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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4981-4985
Copyright © 2004 by The Endocrine Society

Effects of the Trp64Arg Polymorphism in the ß3-Adrenergic Receptor Gene on Insulin Sensitivity in Small for Gestational Age Neonates

Xinli Wang, Yunpu Cui, Xiaomei Tong, Hongmao Ye and Song Li

Department of Pediatrics, Third Hospital Peking University, Beijing 100083, People’s Republic of China

Address all correspondence and requests for reprints to: Xinli Wang, Ph.D., Department of Pediatrics, Third Hospital Peking University, Beijing 100083, People’s Republic of China. E-mail: Xinli_Wang1217{at}yahoo.com.cn.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To evaluate whether the Trp64Arg polymorphism in the ß3-adrenergic receptor (AR) gene is associated with decreased birth weight and might account for some of the association between birth weight and impaired insulin sensitivity, the ß3-AR genotype was assessed in 296 neonates of singleton pregnancies, including 76 neonates classified as small for gestational age (SGA) and 220 neonate classified as appropriate for gestational age (AGA). Fasting glucose and insulin levels were measured on d 3 after birth. The insulin levels and insulin-to-glucose ratio were significantly higher in the SGA group than in the AGA group. Frequency of the Trp64Arg allele was similar in the AGA and SGA groups (0.15 and 0.17, respectively). Moreover, when we adjusted for sex and gestational age, there was no significant difference in birth weight, fasting glucose, insulin levels, or insulin-to-glucose ratio between those with and without the mutation. However, in the SGA group, carriers of the Trp64Arg allele had significantly higher fasting insulin levels and insulin-to-glucose ratios than noncarriers (17.54 ± 2.11 vs. 13.18 ± 1.47 µIU/ml, P < 0.05; and 4.89 ± 0.60 vs. 3.14 ± 0.42, P < 0.05, respectively), whereas no association was detected for this polymorphism in the AGA group.

SGA is an important factor that predisposes to insulin resistance, and the Trp64Arg ß3-AR gene polymorphism may contribute to insulin resistance associated with reduced fetal growth.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EPIDEMIOLOGICAL STUDIES HAVE demonstrated an association between low birth weight and an increased risk of adult diseases, including essential hypertension, type 2 diabetes, and ischemic heart disease (1, 2, 3, 4). A common feature of all these diseases is insulin resistance (5). Recently, some studies have shown that neonates and prepubertal children who were small for gestational age (SGA) at birth had significantly higher plasma insulin than those who were appropriate for gestational age (AGA) at birth (6, 7, 8, 9). These results suggested that intrauterine growth restriction might be a factor predisposing to insulin resistance. However, it is not known whether this susceptibility to insulin resistance is explained by an unfavorable intrauterine environment or by specific susceptibility genotypes predisposing to reduced fetal growth, insulin resistance, and type 2 diabetes. The same genetic factors that cause impaired insulin secretion and/or insulin resistance may alter both intrauterine growth and glucose tolerance in adulthood, thereby providing a link between them. Recently, it was observed that mutations in the glucokinase gene associated with the type 2 form of maturity-onset diabetes of the young (MODY) resulted in a reduced birth weight, which was most likely caused by changes in fetal insulin secretion (10). This suggested that genetic factors that modify insulin secretion might be involved in intrauterine growth retardation. Nevertheless, the low prevalence of the specific mutation causing type 2 MODY, or other forms of MODY, means that these specific gene defects are highly unlikely to explain the association of low birth weight and diabetes that is seen across many populations.

ß3-adrenergic receptor (AR) is expressed in brown adipose tissue and is an important regulator of energy expenditure and lipolysis (11, 12). A ß3-AR variant replacing the tryptophan in codon 64 of the gene with arginine has been described and is very common in diverse ethnic groups in its heterozygous form (13, 14, 15, 16, 17, 18). This Arg64 allele was initially shown to be associated with an earlier onset of type 2 diabetes in Pima Indians homozygous for the variant allele (13), and later studies confirmed these findings in diabetic Finns (14), Mexican-Americans (17), and Japanese cohorts (19). Other population-based studies have identified significant associations between this allele and other metabolic alterations linked to type 2 diabetes, including dyslipidemia, insulin resistance, and atherosclerosis (19, 20, 21, 22).

Therefore, we were interested in evaluating whether the Trp64Arg polymorphism in ß3-AR, which is one of the candidate genes for type 2 diabetes, is associated with decreased birth weight and might account for any association between birth weight and impaired insulin sensitivity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All studies were performed after parents gave written informed consent; the study protocol was approved by the Ethics Committee of Third Hospital, Peking University.

The study sample consisted of 296 singleton neonates (177 boys and 119 girls), including 76 SGA neonates (37 preterms and 39 full terms) and 220 AGA neonates (84 preterms and 136 full terms), all of whom had a 1-min Apgar score of more than 7 and a 5-min Apgar score of 10. SGA was defined as a birth weight below the 10th percentile of the local sex-specific distribution for gestational age. The SGA neonates were selected from consecutive SGA deliveries in the Department of Obstetrics of the Third Hospital, Peking University, between April and December 2001. The AGA neonates were selected at random from newborns whose birth weights were between the 25th and 75th percentile of the local sex-specific distribution for gestational age. We excluded infants born to women with diabetes, gestational diabetes, or chronic hypertension and infants with intrauterine infections and congenital malformations.

