestational age (model A); age, gestational age, and BMI (initial; model B); and, finally, age, gestational age, BMI, and glucose tolerance status (model C). Univariate Pearson’s correlation analysis was performed. Furthermore, we fit multiple linear regression models adjusting for variables shown to be related to the variables of interest (fasting and postload insulin and glucose levels) in univariate analysis. Finally, a logistic regression model was fit with GDM as the dependent variable (Table 4Go). P < 0.05 (two-sided) was considered statistically significant.


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  		Table 2. Demographic and metabolic data by genotype in the overall population

 

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  		Table 3. P values for differences between ß3-adrenergic receptor genotypes (Trp64Trp vs. Trp64Arg) as independent variable as determined by ANCOVA after adjustment for: model A, age and gestational age; model B, age, gestational age and BMI (initial); and model C, age, gestational age, BMI (initial), and glucose tolerance status

 

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  		Table 1. Frequency of the ß3-adrenergic receptor genotypes by glucose tolerance status

 

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  		Table 4. Logistic regression analysis for GDM as dependent variable

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Frequency of ß3-adrenergic receptor genotypes

The frequency of the Arg64 allele was 9.15%. The frequency of heterozygote carriers of the Trp64Arg genotype was 16.8%. There were no homozygotes for the Arg allele.

Trp64Arg polymorphism in relation to the glucose tolerance status

In individuals with GDM, the Trp64Arg genotype was found more frequently than in those with normal glucose tolerance (25.7% vs. 11.0%; by {chi}2 test, P = 0.01; Table 1Go). Using a logistic regression model with the absence or presence of GDM as the dependent variable and age, gestational age, BMI (initial), and the absence or presence of the Trp64Arg mutation as independent variables, the Trp64Arg polymorphism was significantly related to the glucose tolerance status with an odds ratio of 5.9 (P = 0.01; 95% confidence intervals, 1.54–24.1; Table 4Go).

Trp64Arg polymorphism in relation to body weight, weight gain, and serum lipids

Body weight and BMI, both prepregnancy and actual, were not significantly different by genotype (Table 2Go). Likewise, subjects in the highest vs. the lowest quartile of BMI had similar percentages of the Trp64Arg mutation (11% vs. 5%; P = 0.31). Women with the Trp64Arg polymorphism showed an enhanced increase in body weight and BMI during pregnancy (Table 2Go). This difference remained significant after accounting for age, gestational age, BMI, and glucose tolerance status (Table 3Go). Accordingly, the percentage of carriers of the Trp64Arg polymorphism was higher in women in the upper vs. the lowest quartile of {Delta}BMI (21% vs. 3%; P = 0.01). No significant differences were found between genotypes with respect to serum cholesterol and triglycerides (Table 2Go) even after adjustments for age and/or BMI (data not shown).

Trp64Arg polymorphism in relation to glucose, insulin, and C peptide during the OGTT

Table 2Go shows unadjusted data for differences between genotypes. Carriers of the Trp64Arg polymorphism showed higher C peptide and glucose levels 60 min after the glucose load during the OGTT. Fasting blood glucose was slightly higher without reaching statistical significance (P = 0.075). Furthermore, the increases in blood glucose ({Delta}glucose60) and C peptide ({Delta}C-peptide60) within 60 min during the OGTT were higher in the presence of the Trp64Arg polymorphism.

Table 3Go shows adjusted data for differences between genotypes. Differences in postload glucose, insulin, and C peptide levels remained statistically significant after demographic and metabolic adjustments (models A and B) and postload insulin levels (insulin60 and {Delta}insulin60) were significantly related to the genotype independent of the glucose tolerance status (model C).

Univariate correlation analysis

Prepregnancy BMI was related to age (r = 0.20; P = 0.02), fasting insulin (r = 0.29; P = 0.007), and blood glucose at 60 min (r = 0.19; P = 0.03). Actual BMI was related to gestational age (r = 0.21; P = 0.02) as well as fasting insulin (r = 0.36; P = 0.0001) and fasting (r = 0.16; P = 0.05) and 60 min blood glucose (r = 0.18; P = 0.03). These results were the basis for the adjustments performed in multivariate analyses as shown below.

Multiple linear regression analysis

We used multivariate regression models to analyze the relation of the Trp64Arg polymorphism to fasting and postload glucose and insulin values (dependent variables). Age, gestational age, BMI (initial), and the absence or presence of the Trp64Arg mutation entered as independent variables into the models. Thus, the Trp64Arg polymorphism was significantly related to fasting (P = 0.03) and 60 min (P = 0.04) glucose levels as well as 60 min insulin levels (P = 0.01) and {Delta}insulin60 (P = 0.01). No relation of ß3-adrenergic receptor genotype was found to fasting insulin and 120 min glucose levels.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study revealed two significant findings. First, the Trp64Arg ß3-adrenergic receptor genotype was associated with mild gestational diabetes, as defined by 60 min postload glucose levels, and second, this polymorphism was associated with increased weight gain during pregnancy.

