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  • Mutation?


There is a possible association between the Trp64Arg polymorphism and insulin resistance (IR).

The ß3-adrenergic receptor (ß3-AR) is mainly expressed in adipose tissue and plays an important role in lipid metabolism and metabolic rate by mediating lipolysis and thermogenesis (1). Recently a missense mutation? in the ß3-AR gene? (Trp64Arg) has been shown in various groups and reported to be associated with an early onset of NIDDM, an increased capacity to gain weight, visceral fat accumulation, and clinical features of insulin resistance syndrome (2,3,4,5)

Numerous studies have been conducted to examine the relationship between the ß3-adrenergic receptor Trp64Arg polymorphism and components of IR syndrome. However, the results have been inconsistent and have led to controversy about whether this polymorphism is associated with these clinical features. A recent meta-analysis demonstrated the moderate effects of the Trp64Arg polymorphism on IR in the Asian population and in obese and diabetic subgroups. (6)



Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene

Diabetes Obes Metab. 2006 May;8(3):322-30.

Hojlund K, Christiansen C, Bjornsbo KS, Poulsen P, Bathum L, Henriksen JE, Lammert O, Beck-Nielsen H.

  • AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin secretion could play a role. METHODS: In 10 male twin pairs discordant for the Trp64Arg polymorphism, we examined insulin response to glucose by an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), body composition by the bioimpedance method, dual-energy X-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild-type co-twins. Correspondingly, insulin resistance and insulin secretion determined by homeostasis model assessment were significantly lower in twins carrying the Trp64Arg polymorphism. However, there were no significant differences in adiponectin levels, insulinogenic index assessed by OGTT, or insulin sensitivity, acute insulin response to glucose, glucose effectiveness or insulin disposition index assessed by minimal modelling of the FSIGT. Furthermore, there were no differences in sleeping, resting or post-prandial energy expenditure. CONCLUSIONS: In male twins with a high similarity in genetic and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.



1. Walston J, Silver K, Bogardus C et al. Time of onset of NIDDM and genetic variation in the ß3-adrenergic-receptor gene. N Engl J Med1995; 333: 343–347

2. Widen E, Lehto M, Kanninen T et al. Association of a polymorphism in the ß3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med1995; 333: 348–351[Abstract/Free Full Text

3. Kadowaki H, Yasuda K, Iwamoto K et al. A mutation in the ß3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects. Biochem Biophys Res Commun1995; 215: 555–560

4. Sakane N, Yoshida T, Umekawa T et al. ß3-adrenergic-receptor polymorphism: A genetic marker for visceral fat obesity and the insulin resistance syndrome. Diabetologia1997; 40: 200–204

5. Silver K, Mitchell BD, Walston J et al. Trp64Arg beta 3-adrenergic receptor and obesity in Mexican Americans. Hum Genet1997; 101: 306–311

6. Siyan Zhan and Suzanne C. Ho Meta-Analysis of the Association of the Trp64Arg Polymorphism in the ß3 Adrenergic Receptor with Insulin Resistance Obesity Research 13:1709-1719 (2005)



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