Routine measurements of weight, length, head circumference, and chest circumference were performed at birth. Blood was obtained by heel prick before feeding between 0830 and 0930 on d 3–4 of life (each individual was given an infant formula milk meal after a 4-h fast; Nestle Nan1; Nestle, Nestec Ltd., Vevey, Switzerland) and analyzed for glucose and insulin concentration.

Genomic DNA was extracted from umbilical cord blood leukocytes by standard techniques using phenol/chloroform. PCR was carried out in a volume of 50 µl containing 100 ng genomic DNA and 25 pmol of upstream primer BSTNUP (5'-CGCCCAATACCGCCAACAC-3') and downstream primer BSTNDOWN (5'-CCACCAGGAGTCCCATCACC-3'). The amplification cycle was performed with denaturation at 95 C for 5 min followed by 30 cycles of denaturation at 94 C for 40 sec, annealing at 61 C for 40 sec, extension at 72 C for 1 min, and a final extension at 72 C for 5 min. The size of amplified DNA was ascertained with ethidium bromide staining on 1.5% agarose gel. PCR products were completely digested with 10 U of BstNI (Promega, Madison, WI) for 3 h at 61 C. The digested samples were separated by electrophoresis through a 3% agarose gel and visualized by staining with ethidium bromide.

Glucose concentrations were measured by SureStep Plus System from LifeScan (Milpitas, CA). Inter- and intraassay coefficients of variation for glucose were 0.9 and 1.8%, respectively. Insulin was measured by enzyme-amplified immunoassay using an active insulin ELISA Kit (DSL-10-1600; Diagnostic Systems Laboratories, Webster, TX). The detection limit of this assay was 0.26 µIU/ml (1.81 pmol/liter) in our laboratory, and the intra- and interassay coefficients of variation were 2.6 and 5.2%, respectively.

Statistical analysis

Data are expressed as means ± SE and ranges, unless stated otherwise. The allele frequencies were calculated by gene counting method. The {chi}2 test was used for qualitative variables. Fasting insulin data and insulin-to-glucose ratio had skewed distributions and were log transformed for analysis. ANOVA and analysis of covariance were used for quantitative variables. All statistical analyses were performed using the SPSS for Windows 9.0 statistical software package (SPSS Inc., Chicago, IL). P ≤ 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Because the effects of a low birth weight and ß3-AR genotypes on insulin variables were not significantly heterogeneous in boys and girls, a pooled analysis adjusted for sex is presented. The main characteristics of the AGA and SGA infants according to gestational age are shown in Table 1Go. The SGA subjects were significantly thinner and shorter at birth than AGA subjects. Plasma glucose levels were similar in the AGA and SGA groups both in full-term and in preterm infants; however, insulin levels and the insulin-to-glucose ratio were significantly higher in the SGA groups than in the AGA groups both in full-term and in preterm infants. In SGA subjects, insulin levels and the insulin-to-glucose ratio tended to be higher in full-term newborns than in the preterm newborns (P = 0.01 and P = 0.02, respectively). But, the difference of insulin levels and the insulin-to-glucose ratio between full-term newborns and preterm newborns were not significant in AGA subjects (P > 0.05).


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  		TABLE 1. The main characteristics of the AGA and SGA according to gestational age

 
The numbers of patients with the ß3-AR Trp64Trp, Trp64Arg, and Arg64Arg genotypes were 156, 62, and two, respectively, in the AGA group, and 51, 24, and one, respectively, in the SGA group. The genotypes were in Hardy-Weinberg equilibrium in both groups.

The allele frequencies of the Arg64 of ß3-AR gene were 0.15 and 0.17 in the 220 patients in the AGA group and in the 76 patients in the SGA group, respectively. There were no significant differences in the frequencies of this polymorphism ({chi}2 = 0.762, P > 0.05) between the SGA and AGA groups. Moreover, when the 296 subjects were divided into two groups according to the presence or absence of the Trp64Arg allele of the ß3-AR gene, anthropometric data at birth, glucose, insulin, and insulin-to-glucose ratio on d 3 were not significantly different among subjects with or without the Trp64Arg polymorphism (Table 2Go).


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  		TABLE 2. The main characteristics of 296 neonates according to genotype of the ß3-AR

 
The homogeneity of association of Trp64Arg polymorphism with birth weight as well as insulin resistance parameters between the AGA group and SGA group were tested. The Trp64Arg polymorphism had no significant effect on birth weight and fasting plasma glucose values after adjusting for gestational age both in the SGA and AGA groups (Table 3Go). In contrast, the association of Trp64Arg polymorphism with the fasting insulin levels and insulin-to-glucose ratio differed between the SGA and AGA groups (Table 3Go). Whereas no association was detected in the AGA group for the Trp64Arg polymorphism after adjustment for gestational age, carriers of the Trp64Arg allele had significantly higher fasting insulin levels and insulin-to-glucose ratios than noncarriers in the SGA group after adjustment for gestational age.