The overall Arg64 allelic frequency found in our population of Caucasian pregnant women (9.2%) is comparable to that seen in various nonpregnant, nondiabetic populations of Caucasian origin (7.5–12.5%) (9, 13, 17, 18, 19). The Arg64 allelic frequency differs among ethnic groups (20); therefore, caution is warranted in extending the findings of the present study to non-Caucasian populations.

The relative contribution of the ß3-adrenergic receptor genotype to the etiology of type 2 diabetes is still a matter of debate. In most studies the association of the ß3-adrenergic receptor genotype with the prevalence of type 2 diabetes failed to reach statistical significance (9, 15, 21, 22); however, in a meta-analysis, the association was significant (14), leading to the view of a modest, but nevertheless important, contribution of the Trp64Arg ß3-adrenergic receptor genotype to the polygenic disorders of insulin resistance and type 2 diabetes (14). Moreover, a consistent association with younger age at onset of diabetes has been reported in several studies (9, 14, 15, 23).

To our knowledge, no data have been published yet on the relation of the Trp64Arg ß3-adrenergic receptor polymorphism to glucose tolerance during pregnancy. The present study revealed a higher prevalence of the Trp64Arg genotype in women with GDM, as defined by blood glucose levels after 60 min during the OGTT. Analysis of our data using different diagnostic criteria (WHO) (24) revealed no significant differences between genotypes, presumably because of low statistical power due to a limited number of women with more severe GDM in our population (data not shown). As neither IGT nor type 2 diabetes is diagnosed based on 60 min glucose values, the results of previous studies in nonpregnant populations are not necessarily comparable to those of the present study. Glucose tolerance during pregnancy is considered a continuum, and the distinction between normal and pathological is made arbitrarily (25). Furthermore, it is still a matter of debate which maternal metabolic parameter most accurately predicts fetal and neonatal mortality/morbidity and has therefore to be given priority in the diagnosis of GDM. However, the 60 min postload glucose value rather than the 120 min value seems to be of predominant significance, showing a strong relation to fetal hyperinsulinism and neonatal morbidity (16). We suggest that the Trp64Arg polymorphism, resulting in a slight increase in susceptibility to increased insulin resistance, may disturb the subtle balance between insulin resistance and insulin secretion during pregnancy, eventually leading to impaired glucose tolerance and GDM.

Mechanisms linking the ß3-adrenergic receptor polymorphism to impaired glucose tolerance are not very well understood. It has been suggested that impaired lipolysis could promote insulin resistance and hyperinsulinism (26), presumably via enlargement of visceral adipose cells. Treatment of mice with a selective ß3-adrenergic receptor agonist led to increased lipolysis and increased insulin levels (27).

In the present study, the Arg64 allele was associated with significantly higher postload glucose, insulin, and C peptide levels and tended to be associated with higher fasting glucose levels, whereas fasting insulin, fasting C peptide, and fasting serum lipids showed no difference. Similar results have been reported in nonpregnant populations. Fasting glucose (18, 19, 22, 28, 29, 30), fasting insulin (18, 19, 22, 28, 29, 30), and fasting serum lipids (18, 22, 28, 29) were not different in carriers of the Trp64Arg genotype compared to those in carriers of the Trp64Trp wild-type, whereas they showed a higher insulin response (9) and higher postload insulin levels (23) as well as a higher area under the blood glucose curve during an OGTT (10).

We also found an association of the Trp64Arg ß3-adrenergic receptor genotype with increased weight gain during pregnancy. In nonpregnant populations the Trp64Arg genotype has been associated with excessive weight gain in most (13, 14, 31), but not all, studies (28, 29). Likewise, weight loss in response to dietary intervention was less pronounced in carriers of the Arg64 allele in obese type 2 diabetic patients (32) and in nondiabetic obese (33), but not in morbidly obese (29), subjects. Excessive weight gain during pregnancy has been reported in pregestational type 2 diabetic women, who are homozygote for the Arg allele (34). Obesity has been associated with unfavorable neonatal outcome (5, 6, 7, 8), and excessive weight gain during pregnancy has been associated with perinatal mortality and placental and fetal disorders (35). In light of these data, analysis of neonatal outcome according to the maternal ß3-adrenergic receptor genotype may be of particular interest.

In summary, the results of the present study extend current knowledge about the association of the Trp64Arg ß3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The clear-cut association with mild GDM found in this study suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance. These results also prompt further questions, such as the response to treatment of GDM (especially dietary) and subsequent neonatal outcome according to maternal ß3-adrenergic receptor genotype.

Received November 2, 1998.

Revised January 15, 1999.

Accepted January 26, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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