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  		TABLE 3. The main characteristics of the SGA and AGA groups according to genotype of the ß3-AR

 
If an insulin level greater than 15 µIU/ml (105 pmol/liter) was considered as hyperinsulinemia, then Trp64Arg allele was a significant risk factor for hyperinsulinemia in the SGA group (P = 0.015; Fig. 1Go), with carriers of the Trp64Arg allele showing a 3.36-fold increased risk of hyperinsulinemia compared with noncarriers (95% confidence interval, 1.24- to 9.15-fold). Hyperinsulinemia was not similarly increased in the AGA group in carriers of the Trp64Arg allele (odds ratio 0.73; 95% confidence interval, 0.23–2.34).



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  		FIG. 1. Percentage of AGA and SGA patients with hyperinsulinemia compared with carriers or noncarriers of the Trp64Arg allele.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study of 296 3-d-old neonates, a negative association was found between birth weight and plasma insulin and insulin-to-glucose ratio, and this relationship was apparent in premature infants as well as term infants. These results are in agreement with recent studies in other ethnic populations (7, 9).

Insulin resistance is usually defined by the ability of insulin to stimulate glucose uptake in its target tissues in the periphery. Resistance of the body to the actions of insulin results in overproduction of this hormone by the pancreatic ß cells to maintain glucose homeostasis, with ensuing hyperinsulinemia (23). In the present study, glucose levels on d 3 were similar in the SGA and AGA neonates, whereas there was a significantly higher insulin level and insulin-to-glucose ratio in SGA neonates, which suggests that these infants require a higher insulin secretory response to maintain glucose homeostasis, consistent with reduced insulin sensitivity, compared with AGA infants.

The overall allele frequency of the Trp64Arg mutation of ß3-AR gene was 0.16 in 296 3-d-old Chinese neonates, which was close to the frequency reported for Chinese and Japanese (15, 18, 21, 22), higher than the frequency reported for Caucasians in Europe (0.04–0.12), and lower than the 0.31–0.37 frequency reported for the Pima Indians (13, 14, 24, 25, 26). To our knowledge, no data have yet been published on the relation of the Trp64Arg ß3-AR gene polymorphism to SGA and fasting plasma glucose and insulin levels among neonates. The present study revealed that the frequency of the Trp64Arg ß3-AR allele did not significantly differ between SGA and AGA subjects; however, in contrast, SGA subjects who carried the Trp64Arg allele seemed to be less insulin sensitive than the noncarriers. The Trp64Arg ß3-AR gene polymorphism seems to modulate the predisposition to insulin resistance associated with reduced fetal growth. These findings support the hypothesis that insulin resistance in adulthood might be the consequence of interactions between detrimental environmental factors during fetal life and genetic susceptibility.

There is now accumulating evidence that most of the susceptible genes to multifactorial diseases do not have a primary causative role in predisposition to disease but rather act as response modifiers to risk factors (27). The association between reduced fetal growth and insulin resistance has been clearly demonstrated in numerous study populations, but SGA subjects show a variable susceptibility to insulin resistance (2, 3, 4, 6, 28, 29). The present data provide an additional example of this genetic contribution that can explain, at least in part, the variable susceptibility to insulin resistance in this population.

The mechanism through which the Trp64Arg variant alters insulin sensitivity cannot be elucidated from our studies. The ß3-AR has been recognized to play a key role in the lipolytic action of catecholamines (30). The Trp64Arg polymorphism appears at the beginning of the first intracellular loop of the ß3-AR (13). On the basis of studies of the related ß2-AR and rhodopsin, the first intracellular loop is thought to be important for the proper movement of the receptor to the cell surface and possibly also for its coupling to G proteins (13). Defective expression at the cell surface or impaired signaling may lead to decreased lipolysis and thermogenesis in visceral fat tissue that may contribute to insulin resistance and type 2 diabetes. Some previous studies have shown that insulin resistance in SGA subjects is strongly associated with a decreased antilipolytic action of insulin (3, 31). Therefore, we speculate that Trp64Arg polymorphism, which is able to alter lipolysis regulation, might interact with reduced fetal growth to promote insulin resistance later in life.

In summary, these data demonstrate that SGA is an importance factor predisposing to insulin resistance, and the Trp64Arg ß3-AR gene polymorphism may contribute to insulin resistance associated with reduced fetal growth.


   Acknowledgments
 
The authors thank Dr. Jacqueline Gindler (National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention) for proofreading the English.


   Footnotes
 
Abbreviations: AGA, Appropriate for gestational age; AR, adrenergic receptor; MODY, maturity-onset diabetes of the young; SGA, small for gestational age.

Received November 20, 2003.

Accepted June 29, 2004.


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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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